Cisplatin-based Concurrent Chemoradiation Research Articles

Treatment-related hearing loss in weekly versus triweekly cisplatin chemoradiation for head and neck cancer

PurposeCisplatin-induced hearing loss is a common side effect in patients treated with cisplatin-based chemoradiation (CRT) for head and neck squamous cell carcinoma. The extent of hearing loss after concurrent CRT was compared between triweekly (3 × 100 mg/m2) and weekly (7 × 40 mg/m2) cisplatin CRT.MethodThis retrospective cohort study was conducted in the Antoni van Leeuwenhoek Hospital and included 129 patients with cisplatin-based CRT for head and neck cancer (72 treated in the triweekly and 57 in the weekly regimen). Baseline and follow-up pure tone audiometry was conducted to assess hearing loss. Clinically relevant hearing loss was defined as a decline upon treatment of ≥ 10 decibel at a pure tone average 1-2-4 kHz and/or 8-10-12.5 kHz.ResultsThe incidence of clinically relevant cisplatin CRT induced hearing loss was 42% in the triweekly versus 19% in the weekly group (p < 0.01). The mean threshold shift at a pure tone average (PTA) 1-2-4 kHz was 9.0 decibel in the triweekly compared to 4.3 decibel in the weekly CRT group (p < 0.01). At PTA 8-10-12.5 kHz, the incidence of clinically relevant hearing loss was 75% in the triweekly compared to 74% in the weekly CRT group (p = 0.87). The mean threshold shift at PTA 8-10-12.5 kHz was 20.2 decibel versus 15.6 decibel, respectively (p = 0.07).ConclusionCisplatin-dose reduction to a weekly cisplatin CRT regimen for head and neck cancer may reduce the incidence of clinically relevant hearing loss at frequencies vital for speech perception.

Effectiveness and toxicity of multidisciplinary treatment of head and neck cancer among people with HIV: Real-world evidence from a tertiary cancer center in Brazil.

e24139 Background: The incidence of head and neck squamous cell carcinoma (HNSCC) is rising among people with HIV (PWH). Previous studies have shown an increase in treatment-related toxicities in this population. This study aims to determine the demographics and treatment outcomes in this patient group at a tertiary cancer center in Brazil. Methods: HNSCC patients (pts) with HIV diagnosis treated at our institution between 2009 and 2022 were included. Medical charts were analyzed to extract clinical data. Log rank was used to compare survival estimates and stratified Cox regression model was used for univariate and multivariate analyses. Results: Our search identified 75 pts with HIV among 5956 pts with HNSCC. Median age at cancer diagnosis was 53 years (IQR 49-59.5), 80% were male and 82.7% had a smoking history. Most pts had an oropharynx primary tumor (38.7%) and locally advanced disease (80%), with T3 and T4 tumors in 55 pts (73.3%) and N+ in 48 pts (64.1%). A feeding tube (FT) was placed in 32% of pts before treatment. HIV viral load was detectable in 23 (30.7%) pts and 19 (25.3%) had a CD4 count of fewer than 200 cells/mm³, while 97.3% of the pts were on combination antiretroviral therapy at the time of HNSCC diagnosis. 26 pts were operated with curative intent and 20 pts received adjuvant therapy. In the total population, concurrent cisplatin-based chemoradiation (CCRT) was prescribed to 26 pts (34.7%) and 34 (45.3%) received radiotherapy (RT) alone. 65.4% of the pts in the CCRT group and 20.6% in the RT group were unable to complete treatment as prescribed, mostly due to toxicity. No pts with positive viral load or CD4 &lt; 200 cells/mm³ were able to complete CCRT. Treatment toxicity led to hospitalization in 24% of pts and 7 pts needed FT placement. There were 8 deaths during treatment, 5 in pts with CD4 &lt; 200 cells/mm³. Positive viral load was associated with CCRT interruption (p = 0.03) and a CD4 count of less than 200 cells/mm³ increased the risk of death during treatment (p = 0.02). Median overall survival (OS) was 31.7 months (IQR 14.6-53.7). Multivariate analysis did not show a statistically significant decrease in OS in pts with positive viral load or CD4 &lt; 200 cells/mm³. Factors associated with worse OS on multivariate analysis were FT usage (HR = 2.91; 95% CI: 1.45-5.83) and Eastern Cooperative Oncology Group Performance Status (ECOG-PS) greater than 1 (HR = 3.26; 95% CI: 1.46-7.24). Conclusions: HNSCC treatment in PWH is associated with a high discontinuation rate, even in pts with antiviral therapy. High toxicity rates and deaths during treatment were observed. Positive viral load and low CD4 count were considered contributing factors. ECOG-PS and enteral feeding tube usage were independently associated with worse survival. The development of more tailored strategies in this population is needed to improve outcomes in patients with HNSCC and HIV.

Clinical phosphoproteomics reveals aberrant signalling pathways and kinases in treatment-resistant cervical cancer.

e17529 Background: Cisplatin-based concurrent chemoradiation therapy (CCRT) is the standard for locally advanced cervical cancer. While cisplatin stands out as a highly effective chemotherapeutic option for cervical cancer, resistance to the drug often triggers relapses. Moreover, previous studies have highlighted the detrimental impact of cisplatin's toxicity, which extends beyond treatment efficacy to influence the overall prognosis of patients. Combination treatment with drugs targeting different molecular pathways increases the effectiveness of the treatment by disrupting multiple critical processes that cancer cells rely on for survival. Herein, we analyzed the phosphoproteomic profile of cervical cancer patients resistant to concurrent chemoradiotherapy to identify the crucial kinases responsible for therapeutic resistance. Methods: We used mass spectrometry for phosphoproteomic analysis to study signaling pathways and dysregulated kinases in CCRT resistance. Biopsy samples collected pre-therapy were processed by protein extraction, digestion, and labeling with 10-plex TMT. Peptides were fractionated by basic pH liquid chromatography, enriched using IMAC, and analyzed on an Orbitrap-Fusion-Tribrid mass spectrometer. Data analysis was performed using Proteome Discoverer and various bioinformatics and statistical methods. Results: The phosphoproteomic analysis revealed distinct phosphorylation signatures between the responders and non-responders. In concordance with the phosphoproteomic data the expression of phospho-SMC1A and CSNK2A1 is preserved in non-responder cohort of cervical cancer patients in concordance with the phosphoproteomic data. Further, the pathway analysis showed elevated presence of the DNA repair pathway in the treatment-resistant cohort. Furthermore, dysregulation in the phosphorylation of key DNA repair proteins, such as SMC1A, HMGN1, MGMT, DDB2, and MSH6, suggests their involvement in treatment. The kinase prediction analysis suggested the activation of kinases such as CSNK2A1, PRKDC, PLK1, NEK2 and ATM in non-responders. Subsequently, cell line based functional experiments indicated the potential of CSNK2A1 inhibitor silmitasertib in sensitizing the cells to cisplatin treatment. Conclusions: Phosphoproteomicanalysis of the cervical cancer revealed distinct phosphorylation signature and kinases involved in treatment resistance. Our findings indicated that dysregulated phosphorylation and increased expression of the kinase CSNK2A1 play a pivotal role in the treatment response of cervical cancer patients. Moreover, CSNK2A1 can sensitizes the cells to cisplatin uncovering the potential of combination treatment strategies. Our study uncovers the potential of clinical phosphoproteomics to design tailored treatment strategies in patients resistant to standard treatments.

Response-adapted therapy for locally advanced nasopharyngeal carcinoma based on clinical response and circulating Epstein-Barr virus DNA level post induction chemotherapy.

TPS6112 Background: For locally advanced nasopharyngeal carcinoma (NPC), the mainstay treatment is cisplatin-based concurrent chemoradiation (CCRT). Recent phase III clinical trials have demonstrated that induction chemotherapy (ICT) plus CCRT, compared with CCRT alone, further improved progression-free survival (PFS). However, not every patient has good response to ICT. Evidence has accumulated that those with poor response to ICT, or those with detectable Epstein-Barr Virus (EBV) DNA post ICT, correlated with poorer PFS. In addition, real-time monitoring of plasma EBV DNA response adds prognostic information, and has the potential utility for risk-adapted treatment intensification in NPC. The aim of this study is to clarify whether response-adapted strategy based on clinical efficacy and EBV DNA response confers survival benefit to patients with locally advanced NPC. Methods: This is an open-label, 3-arm, phase II study. Patients with pathologically confirmed, locally advanced NPC (III-IVA, excluding T3N0M0, 8th AJCC staging system), with pretreatment detectable plasma EBV DNA level and ECOS PS 0-1 were eligible. Patients will receive one cycle of GP-based ICT. After one cycle of ICT, plasma EBV DNA and head and neck MR are performed. Based on clinical efficacy (evaluated per RECIST 1.1 criteria) and changes of plasma EBV DNA after one cycle, patients will be divided into three arms. Patients with good response (Arm A: Early Responders, undetectable EBV DNA level and CR/PR) will directly receive CCRT. Patients with intermediate response (Arm B: Intermediate Responders, detectable EBV DNA and CR/PR/decreased SD; or undetectable EBV DNA yet without CR/PR) will be randomized to experiment subgroup (GP combined with Toripalimab for two additional cycles then CCRT and maintenance Toripalimab treatment) and standard subgroup (GP for two additional cycles then CCRT). Patients with poor response (Arm C: Treatment Resistant, increased EBV DNA level, or PD/enlarged SD) will be switched to TP regimen combined with Toripalimab, followed by CCRT and maintenance Toripalimab treatment. Sample size calculation is based on 2-year PFS rate for arm B as the primary endpoint (one-sided α = 0.10, power = 0.80). Our target sample size is estimated to be 198-240, among them 168 for arm B. Secondary endpoints include adverse events determined by CTCAE v5.0, ORR at 3 months post-CRT, 2-year locoregional recurrence-free survival (LRFS) rate, 2-year distant metastasis-free survival (DMFS) rate, 2-year overall survival (OS) rate, as well as quality of Life for arm B. Exploratory endpoints include 2-year PFS rate, LRFS rate, DMFS rate, OS rate, ORR at 3 months post-CRT, adverse effects, and quality of life for arm A and arm C. This trial opened to accrual in July 2022 and the recruitment is ongoing. Clinical trial information: NCT05628922 .

Efficacy and safety of camrelizumab in combination with radiation and chemotherapy for recurrent or metastatic cervical cancer.

5542 Background: Cisplatin-based concurrent chemoradiation regimens have been suggested to be beneficial in recurrent or metastatic cervical cancer. Immunotherapy has also shown good therapeutic efficacy in recurrent or metastatic cervical cancer. Among them, Pembrolizumab in combination with chemotherapy has been used for first-line treatment of advanced PD-L1-positive cervical cancer. Meanwhile, Camrelizumab has shown good anti-tumor activity and manageable toxicity in patients with locally advanced cervical cancer. The primary objective of this study is to evaluate the efficacy and safety of Camrelizumab in combination with concurrent chemoradiation in patients with recurrent or metastatic cervical cancer. Methods: Patients diagnosed with recurrent or metastatic cervical cancer received Camrelizumab combined with concurrent chemoradiotherapy, radiotherapy:External beam radiotherapy (EBRT) 1.8-2.15 Gy/f, a total of 28 fractions; Brachytherapy: high-risk CTV using image guidance 28 Gy in 4 fractions (18 Gy in 3 fractions for posthysterectomy recurrent patients); chemotherapy regimen used TP regimen (paclitaxel: 175 mg/m2, cisplatin: 75 mg/m2, Q3W 6 cycles); Camrelizumab 200 mg Q3W 6 cycles. The primary endpoint of this trial was objective response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and incidence of adverse reactions. Results: From September 16, 2020 to September 30, 2022, a total of 29 patients were recruited. 27 of these patients completed 6 cycles of planned treatment. 27 patients had a median age of 53 years (33-73 years), ECOG PS 0 (n = 8), ECOG PS 1 (n = 14), ECOG PS 2 (n = 1). The ORR rate was 96.30% (26/27), including 17 patients with CR, 9 patients with PR, and 1 patient with SD Treatment-related AEs were mainly lymphocyte count decreased, anemia, and white blood cell count decreased, with overall safety manageable and no treatment-related deaths. Conclusions: Camrelizumab combined with concurrent chemoradiation in patients with recurrent or metastatic cervical cancer has good efficacy, low side effects and acceptable toxicity. Clinical trial information: NCT04884906 .

Interim PET-CT Scan to Improve Risk Modeling for Patients with Extranodal Natural Killer/T-Cell Lymphoma Treated with Non-Anthracycline Containing L-Asparaginase Based Regimen

Background Extranodal natural killer/T-cell lymphoma (ENKTL) is a rare and distinct subtype of non-Hodgkin lymphoma characterized by predominant involvement of the nasal cavity and nasopharynx and the application of L-asparaginase (L-asp) based non-anthracycline containing induction therapy has improved clinical outcomes of the patients. Currently, prognostic index of natural killer lymphoma plus Epstein-Barr virus is widely used to evaluate prognosis of patients with ENKTL. In this study, we evaluated the value of interim fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) for the better prognostication of ENKTL patients. Methods Patients with histologic diagnosis of ENKTL from May 2009 to May 2020 treated with L-asp based non-anthracycline containing induction regimen and who had interim PET-CT analysis at Asan Medical Center, Seoul, Korea were included. Response was assessed using the Deauville 5-point scales (DS). Progression-free survival (PFS) was defined as time from the induction therapy to disease progression or any cause of death, and overall survival (OS) was defined as time from the induction therapy to any cause of death. Survival curves were estimated by Kaplan-Meier method and compared using log-rank test. Key baseline characteristics and candidate prognostic factors including age, Eastern Cooperative Oncology Group performance status, Epstein-Barr virus (EBV) detection from blood at baseline, distant lymph node (LN) involvement, initial stage, location of disease (nasal vs. non-nasal), and serum lactate dehydrogenase level were included in the univariate analysis. In the multivariate analysis, variables exhibiting a potential association with survival (p < 0.05) in the univariate analysis were included. Results A total of 58 patients were included in the analysis. Median age was 55 years (range, 19-80), 34 patients (58.6%) were male, 19 patients (32.8%) had non-nasal disease and 43 patients (74.1%) had stage 4 disease at diagnosis. Among 43 patients with stage 4 disease, 19 patients (44.2%) received VIDL regimen consisting of etoposide, ifosfamide, dexamethasone and L-asp while 23 patients (55.8%) received SMILE regimen consisting of ifosfamide, etoposide, methotrexate, dexamethasone and L-asp as induction treatment. All 15 patients with stage 1 or 2 disease received combined modality treatment with cisplatin-based concurrent chemoradiation and L-asp containing chemotherapy. With median follow-up duration of 52.7 months (95% confidence interval [CI] 37.7-81.3), median PFS and OS were 9.9 months (95% CI 4.8-28.6) and 25.6 months (95% CI 13.3-not applicable), respectively. Thirty-two patients (55.2%) had interim PET-CT DS (iDS) of 4-5. Patients with iDS 4-5 showed significantly worse outcomes in terms of both PFS and OS compared to patients with iDS 1-3 with hazards ratio (HR) of 2.13 (95% CI 1.11-4.06, p = 0.019) and 2.51 (95% CI 1.19-5.33, p = 0.013), respectively. The 2-years PFS rates for patients with iDS 4-5 and iDS 1-3 were 27.3% (95% CI 15.3-44.8) and 49.0% (95% CI 32.9-69.3), respectively. The 2-years OS rates were 35.6% (95% CI 22.1-54.0) and 64.3% (95% CI 48.0-86.2), respectively. In the univariate analysis, age, EBV detection from blood at baseline, initial stage, location of disease (nasal vs. non-nasal), distant LN involvement and iDS showed potential association (p < 0.05) with OS. In multivariate analysis, iDS were independently associated with OS with HR of 3.96 (iDS 4-5 vs. 1-3, 95% CI 1.76-8.94, p < 0.001), along with location of disease with HR of 4.03 (non-nasal vs. nasal, 95% CI 1.83-8.91, p < 0.001). Conclusion The interim PET-CT response based on the DS is useful for predicting OS of patients with ENKTL in the era of non-anthracycline-based L-asp containing induction therapy.

NANORAY-312: A Phase III Pivotal Study of NBTXR3 Activated by Investigator's Choice of Radiotherapy Alone or Radiotherapy in Combination with Cetuximab for Platinum-Based Chemotherapy-Ineligible Elderly Patients with Locally Advanced HNSCC

<h3>Purpose/Objective(s)</h3> Elderly patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) are largely underrepresented in clinical trials (CT). This population lacks broad access to CTs due to an increased prevalence of comorbidities and age-related conditions. However, as population aging increases, more elderly patients will be diagnosed with LA-HNSCC although many will not be eligible to receive standard cisplatin-based concurrent chemoradiation (CRT). Toxicities, treatment burden and compliance associated with cisplatin are a concern. NBTXR3, a first-in-class radioenhancer, is composed of functionalized hafnium oxide nanoparticles, administered by a one-time intratumoral injection and activated by radiotherapy (RT). It has EU marketing approval for preoperative treatment of locally advanced soft tissue sarcomas. NBTXR3 locally amplifies tumor-killing effects of radiotherapy without adding toxicity to surrounding healthy tissue. NBTXR3 has been shown to prime the adaptive immune response in cancer models. In a Phase I trial of NBTXR3 + RT alone in elderly LA-HNSCC patients, this combination was shown to be safe and an Objective Response Rate (ORR) of 85.4% and CRR of 51.2% was reported at ASTRO 2021. A pivotal randomized phase III study is now recruiting. <h3>Materials/Methods</h3> NANORAY-312 is a global, open-label, randomized (1:1), 2-arm, Phase III (Pivotal Stage) study to investigate the efficacy and safety of NBTXR3/RT ± cetuximab versus RT ± cetuximab (Investigator's choice) in treatment-naïve, platinum-ineligible, elderly patients with LA-HNSCC. 500 patients will be enrolled. Eligible patients are ≥65 years with at least one measurable (RECIST 1.1) biopsy-confirmed T3-4 (AJCC v8) SCC of the oral cavity, oropharynx, hypopharynx, or supraglottic larynx which is amenable for intratumoral injection. Patients will receive IMRT (70 Gy in 35 fractions / 7 weeks). For patients with oropharyngeal cancer, human papilloma virus (HPV) status must be declared. In addition to the primary tumor, a single accessible LN in the neck is considered an eligible site for intranodal injection. <h3>Results</h3> The primary endpoint is PFS. The key secondary endpoint is OS. Other secondary endpoints include ORR, safety and tolerability, and quality of life. Exploratory endpoints include tumor immune response biomarkers, and radiographic change in the size of the tumor after 50 Gy of RT. Enrollment began in January 2022 and continues. <h3>Conclusion</h3> NBTXR3/RT ± cetuximab is under investigation in elderly patients with LA-HNSCC, a population which is underrepresented in clinical trials and with limited treatment options. This study has the ClinicalTrials.gov identifier NCT04892173.

A prospective comparative study of concurrent chemoradiation in advanced carcinoma cervix patients with weekly cisplatin vs. weekly cisplatin and paclitaxel

Background: Cisplatin-based concurrent chemoradiation is the standard treatment for carcinoma cervix. However, there is a need to explore alternative chemotherapeutic agents to further improve the treatment outcome. In this study, weekly paclitaxel and cisplatin-based chemoradiation was compared with weekly cisplatin-based chemoradiation in terms of disease control and toxicity profile. Materials and Methods: Sixty-four patients with FIGO stage IB2-IIIB squamous cell carcinoma of the uterine cervix were divided (by simple random sampling) into two groups: control arm patients who received radiotherapy (50 Gy in 25 fractions over 5 weeks) with concurrent weekly cisplatin (40 mg/m2) and study arm patients received same radiation dose with weekly cisplatin (30 mg/m2) and paclitaxel (40 mg/m2). After that, all patients received brachytherapy 21 Gy/three fractions, one fraction/week. All patients were followed up weekly during treatment, then 4–6 weeks after treatment completion, and thereafter monthly for at least 6 months. Results: The overall treatment response (complete+ partial response) was numerically higher in the cisplatin-containing control arm, but not significant (93% vs. 80%, P-value = 0.406). High-grade early rectal (60% vs. 25%, P-value = 0.014) and acute gastrointestinal toxicity (66% vs. 6%, P-value &lt;0.001) were significantly higher in the cisplatin and paclitaxel-containing arm. Hematological, renal, late rectal, and bladder toxicities were also numerically higher in the study arm, but not statistically significant. Conclusion: There was no significant benefit of weekly paclitaxel and cisplatin as an alternative to weekly cisplatin-based chemoradiation in the treatment of carcinoma cervix.

A prospective randomized study to compare weekly versus tri-weekly cisplatin-based concurrent chemoradiation in the treatment of locally advanced carcinoma cervix

Background: Concurrent chemoradiotherapy with cisplatin is the standard treatment for locally advanced carcinoma cervix. Cisplatin can be given either as weekly or a tri-weekly regimen with radiotherapy. However, there were few studies comparing both, so our study aimed at comparing weekly versus tri-weekly cisplatin-based chemoradiation in terms of loco-regional control and acute toxicity profile. Aims and Objectives: To compare the treatment response and acute toxicity profile of thse two concurrent chemotherapy schedule. Materials and Methods: Patients with non-metastatic, squamous cell carcinoma of uterine cervix International Federation of Gynecology and Obstetrics stage IB2-IVA were randomized into two arms-control arm patients received external beam radiotherapy (50Gy in 25 fractions over 5 weeks) with concurrent weekly cisplatin (40mg/m2), and study arm patients received radiotherapy with same dose, along with tri-weekly concurrent cisplatin (75 mg/m2) for two cycles. After that, all patients received brachytherapy 21 Gee/3 fractions, one fraction/week. All patients were followed up weekly during treatment and then monthly for at least a period of 6 months for evaluation of toxicity and treatment response. Results: Six weeks after treatment completion, complete treatment response was comparable in both the arms(43.33% vs. 46.67%, P=0.35). Incidences of leucopenia were significantly high in weekly cisplatin arm (P=0.002).Nephrotoxicity of higher grade was also numerically more in control arm (P=0.654). However, treatment compliance was better in tri-weekly cisplatin arm, reflected by reduced treatment interruptions (46.67% vs. 53%). Conclusion: Tri-weekly cisplatin-based concurrent chemoradiation is equally effective as weekly cisplatin-based approach with comparable acute toxicity in treatment of carcinoma cervix.

NANORAY-312: A phase III pivotal study of NBTXR3 activated by investigator’s choice of radiotherapy alone or radiotherapy in combination with cetuximab for platinum-based chemotherapy-ineligible elderly patients with locally advanced head and neck squamous cell carcinoma.

TPS6110 Background: Elderly patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) are largely underrepresented in clinical trials (CT). Broad access to CTs in this population is challenging due to an increased prevalence of comorbidities and ageing-related conditions. However, as population-age increases, more and more elderly patients are diagnosed with LA-HNSCC although many are not eligible to receive standard cisplatin-based concurrent chemoradiation (CRT). CRT-related toxicities, treatment burden and compliance are a concern. NBTXR3, a first-in-class radioenhancer, composed of functionalized hafnium oxide nanoparticles, is administered by one-time intratumoral injection and activated by radiotherapy (RT). NBTXR3 is designed to locally amplify the tumor-killing effect of radiotherapy without additional toxicity to surrounding healthy tissue. NBTXR3 has been shown to prime the adaptive immune response in cancer models. NBTXR3 obtained EU marketing approval in preoperative treatment of locally advanced soft tissue sarcomas. In a Phase I trial of NBTXR3 + RT alone in elderly LA-HNSCC patients, the combination was shown to be safe and an Objective Response Rate (ORR) of 85.4% and CRR of 51.2% was reported at ASTRO 2021. A pivotal randomized phase III study was initiated and is now recruiting. Methods: NANORAY-312 [NCT04892173] is a global, open-label, randomized (1:1), 2-arm, Investigator's choice Phase III (Pivotal Stage) study to investigate the efficacy and safety of NBTXR3/RT±cetuximab versus RT±cetuximab in treatment-naïve, platinum-ineligible, elderly patients with LA-HNSCC. 500 patients will be enrolled. Eligible patients are ≥65 years with at least one measurable (RECIST 1.1) biopsy-confirmed T3-4 (AJCC v8) SCC of the oral cavity, oropharynx, hypopharynx, or supraglottic larynx which is amenable for intratumoral injection. For patients with oropharyngeal cancer, human papilloma virus (HPV) status must be known. In addition to the primary tumor, a single accessible LN in the neck is eligible for intranodal injection. The primary objective is PFS. The key secondary endpoint is OS. Other secondary endpoints include ORR, safety and tolerability and quality of life. Enrollment began in January 2022 and is ongoing. Clinical trial information: NCT04892173.

MO192: Renal Outcomes in High Dose Cisplatin in Locally Advanced Squamous Cell Cancer of the Head and Neck: A Monocentric Experience

Abstract BACKGROUND AND AIMS Head and neck cancer (HNC) represents the sixth most common neoplasm worldwide, accounting for 400 000 deaths globally every year. Among HNC, the squamous cell carcinoma (SCCHN) is the most aggressive histology, being responsible for more than 90% of cases. The overall 5-year survival rate goes from 33% to 68% according to risk factors and primary site. In clinical practice, at least two cycles of three-weekly high-dose cisplatin (100 mg/m2) concomitant to radiotherapy represents the standard of care given LA-SCCHN with a curative intent, both in postoperative and conservative settings. However, concurrent high-dose cisplatin is associated with significant acute and late toxicities. Acute kidney injury (AKI) is a common and serious side effect of high-dose cisplatin-based concurrent chemoradiation (CRT). AKI is a predictor of immediate and long-term adverse outcomes. The aim of this study was to investigate the nephrotoxicity of chemotherapy in real life of LA-SCCHN patients during and after treatment with high-dose cisplatin-based CRT, with a particular focus on AKI onset. METHOD Ninety-three consecutive patients affected by LA-SCCHN and treated with high-dose cisplatin-based CRT were enrolled in a prospective observational monocentric study. All patients received adequate supportive care such as SF 750 mL + 16 mEq MgSO4 IV 200 mL/h before and after cisplatin administration (a total of 1500 mL at day 0 and again at day 1), with 375 mL mannitol 10% if diuresis after hydration was less than 100–200 mL/h and dexamethasone 12 mg IV as chemo premedication at day 0 and 8 mg PO at days 1 to 3 as antiemetic prophylaxis followed by 6 days of steroid progressive decalage. Demographic data, medical history, and clinical, laboratory and histological data at presentation were reported from the medical records. Serum creatinine was recorded at baseline and after each cycle of treatmentat day 1 and day 10, respectively. eGFR was calculated using CKD-EPI 2012 formula. Bayesian linear regression was used to evaluate the impact of the clinical and pathological features on eGFR decay through cycles and AKI incidence. RESULTS The cohort was composed of 93 patients with a median age of 59 years, M/F ratio 2.4, median BMI 24.9 (IQR: 22.3, 27.4), median eGFR 92.2 mL/min. A total of 58% of patients presented basal eGFR &amp;gt; 90 mL/min, while 42% &amp;lt;90 mL/min (only 4 patients with eGFR &amp;lt; 60 mL/min). Approximately 34.4% patients presented hypertension, and the 8.6% were diabetics. AKI onset was 22.6% in the overall cohort: among those 21 patients who developed AKI, no one showed stage II-III AKI according to the KDIGO classification. Using a definition of AKI based only on an increase in serum creatinine &amp;gt; 1.5 higher than 1.5 times the baseline value, AKI incidence was 14% with a significative difference (P = .04) between patients with baseline eGFR &amp;gt; 90 mL/min and patients with eGFR &amp;lt; 90. Statistical analysis preformed using a logistic regression model showed a correlation between arterial hypertension and AKI incidence, while other comorbidities (such as diabetes) and concurrent medications were not associated with an increased in AKI incidence. CONCLUSION AKI was a common complication of high-dose cisplatin treatment in our LA-SCCHN patients’ cohort (22.6%): interestingly, the totality of AKI cases was represented by stage I AKI. The main risk factor for AKI development was a diagnosis of arterial hypertensions (Figure 1), while no correlation with concomitant medications and diabetes was found. The overall AKI incidence in our cohort was lower than reported in previous Studies, likely due to the use of a preventive protocol based on hydration and mannitol use; among those patients who developed AKI, no modification in cisplatin treatment scheme were needed, particularly all the patients reached a cumulative cisplatin dose ≥200 mg/m2.

DEHART: Dose-Escalated Hypofractionated Adaptive Radiation Therapy with Atezolizumab for Head and Neck Cancers

<h3>Purpose/Objective(s)</h3> To determine the maximum-tolerated dose (MTD) of Dose-Escalated Hypofractionated Adaptive Radiation Therapy (DEHART) delivered with concurrent atezolizumab (Genentech) in patients with locally advanced or <i>de novo</i> metastatic head and neck squamous cell carcinomas (HNSCCs). (ClinicalTrials.Gov Identifier NCT04477759) We hypothesize that using DEHART we will be able to safely deliver ablative radiation doses for HNSCC in 15 fractions. <h3>Materials/Methods</h3> This is an NIH-funded (R21 CA256144-01) Phase I dose-escalation trial to determine the MTD of weekly adapted MR-guided radiation therapy delivered using the DEHART regimen with concurrent atezolizumab for patients with locoregionally advanced or <i>de novo</i> metastatic HNSCCs. Eligible patients are 18 years or older including all patients presenting with <i>de novo</i> metastatic HNSCC or patients presenting with localized AJCC 8^th edition T3-T4 N0-N3, T0-T4 N1-N3 HNSCC who meet at least one of the following criteria: 1) they are not candidates for concurrent bolus cisplatin; 2) they refuse concurrent cisplatin-based chemoradiation; 3) they have unresected or unresectable oral cavity cancer; or 4) they have recurrent disease after definitive surgical resection. DEHART is a novel adaptive MR-guided radiation regimen in which the gross tumor volume (GTV) plus a 3 mm PTV margin receives the experimental dose (50 Gy, 55 Gy or 60 Gy) in 15 fractions, a 1 cm anatomically-confined margin on the GTV plus a 3 mm PTV margin receives 45 Gy in 15 fractions, and elective lymph node basins plus a 3 mm PTV margin receives 40 Gy in 15 fractions. On fractions 6 and 11 of radiation, the GTV volume is adapted based on MR-documented tumor regression. All patients are treated on a linear accelerator. All patients receive the DEHART radiation regimen with concurrent and adjuvant monthly atezolizumab for 1 year. Atezolizumab (1680 mg) is delivered on the first day of radiation and every 4 weeks thereafter for up to 1 year after treatment. The primary endpoint of the study is the MTD of DEHART determined using a modified Time-To-Event Continual Reassessment Methodology (TITE-CRM). The MTD is the radiation dose at which there is a 30% rate of dose-limiting toxicity (DLT) up to 12 months after completion of radiation therapy. DLTs include an inability to complete radiation within 30 days of starting radiation deemed not to be related to disease progression and any Grade 4+ toxicity probably or definitely related to treatment with radiation and/or atezolizumab. Secondary study endpoints include locoregional control, overall survival, and patient quality-of-life as measured by the MD Anderson Symptom Inventory for Head and Neck (MDASI-HN) and the MD Anderson Dysphagia Inventory (MDADI-HN). <h3>Results</h3> TBD <h3>Conclusion</h3> TBD

Therapeutic effects and prognostic factors of 125I brachytherapy for pelvic recurrence after early cervical cancer surgery

To investigate the efficacy of 125I seed implantation in the treatment regimen of pelvic recurrence after early cervical cancer surgery and to analyse prognostic factors. To evaluate efficacy and analyse prognostic factors of 125I seed implantation for pelvic recurrence after early cervical cancer surgery. A prospective study was conducted on 62 patients who experienced pelvic recurrence after early cervical cancer surgery between August 2005 and September 2015. The 62 patients were treated and assessed in 2 groups (n = 30). All 62 patients were randomized into two groups that received two different treatment regimens: the treatment group (n = 30), which received 125I particle implantation therapy, and the control group (n = 32), which received whole-pelvic irradiation using the anteroposterior/posteroanterior field and cisplatin-based concurrent chemoradiation therapy. The efficacy/efficiency of 125I seed implantation and prognostic factors were analysed by logistic regression. Overall survival was determined by Kaplan–Meier analysis. Multivariate analysis results were obtained by the Cox proportional hazards regression model. The effective control rates at 1, 3, 6 and 12 months were 76.7%, 80.0%, 83.3%, and 86.7% in the 125I particle implantation group. The total effective control rates at 1, 3, 6 and 12 months were 65.6%, 65.5%, 62.5%, and 71.9% in the chemoradiotherapy group. Significant differences were observed between the two groups. The overall survival rates at 1, 2, 3, 4, and 5 years and the median overall were 96.7%, 93.3%, 86.7%, 71.9%, 65.6% and 4.34 years, respectively, in the 125I seed implantation group and 81.3%, 71.9%, 62.5%, 56.3%, 53.1% and 3.59 years, respectively, in the control group. There were statistically significant differences in survival rates depending on the diameter of the largest recurrent pelvic tumour (χ2 = 6.611, P = 0.010). The multivariate analysis showed that the survival rates were related to the diameter of the largest recurrent pelvic tumour (χ2 = 4.538, P = 0.033). 125I implantation is an effective, safe, and promising method for the treatment of pelvic recurrence after early cervical cancer surgery. The diameter of the recurrent pelvic tumour was identified as a significant independent prognostic factor in patients who received 125I implantation.

Matched pair analysis for comparison of survival outcome of alternative regimens to standard three-weekly cisplatin-based concurrent chemoradiation of head and neck cancer.

BackgroundTo compare head and neck cancer (HNC) patients treated with three-weekly versus weekly cisplatin-based or other chemotherapy-based concurrent chemoradiation (CRT) and CRT with versus without induction chemotherapy (ICT) to investigate differences in overall survival (OS) and cancer-specific survival (CSS).MethodsHNC patients treated with definitive or adjuvant CRT at Roswell Park Comprehensive Cancer Center between 2003 and 2017 were retrospectively reviewed. Propensity score matching was performed to obtain three sets of balanced matched pairs: three-weekly and weekly cisplatin CRT, three weekly and non-cisplatin CRT, CRT with and without ICT. Multivariate Cox regression and Kaplan-Meier analyses were used to estimate and compare survival outcomes.ResultsA total of 623 patients received either definitive (81%) or post-operative (19%) RT. Of these, 283 patients concurrently received three-weekly cisplatin (45%); 189 patients (30%) received weekly cisplatin; 151 patients (24%) received non-cisplatin regimen. Median follow-up was 55.4 months (interquartile range, 38.0–88.7). Patients who received CRT alone and those who received ICT and CRT had no difference in 5-year OS (51.5% and 41.0% respectively, P=0.53) and CSS (64.9% and 49.7% respectively, P=0.21). Compared to patients who received three-weekly cisplatin, patients who received weekly cisplatin had no difference in 5-year OS (59.3% vs. 54.1%, P=0.35) and CSS (70.3% vs. 62.4%, P=0.09); patients who received non-cisplatin CRT also had no difference in 5-year OS (54.5% vs. 58.3%, P=0.51) and CSS (67.5% vs. 64.7%, P=0.45).ConclusionsNo significant difference in OS and CSS was observed in any of the three pairs of CRT regimens. ICT prior to CRT did not improve survival of CRT alone. Non-cisplatin and weekly cisplatin regimens did not prove to be inferior to the standard three-weekly cisplatin.

Renal function impairment in cervical cancer patients treated with cisplatin-based chemoradiation: A review of medical records in a Zimbabwean outpatient department.

There is a potential increase in risk of renal function impairment among patients with invasive cervical cancer (ICC) who are HIV-positive and treated with cisplatin-based concurrent chemoradiation (CCRT). This concern is due to overlapping nephrotoxicity of the drugs, and nephropathy from the diseases themselves. There is limited literature available for the short-term renal outcomes for HIV-positive patients with ICC during routine clinical management. This study aimed to assess if HIV-infection increased the risk of renal impairment in ICC patients treated with CCRT, and explore the respective risk factors. This was a retrospective review of records of ICC patients treated with at least one cycle of weekly cisplatin during CCRT at the Parirenyatwa Radiotherapy Center from January 2017-December 2018. The RIFLE criteria were used to classify renal impairment. Analyses were performed with Fisher's Exact tests, Wilcoxon rank sum tests. Odds ratios (OR) were generated using logistic regression. All statistical tests were 2-sided at a 5% level of significance. Seventy-two eligible patients were identified, 32 (44.44%) were HIV-positive. HIV-positive patients were younger (p = 0.002), had lower albumin levels (p = 0.014) and received lower cisplatin doses (p = 0.044). The mean percent reduction in estimated glomerular filtration rate (eGFR) from baseline was -19% (95% CI: -25.9% to -13.2%) for all patients. Thirty-one (43.1%) patients experienced renal impairment, 50% and 37.5% of HIV-positive and -negative patients respectively (p = 0.287). HIV-infection was associated with an adjusted OR of 1.16 (95% CI 0.35-3.43, p = 0.769). Baseline eGFR< 60ml/min was the only independent predictor of renal impairment, OR 0.25 (95% CI: 0.07-0.85). Baseline eGFR<60ml/min was also associated with receipt of lower cisplatin doses (p = 0.044). HIV-infection was not associated with elevated risk of renal impairment. Patients with an eGFR<60ml/min appear to be managed more cautiously reducing their risk for renal impairment during cisplatin therapy. The high prevalence of renal impairment in this population suggests the need for optimization of pre-treatment protocols.

Treatment Outcome of Cervical Cancer Patients Treated with Low-Versus High Dose Rate Brachytherapy after Concurrent Chemo-Radiation

Cervical cancer (CC) is the commonest gynecological cancer seen in the Ghanaian woman. Majority of patients here present with locally advanced diseases due poor screening practices aimed at detecting and treating precancerous conditions. The current standard curative treatment for locally advanced CC is concurrent cisplatin-based chemo-radiation plus intracavitary brachytherapy. The brachytherapy (BT) component has been Low-Dose Rate (LDR) BT for almost a century now until a few decades ago when High-Dose Rate (HDR) BT was developed to overcome disadvantages of LDR BT such as long treatment duration. In October 2014, HDR BT was introduced as the BT technique for the management of CC patients at this Centre, after several years of using LDR BT. The hypothesis for this study was that there was no difference in the treatment outcomes of CC patients treated with HDR BT compared with those who received LDR BT at this center. The aim of this study was to compare the treatment outcomes and toxicity of CC patients treated with LDR BT versus HDR BT treated at this Centre. Patients with histologically confirmed CC treated from January 2008 to December 2017 were enrolled after applying the inclusion and exclusion criteria. Information regarding patient demographics, stage of disease, type of BT received, total radiation dose received, response to treatment and treatment related toxicities experienced were extracted from the medical records of the patients. The primary end points of the study included local control (LC), disease free survival (DFS) and overall survival (OS) all at 2 years. Toxicities were also assessed. Primary endpoints were estimated using the Kaplan-Meier method. Comparisons between treatment groups were performed using the log-rank test and Cox proportional hazards models. Over the 10-year period, 284 LDR (2008 –mid-2014) and 136 HDR (mid-2014-2017) patients fit the inclusion criteria. The median follow-up was 22 months (1-132months) vs. 11 months (1-41months) in LDR vs. HDR group respectively. For stages IB, IIA, IIB, IIIA and IIIB disease, the 2-year LC rates for LDR vs. HDR were 63 % vs. 61% p = 0.348, 86% vs. 90% p = 0.680, 86% vs. 88% p = 0.829, 66% vs. 60% p = 0.556 and 77% vs. 40% p = 0.005 respectively. The 2-year DFS for LDR vs. HDR BT were 64% vs. 61% p = 0.495, 81% vs. 69% p = 0.179, 81% vs. 80% p = 0.540, 62% vs. 33%, p = 0.818, and 71% vs.30%, p = 0.001 for stages IB, IIA, IIB, IIIA and IIIB respectively. The OS were comparable in both treatment groups stage for stage. Frequencies of acute and chronic toxicities for LDR vs. HDR were 22.6 % vs. 23.5%, and 3.9% vs. 6.9%, respectively. Comparable LC, DFS and OS were observed for IB, IIA, IIB and IIIA patients treated with LDR vs. HDR BT. HDR BT for the treatment of CC is therefore an acceptable alternative to LDR BT. However, the poorer LC and DFS rates observed for IIIB patients, and the higher frequencies of toxicities in the HDR BT cohort highlights the need for refining the HDR BT techniques at the Centre.

Radiotherapy With Weekly Cetuximab Versus Triweekly Carboplatin In The Definitive Treatment Of Cisplatin-Ineligible Patients With HPV-Associated Oropharyngeal Squamous Cell Carcinoma: One Institution’s Retrospective Experience

Although Triweekly Cisplatin-based concurrent chemoradiation has recently been shown to be superior to Cetuximab-based concurrent therapy in HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) in multiple randomized trials, the optimal concurrent agent in those who are poor candidates for Cisplatin is unknown. Here we report the cancer control and survival outcomes in this cohort of patients who underwent radiotherapy concurrent with either triweekly Carboplatin or weekly Cetuximab at our institution. A retrospective review was conducted from November 2006 through September 2016 of patients with non-metastatic p16-positive OPSCC who underwent definitive intensity modulated radiotherapy to a median dose of 70 Gy (range 66-70 Gy) concurrent with weekly Cetuximab (n = 40) per Bonner protocol or triweekly Carboplatin (AUC = 5) (n = 191). No patient received accelerated radiotherapy. Patients receiving induction chemotherapy or oncological surgery of any kind prior to concurrent therapy were excluded. All patients had stage conversion according to the AJCC 8th Edition Cancer Staging Manual. Three-year locoregional recurrence (LRR), distant metastasis (DM), overall recurrence rate (ORR), overall survival (OS), and cause-specific survival (CSS) are reported. Cetuximab and Carboplatin groups were compared accounting for age, sex, smoking history, T stage, and N stage. Patients who received Carboplatin were younger (median age 62 vs. 70, P<0.001). The Cetuximab group had a higher percentage of patients with >10 pack-years of smoking (57% vs. 37%, P<0.02). The two cohorts were otherwise well-balanced with respect to other baseline patient and disease characteristics including T and N stage. After a median follow up of 40 months for surviving patients, those receiving Carboplatin had lower 3-year rates of LRR (8% vs. 16%, p = 0.02), DM (11% vs. 21%, p = 0.01), and ORR (17% vs. 29%,p = 0.008), and superior OS (90% vs. 63%, p = 0.003) and CSS (93% vs. 77%, p = 0.01). Our study suggests that, if medically feasible, triweekly Carboplatin concurrent with radiotherapy should be preferred to that with cetuximab in patients with p16+ OPSCC who are not eligible to receive cisplatin as it results in superior cancer control and survival outcomes.

Incidence and risk factors for acute kidney injury in head and neck cancer patients treated with concurrent chemoradiation with high-dose cisplatin

BackgroundThree-weekly high-dose cisplatin (100 mg/m2) is considered the standard systemic regimen given concurrently with postoperative or definitive radiotherapy in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Concurrent chemoradiation (CRT) with high-dose cisplatin is associated with significant acute and late toxicities, including acute kidney injury (AKI). The aims of this study were to investigate the incidence of AKI in patients with LA-SCCHN during and after treatment with high-dose cisplatin-based CRT, to identify risk factors for cisplatin-induced AKI, and to describe the impact of AKI on long-term renal function and treatment outcomes.MethodsThis is a retrospective cohort study with measurements of renal function before CRT, weekly during CRT, every 1 or 2 days during hospitalizations, and 3 and 12 months after CRT in patients with LA-SCCHN. AKI was defined as increase in serum creatinine (sCr) of ≥1.5 times baseline or by ≥0.3 mg/dL (≥26.5 μmol/L) using the Kidney Disease Improving Global Outcomes (KDIGO) classification. Logistic regression models were estimated to analyze renal function over time and to identify predictors for AKI.ResultsOne hundred twenty-four patients completed all measurements. AKI was reported in 85 patients (69%) with 112 episodes of AKI. Sixty of 85 patients experienced 1 AKI episode; 20 patients experienced ≥2 AKI episodes. Ninety-three (83%) AKI episodes were stage 1, 13 (12%) were stage 2, and 6 (5%) AKI episodes were stage 3. Median follow-up time was 29 months (Interquartile Range, IQR 22–33). Hypertension (Odds Ratio, OR 2.7, 95% Confidence Interval, CI 1.1–6.6; p = 0.03), and chemotherapy-induced nausea and vomiting (CINV; OR 4.3, 95% CI 1.6–11.3; p = 0.003) were associated with AKI. In patients with AKI, renal function was significantly more impaired at 3 and 12 months post-treatment compared to patients without AKI. AKI did not have a negative impact on treatment outcomes.ConclusionAKI occurred in 69% of patients with LA-SCCHN undergoing CRT with high-dose cisplatin. Long-term renal function was significantly more impaired in patients with AKI. Hypertension and CINV are significant risk factors. Optimizing prevention strategies for CINV are urgently needed.

Neutrophilia as prognostic biomarker in locally advanced stage III lung cancer.

ObjectiveTo study the prognostic value of baseline leukocytosis or neutrophiliain two retrospective cohorts of stage III Non-Small Cell Lung Cancer (NSCLC) patients.Materials and methodsClinical records of consecutive previously untreated NSCLC patients in our Institution between June 2001 and September 2016 for stage III NSCLC were collected. The prognostic value of pretreatment leucocyte disorders was examined, with focus on patterns of relapse and survival. Leukocytosis and neutrophilia were defined as a leukocyte count or a neutrophil count exceeding 10 and 7 G/L, respectively.ResultsWe identified 238 patients, displaying baseline leukocytosis or neutrophilia in 39% and 40% respectively. Most were diagnosed with adenocarcinoma (48%), and stage IIIB NSCLC (58%). 3-year actuarial overall survival (OS) and progression-free survival (PFS) were 35% and 27% respectively. Local relapses were reported in 100 patients (42%), and distant metastases in 132 patients (55%). In multivariate analysis, leukocytosis, neutrophilia, and induction chemotherapy regimen based on carboplatin/paclitaxel were associated with worse OS and PFS (p<0.05). Neutrophilia independently decreased Locoregional Control (LRC) (HR = 2.5, p<0.001) and Distant Metastasis Control (DMC) (HR = 2.1, p<0.001). Neutrophilia was significantly associated with worse brain metastasis control (p = 0.004), mostly in adenocarcinoma patients (p<0.001).ConclusionIn stage III NSCLC patients, treated with concurrent cisplatin-based chemoradiation, baseline leukocytosis and neutrophilia were associated with worse OS, PFS, LRC, and DMC. In addition with previously available markers, this independent cost-effective biomarker could help to stratify stage III NSCLC population with more accuracy.

The management of locally advanced cervical cancer.

Cervical cancer is still a major cause of morbidity and mortality among women worldwide. Surgery and chemoradiation are widely utilized treatments for cervical cancer. Despite the available standard treatment of choice, outcome is suboptimal among patients with LACC. It is vital to integrate the evidence generated from high-quality research work for effective management of these cases. This review intends to critically evaluate the latest evidence supporting the available treatment modalities and to provide a comprehensive overview of recent advances and ongoing research in the management of LACC. Research advances in imaging and radiotherapy technologies, incorporating imaging into brachytherapy planning, use of newer targeted agents, chemotherapy intensification and immunotherapy are some of the new therapeutic options that have been in the forefront of research to improve the outcome of patients with LACC. Advanced imaging modalities are increasingly being utilized to tailor treatments. Neoadjuvant chemotherapy followed by surgery does not improve outcomes in FIGO Stage IB2-IIB. Although cisplatin-based concurrent chemoradiation is the standard of care, more aggressive systemic therapies (neoadjuvant or adjuvant chemotherapy and chemoradiation) and use of newer agents, still remains investigational.