Cisplatin-based Chemoradiotherapy Research Articles

Protective effect of magnesium preloading on cisplatin-induced nephrotoxicity: which dose is more suitable?

Cisplatin is a widely used and potent cytotoxic chemotherapy agent, but its nephrotoxicity is a significant limiting side effect. Various premedication approaches have been implemented to preserve renal function, including magnesium (Mg) preloading. However, the optimal Mg dosage is still unknown. Our study aimed to assess the protective effects of different Mg doses as premedication in cisplatin-based chemoradiotherapy for patients with local/locally advanced cervical and head-neck cancers. This retrospective, multicenter study involved premedication with saline infusion containing potassium chloride and magnesium sulfate (MgSO4) for all patients before cisplatin treatment. Patients were divided into two groups: 12 mEq MgSO4 (low-dose Mg preload group, low-Mg) and 24 mEq MgSO4 (high-dose Mg preload group, high-Mg). Renal function was evaluated using serum creatinine (sCr, mg/dl) and estimated glomerular filtration rate (eGFR, ml/min). Acute kidney injury (AKI) was defined per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Renal outcomes and efficacy were compared between the groups. In the low-Mg group (n = 159), sCr levels were significantly higher compared to baseline, various weeks during treatment, and at the 1st, 3rd, 6th, and 12th months post-treatment (p < 0.001). In the high-Mg group (n = 128), no significant changes were observed during treatment and at 1st, 3rd, and 12th months post-treatment (p > 0.05). A significant reduction in mean sCr level from baseline to 6 months was noted in the high-Mg group (p < 0.001). eGFR values are generally correlated with sCr levels. AKI occurred in 21 (13.2%) and 22 (17.7%) patients in the low-Mg and high-Mg groups, respectively (p = 0.292). There was no difference in progression-free or overall survival between the groups. We clearly demonstrated that saline hydration with 24 mEql MgSO4 supplementation before cisplatin treatment has a better renal protective effect than 12 mEql MgSO4 without reducing efficacy, especially in patients with local/local advanced cervical and head-neck cancer receiving cisplatin with concurrent radiotherapy.

Results of Definitive (Chemo)radiotherapy Using Computed Tomography-based Brachytherapy for Cervical Cancer.

Concurrent cisplatin-based chemoradiotherapy (CCRT) is the standard treatment for locally advanced cervical cancer. Especially, CCRT with magnetic resonance imaging (MRI) or computed tomography-based image-guided brachytherapy (CT-based 3D-IGBT) for cervical cancer has resulted in good LC rates. However, progression-free survival (PFS) and overall survival (OS) rates for locally advanced cervical cancer are still low and could be improved. The aim of the study was to evaluate treatment efficacy and late toxicity of external beam radiotherapy (EBRT) and CT-based IGBT with or without concurrent chemotherapy in patients with squamous cell carcinoma of the uterine cervix and investigate patterns of failure. We retrospectively analyzed clinical data of cervical squamous cell carcinoma patients treated with definitive radiotherapy with or without concurrent chemotherapy at Saitama Medical University International Medical Center. Local control (LC), PFS, patterns of failure, and late toxicity were the evaluated outcomes. Overall, 290 patients were enrolled in the study. Median follow-up was 51.5 months. During follow-up, 74 patients developed recurrence: 10 patients with intra-pelvic failure only, 45 with extra-pelvic failure only, and 19 with both. The 3-year LC was 100% for T1b-T2a, 96.8% for T2b, 89.5% for T3b, and 88.5% for T4 disease. The 3-year PFS was 100% for stage IB-IIA, 89.0% for stage IIB, 70.7% for stage IIIB, 72.6% for stage IIIC1r, and 40.1% for stage IVA. The incidence of grade 3-4 gastrointestinal and genitourinary toxicities was 3.0% and 1.7%, respectively. Combination of EBRT and CT-based IGBT with or without concurrent chemotherapy produced favorable LC with acceptable rates of late toxicities. However, extra-pelvic failures frequently occurred and PFS was less satisfactory in patients with stage III-IVA disease, which indicated the need for additional treatment in these patients.

Impact of fosaprepitant in the prevention of nausea and emesis in head and neck cancer patients undergoing cisplatin-based chemoradiation: a pilot prospective study and a review of literature

PurposeCisplatin-based chemoradiotherapy (CRT) is standard treatment for head and neck squamous cell carcinoma (HNSCC). However, IMRT may increase chemotherapy-induced nausea and vomiting (CINV). The purpose of this study is to investigate the effect of fosaprepitant in preventing CINV.MethodsAn infusion of 150 mg fosaprepitant was given through a 30 min. We assessed acute toxicity using CTCAE v.4 and the incidence of CINV using the FLIE questionnaire. The evaluation of CINV was done at the second and fifth weeks of CRT and 1 week after the end. The EORTC QLQ-HN 43 questionnaire was administered before treatment beginning (baseline), at second (T1) and fifth (T2) weeks. A dosimetric analysis was performed on dorsal nucleus of vagus (DVC) and area postrema (AP).ResultsBetween March and November 2020, 24 patients were enrolled. No correlation was found between nausea and DVC mean dose (p = 0.573), and AP mean dose (p = 0.869). Based on the FLIE questionnaire, patients reported a mean score of 30.5 for nausea and 30 for vomiting during week 2 and 29.8 for nausea and 29.2 for vomiting during week 5. After treatment ended, the mean scores were 27.4 for nausea and 27.7 for vomiting. All patients completed the EORTC QLQ-HN 43. Significantly higher scores at T2 assessment than baseline were observed.ConclusionsThe use of fosaprepitant in preventing CINV reduced incidence of moderate to severe nausea and vomiting. No correlation has been found between nausea and median dose to DVC and AP.

Adjuvant chemoradiotherapy (CRT) plus pembrolizumab for locally advanced esophageal squamous cell carcinoma (ESCC) with high risk of recurrence after neoadjuvant CRT plus surgery: A single-arm phase II study.

320 Background: Adjuvant anti-PD-1 therapy with nivolumab has shown efficacy in reducing recurrence rates in patients with locoregional esophageal cancer including squamous cell carcinoma who achieved R0 resection but harboring pathologic residual disease following neoadjuvant CRT. However, the efficacy of adjuvant anti-PD-1 therapy in improving outcomes for patients at higher risk of recurrence, especially those with involved or close resection margin (≤1 mm), remains unclear. Methods: We conducted a phase II trial of adjuvant cisplatin (30mg/m2 IV every week for 2 cycles)-based CRT (180-200cGy per fraction for 10-13 fractions) followed by pembrolizumab (200mg IV every 3 weeks for 18 cycles) in patients with locally advanced ESCC who had high-risk recurrence features in esophagectomy tumor tissues, including involved or close margin (≤1 mm), extranodal extension (ENE) of involved lymph node, and ypN2-3, following neoadjuvant CRT (ClinicalTrials.gov Identifier: NCT03322267). Primary endpoint was 1-year relapse-free survival (RFS) rate in comparison with a historical control of 32%.1 Secondary endpoints included RFS, overall survival (OS), and toxicity. Results: Between Nov 2018 and Dec 2022, we enrolled a total of 25 patients with high risk recurrence features, including margin ≤1 mm (18 patients), ENE of involved lymph node (9), and ypN2-3 (9). Majority of patients were male (88%) and current smokers (84%). The median follow-up duration was 16.5 months (95% CI 10.6-27.1). One-year RFS rate was 63.3% (95% CI 44.5-79.8). Median RFS and OS were 15.3 months (95% CI 10.2-20.4) and 38.3 months (95% CI 10.2-66.3), respectively. Any grade treatment emergent adverse events (TEAEs) occurred in 56% and 75% of patients during cisplatin-based CRT and pembrolizumab treatment, respectively. Grade 3 TEAEs were infrequent, including leukopenia (4%), pancreatitis (4%), infection (8%), and colitis (4%). There was no grade 4 TRAE. Conclusions: Adjuvant cisplatin-based CRT followed by 1-year treatment of pembrolizumab was well-tolerated, and was associated with an improved 1-year RFS rate in patients with pathologic residual disease and high risk for recurrence following trimodality therapy for locally advanced ESCC. 1. Guo JC et al: J Thorac Oncol 2015;10:1481-9. Clinical trial information: NCT03322267 .

Presence of low volume metastases does not alter management in node-negative, early-stage cervical cancer patients who underwent postoperative adjuvant therapy: A retrospective cohort study

ObjectiveThis study sought to determine if patients with early stage cervical cancer who possessed intermediate-high risk factors (defined by Peters or Sedlis criteria) and had pathologically negative lymph nodes at the time of surgery had higher rates of low volume metastases (LVM) on retrospective ultrastaging. MethodsThis IRB-approved retrospective cohort study collected data via chart review on early stage, surgically-treated node-negative cervical cancer patients who underwent postoperative adjuvant therapy, treated at a single institution from January 2011 through June 2021. Nodal blocks were retrospectively ultrastaged per standard protocol. Descriptive statistics were performed for analysis. ResultsOver the 10-year study period, n = 20 patients met study inclusion criteria. Most patients were white with squamous cell histology, with a mean number of 25.15 (SD = 12) nodes examined on initial pathologic evaluation. 85 % (n = 17) patients were pathologic stage IB. 85 % of the cohort were recommended for adjuvant radiation, with the remaining 15 % for cisplatin-based chemoradiation. LVM in the form of micrometastasis was retrospectively identified in one patient (5 %) who had received whole pelvic radiation and recurred locally within the irradiated field. ConclusionsThis small retrospective series of surgically managed cervical cancer with intermediate-high risk tumor factors identified only 1 patient with LVM, representing 5% of the total population. The biologic importance of ITC and LVM remains unclear in cervical cancer, however this investigation highlights the low incidence even when all nodes are evaluated in a higher risk cohort. The presence of LVM would not have changed management decisions based on this retrospective analysis.

Phase I feasibility study of Olaparib in combination with loco-regional radiotherapy in head and neck squamous cell carcinoma

PurposePARP-inhibitors have potent radiosensitizing properties in pre-clinical models. To identify the maximum tolerated dose (MTD) of the PARP-inhibitor Olaparib in combination with radiotherapy in patients with head and neck cancer, a single institutional phase-I dose escalation trial was initiated. Patients and methodsThe starting dose of Olaparib was 25 mg BID, combined with radiotherapy (70 Gy in 35 fractions). The MTD was defined as the highest dose-level at which not more than 20 % of patients experience dose-limiting toxicities (DLT) or as the highest reached dose in the absence of DLT’s. ResultsOne week Olaparib‐only treatment (25 mg QD) was administered to all patients prior to the start of radiotherapy. In dose-level I, Olaparib (25 mg BID) was combined with accelerated radiotherapy (70 Gy in 6 weeks). Because of DLT’s in 3 of the 4 treated patients (acute tracheotomy 5 and 7 months and osteoradionecrosis 7 months after treatment), the Olaparib dose was de-escalated to 25 mg QD, and combined with conventional radiotherapy (70 Gy in 7 weeks) (dose-level II). There were no DLT’s observed in 5 patients treated within dose-level II. After a median follow-up of 60 months, the 4-year LRC and OS rates were 77.8 % and 88.9 %, respectively. ConclusionOlaparib 25 mg QD combined with conventionally fractionated radiotherapy was well tolerated and identified as the MTD while severe DLT’s were observed when Olaparib 25 mg BID was combined with accelerated radiation. This combination might be further explored in future Olaparib dose escalation studies in patients with locally-advanced HNSCC unfit for cisplatin-based chemoradiotherapy.

DNA Double-Strand Break Response and Repair Gene Polymorphisms May Influence Therapy Results and Prognosis in Head and Neck Cancer Patients.

Radiotherapy and cisplatin-based chemotherapy belong to the main treatment modalities for head and neck squamous cell carcinoma (HNSCC) and induce cancer cell death by generating DNA damage, including the most severe double-strand breaks (DSBs). Alterations in DSB response and repair genes may affect individual DNA repair capacity and treatment sensitivity, contributing to the therapy resistance and poor prognosis often observed in HNSCC. In this study, we investigated the association of a panel of single-nucleotide polymorphisms (SNPs) in 20 DSB signaling and repair genes with therapy results and prognosis in 505 HNSCC patients treated non-surgically with DNA damage-inducing therapies. In the multivariate analysis, there were a total of 14 variants associated with overall, locoregional recurrence-free or metastasis-free survival. Moreover, we identified 10 of these SNPs as independent predictors of therapy failure and unfavorable prognosis in the whole group or in two treatment subgroups. These were MRE11 rs2155209, XRCC5 rs828907, RAD51 rs1801321, rs12593359, LIG4 rs1805388, CHEK1 rs558351, TP53 rs1042522, ATM rs1801516, XRCC6 rs2267437 and NBN rs2735383. Only CHEK1 rs558351 remained statistically significant after correcting for multiple testing. These results suggest that specific germline variants related to DSB response and repair may be potential genetic modifiers of therapy effects and disease progression in HNSCC treated with radiotherapy and cisplatin-based chemoradiation.

ARTIA-Cervix: A Prospective Clinical Trial to Assess Patient Reported Intestinal Toxicity with Adaptive External Beam Radiation Therapy in the Treatment of Cervical Cancer

Chemoradiation (CRT) remains the standard of care for locally advanced cervical cancer. As recent large phase III trials (OUTBACK, CALLA) reported no difference in primary survival outcomes when novel agents were added to CRT, technological advancements continue to be a focus for improving outcomes. Daily imaging has enabled margin reduction on the cervix, uterus and lymph nodes, which can lower radiation dose to bowel and potentially reduce RT-related symptoms. Daily adaptive RT (ART) combines daily imaging with online dosimetry replanning, allowing for decreased margins on the target. A pre-planning study showed bowel V40Gy and V45Gy reductions of 252 cc to140 cc and 167 cc to 43 cc, respectively. ARTIA-Cervix is a single-arm, prospective, multi-institutional, international clinical trial investigating the potential of ART to decrease patient-reported acute gastrointestinal (GI) toxicity. Planned enrollment is 125 subjects with up to 8 sites participating. Eligibility criteria include locally advanced node-negative cervical cancer FIGO stages IB2-3B. Treatment will consist of cisplatin-based CRT with daily ART, followed by image-guided brachytherapy. Subjects will receive 25 fractions ART at 1.8 Gy per day for a total of 45 Gy. The primary study objective is reduction of patient-reported GI toxicity as measured by PRO-CTCAE score ≥3 at the conclusion of ART. Secondary objectives include patient-reported GU toxicity and sexual quality of life, the development of radiation dosimetry models predicting toxicity, physician-reported toxicities, 2-year disease free survival, and adaptive workflow metrics. Powering of the study and sample size calculation are based on the hypothesis that ART will decrease patient-reported acute GI toxicity from historical rates of 33% to 20% (13% effect size). This study opened to enrollment on April 28th, 2022. The total study duration will be approximately 5 years. ARTIA-Cervix is an international, prospective clinical trial designed to evaluate reduction of treatment-related GI toxicity through daily online ART. The results of this clinical study will add to the growing body of evidence supporting clinical decisions about utilization of ART technologies.

Nab-paclitaxel and cisplatin-based concurrent chemoradiotherapy for locally advanced cervical cancer: A prospective, single-arm phase II clinical trial (182)

Nab-paclitaxel and cisplatin-based concurrent chemoradiotherapy for locally advanced cervical cancer: A prospective, single-arm phase II clinical trial (182)

Assessment of Acute Side Effects Among 3D-Concurrent Radiotherapy With Cisplatin-Treated Head and Neck Cancer Patients.

Three-dimensional conformal radiation therapy has become one of the basic components of multidisciplinary treatment for head and neck cancer. Generally, patients with squamous-cell carcinoma of the head and neck receive cisplatin-based chemoradiation. In the current project, the goal was to assess 3D-CRT with cisplatin-induced acute side effects (dermatitis plus xerostomia) among head and neck cancer patients. This descriptive case series was held at the Institute of Nuclear Medicine and Oncology, Lahore, Pakistan, with an enrollment of 106 head and neck cancer patients following the hospital's ethical approval. All patients received 3D-CRT with concurrent cisplatin chemotherapy according to the oncology treatment protocol at the Institute of Nuclear Medicine and Oncology. The evaluation of enrolled patients was done during treatment at a weekly interval and at one-month post-radiation. Stage 3 patients (17.9%) received chemo-radiation therapy with 40 mg/m2 cisplatin once weekly for seven weeks. All patients received 70 grays in 35 fractions with two grays per fraction over the course of seven weeks following a standard protocol. All enrolled cases had biopsy-proven squamous cell carcinoma of the head and neck. IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp. analyzed the data. Chi-square and Fisher's exact tests were applied, while a p-value ≤ 0.05 was taken as statistically significant. All patients developed acute skin changes (dermatitis plus xerostomia) as a side effect of radiation therapy, with cisplatin having different grades during treatment until seven weeks. However, these changes improved and became less severe in terms of grade after one month of post-treatment among all patients. It was concluded that 3D-CRT was associated with dermatitis and xerostomia during and immediately after follow-up, even though the treatment response was good. However, clinical signs and symptoms improved, indicating that radiation therapy is a relatively safe treatment modality among cancer patients. Moreover, 40 mg/m2 cisplatin once weekly for seven weeks resulted in better loco-regional control and survival among advanced-stage head and neck cancer patients as a part of treatment. Although, higher doses of cisplatin (100 mg/m2 ) every three weeks have more harmful acute side effects and delay treatment for patients due to poor compliance.

Accelerated loss of lean body mass in head and neck cancer patients during cisplatin-based chemoradiation

Background This study investigated changes in body weight, lean body mass (LBM), fat mass (FM), muscle strength and functional performance during radiation treatment in head and neck cancer (HNSCC) patients. Secondly, it investigated the impact of cisplatin-based chemoradiation (CCRT) on LBM loss compared with radiation alone. Methods 48 patients (all tumor sites) received either 6 weeks of radiation alone (n = 16) with 66–68 Gy in 33–34 Fx, 5-6 Fx/week or CCRT, adding weekly cisplatin or carboplatin (n = 32). LBM and FM was evaluated using Dual-energy X-ray Absorptiometry bi-weekly from pre- to two weeks post-treatment. Maximal muscle strength (knee extension, leg - and chest press) and functional performance (stair climb, chair rise, and arm curl) were assessed pre- and post-treatment. Results Body weight and LBM had declined significantly already week 2 into treatment and declined significantly further through week 4 and 6 before leveling off after week 6. Bi-weekly, from treatment start to week 2, 2–4, and 4–6, LBM declined 1.2 ± 0.4 kg (p = .002; 95% CI: 0.4;2.0), 2.0 ± 0.4 kg (p < .0001; 1.2;2.8) and 1.4 ± 0.4 kg (p = .001; 0.6;2.2). With a two-week delay, FM declined significantly from week 2–8. All measures of muscle strength declined significantly from pre- to post-treatment. Functional performance was unchanged. LBM loss from pre- to post-treatment was significantly associated with impaired muscle strength (R 2 = 0.3–0.5). CCRT patients lost 3.1 ± 0.8 kg of LBM (p = .0001; 1.5;4.7) more from pre- to post-treatment compared with patients receiving radiation alone. Analyses adjusting for nimorazole, tumor stage, baseline BMI, mean radiation dose to constrictor muscles and oral cavity confirmed this. Conclusion Accelerated and substantial LBM loss was already initiated within the first two weeks of treatment - before the onset of radiation-induced mucositis. LBM loss was associated with muscle strength impairment. Patients receiving CCRT experienced significantly larger LBM loss than patients receiving radiation alone. Registered on clinincaltrials.gov (Identifier: NCT05890859).

Effect of mannitol-based reduced-volume hydration on kidney function in concomitant cisplatin-based chemoradiation for head-and-neck squamous cell carcinoma.

Nephrotoxicity is frequent in cisplatin-based chemoradiation of head and neck squamous cell carcinoma (HNSCC). Toxicity outcomes and achieved cisplatin-doses after change of departmental hydration policy are presented. We performed a retrospective time-series analysis of HNSCC patients undergoing chemoradiation with conventional hydration (CH) between 01/2017 and 09/2018 versus shorter hydration with mannitol (SHM) between 09/2018 and 08/2019 to compare the rate of acute kidney injury (AKI) and cumulative cisplatin dose. Among 113 HNSCC patients, SHM (n = 35) in comparison to CH (n = 78) correlated with less AKI (54.3% vs. 74.4%; p = 0.034) and higher cisplatin doses (82.9% vs. 61.5% ≥200 mg/m2 ; p = 0.025). AKI ≥grade 2 was lower with SHM (2.9% vs. CH: 22.8%; p = 0.01). AKI occurred more frequently in females (92.6% vs. males: 60.5%, p = 0.002). Females received lower cumulative cisplatin doses (51.9% vs. males: 73.3%; p = 0.037). We observed less AKI and higher cumulative chemotherapy doses with SHM. Female patients were at higher risk of AKI.

First Results of Concurrent Chemoradiation with Two Courses of 5 × 25 mg/m2 Cisplatin for Locally Advanced Head and Neck Cancer.

Many patients with squamous cell carcinoma of the head and neck (SCCHN) receive cisplatin-based chemoradiation. Cisplatin 100 mg/m2 every three weeks is toxic and alternative cisplatin regimens are desired. Two courses of 20 mg/m2/day 1-5 (cumulative 200 mg/m2) were shown to be similarly effective and better tolerated than 100 mg/m2 every three weeks. Previous studies suggested that cumulative doses >200 mg/m2 may further improve outcomes. In this study, 10 patients (group A) receiving two courses of 25 mg/m2/day 1-5 (cumulative 250 mg/m2) in 2022 were retrospectively matched and compared to 98 patients (group B) receiving two courses of 20 mg/m2/day 1-5 or 25 mg/m2/day 1-4 (cumulative 200 mg/m2). Follow-up was limited to 12 months to avoid bias. Group A achieved non-significantly better 12-month loco-regional control (100% vs. 83%, p = 0.27) and metastases-free survival (100% vs. 88%, p = 0.38), and similar overall survival (89% vs. 88%, p = 0.90). No significant differences were found regarding toxicities, completion of chemotherapy, and interruption of radiotherapy. Given the limitations of this study, chemoradiation with two courses of 25 mg/m2/day 1-5 appears an option for carefully selected patients as a personalized treatment approach. Longer follow-up and a larger sample size are needed to properly define its role.

Induction chemotherapy plus radiotherapy alone versus cisplatin-based concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: An open-label, non-inferiority, randomized phase 3 trial.

6001 Background: Cisplatin-based concurrent chemoradiotherapy (CCRT) has long been regarded as standard treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) due to its favorable local control. However, concurrent platinum is associated with intolerable toxicities and ineffective in preventing distant metastasis. Since IMRT enhances the local control and induction chemotherapy (IC) decreases the risk of distant failure, it is worth exploring whether IC plus IMRT alone regimen could replace CCRT for patients with LA-NPC. Methods: This open-label, phase 3, non-inferiority clinical trial was conducted from June 12, 2015 to April 30, 2019. Patients with stage T1-4N2-3 or T3-4N0-1 M0 NPC were randomly assigned (1:1) to receive gemcitabine (1000 mg/m²) and cisplatin (80 mg/m²) IC for 2 cycles followed by IMRT alone or IMRT plus concomitant weekly cisplatin (40 mg/m²) up to 7 cycles. 2-year failure-free survival was set as primary endpoint and non-inferiority margin of 10% was established. Efficacy analysis and safety analysis were dividedly performed in the intention-to-treat and safety population. Results: A total of 249 patients were enrolled, including 124 patients in IC group and 125 patients in CCRT group. Median follow-up time was 60 months (IQR, 48-71). 2-year failure-free survival was 90.2% in IC group versus 86.3% in CCRT group, with an HR of 0.818 (95% CI, 0.479-1.397) and absolute difference of 3.9% (1-sided 95%CI, -4.2 to 11.9). No significant differences were observed between groups in overall survival, locoregional relapse, or distant metastasis. Compared with CCRT group, fewer grade ≥3 AEs occurred in IC group (47.5% vs 61.5%, p = 0.015), including leucopenia, anemia, mucositis, nausea and dysphagia. The IC group had significantly better QoL during and short periods after IMRT, including domains of global health status, physical functioning, fatigue, nausea and vomiting, pain, and appetite loss. Conclusions: For LA-NPC, gemcitabine and cisplatin induction chemotherapy plus IMRT alone was not inferior in 2-year failure-free survival to concurrent chemoradiotherapy. Clinical trial information: NCT02460887 .

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 .

Incorporation of triapine (T) with cisplatin chemoradiation (CRT) for locally advanced cervical and vaginal cancer: Results from NRG-GY006, a phase III randomized trial.

5502 Background: Definitive cisplatin-based chemoradiation (CRT) plus brachytherapy for locally advanced cervical cancer (FIGO IB3-IVA) results in sustained survival for 60-70% of patients. Recent studies integrating anti-PD-1 checkpoint immunotherapy (CALLA, NCT03830866) or consolidation chemotherapy (OUTBACK, ACTRN12610000732088) have not demonstrated a survival benefit over CRT. Intrinsic overexpression of ribonucleotide reductase may enhance DNA damage repair due to CRT. We report on the efficacy and tolerability of adding the ribonucleotide reductase inhibitor, triapine, to CRT. Methods: NRG GY006 is a randomized, open-label phase III clinical trial. Eligible patients had FIGO 2009 locally advanced cervical (stages IB2, II, IIIB or IVA without radiographic evidence of para-aortic nodal involvement) or stages II-IV vaginal cancer. Patients were randomly assigned to receive cisplatin (40 mg/m2 weekly) with RT 45 Gy + lymph node boost alone (CRT) or CRT in combination with 15 total infusions of triapine (25 mg/m2 IV) Mon/Wed/Fri (CRT + T). Both image guided IMRT or 3D RT were allowed but needed to be specified and pass a rigorous credentialing process. All RT plans had a pre-treatment review with expert planning feedback to the sites. The primary endpoint was overall survival (OS); secondary endpoint was progression-free survival. Exploratory endpoints included rate of complete metabolic response on post treatment PET/CT imaging at 3 months and knowledge-based planning for image guided IMRT. The target sample was 450 with 127 OS events. The design was to provide 80% power to detect a 10% improvement in OS at 3 years over the control (or HR = 0.6) at 2.5% significance level including one interim futility analysis at 50% information time. Results: Between 1/15/16 and 9/22/22 448 eligible patients were randomized to CRT (n=224) or CRT+T (n=224). The database was locked on 10/18/22 with 69 deaths. Median age was 47 years (range 23-85 years). The majority had cervical cancer (93.3%) and squamous cell carcinoma (82%). 52% had FIGO stage II disease. Racial/ethnic distribution included non-Hispanic white (53.8%), Hispanic/Latina (22.5%), and black (15.2%). IMRT was used in (74.3%) and HDR brachytherapy (98.2%) of cases. No differences in Grade 3-5 toxicities were observed: CRT =52% and CRT +T= 49% with Two G5 toxicities (cardiac arrest and acidosis) in the CRT+T arm. 343 patients have completed all protocol directed therapy. With a median follow-up of 28 months (IQR 15-45 months), the median PFS and OS for both arms were not reached yet. HR for death was 1.018 (95% CI 0.634-1.635), the conditional power was 15% to detect a HR = 0.6 at 100% information time. Conclusions: The addition of triapine to CRT did not improve OS. Clinical trial information: NCT02466971 .

Abstract 2800: Pharmacokinetics, bioavailability, and pharmacodynamics of oral triapine

Abstract Background: Locally advanced cervical cancer accounts for most deaths from disease. Standard of care includes treatment with cisplatin-based chemoradiation with a 70% response rate. The addition of intravenous (IV) triapine to chemoradiation has shown promising clinical activity in phase 1 and 2 studies but comes with a more intensive treatment regimen. An ongoing phase 1 trial has finished the escalation phase, and we report the pharmacokinetics (PK) and pharmacodynamics (PD) of oral (PO) triapine. Methods: This phase 1 study followed a 3+3 design for dose escalation of oral triapine, starting with initial dose of 100 mg five days a week for five weeks combined with external beam pelvic radiation and weekly IV cisplatin. PK was determined by LC-MS/MS, and PD included methemoglobin levels at 4 h post dose. Within patient PK variability after IV and PO dosing and PO bioavailability were calculated. Results: PK data were available for 10 patients at 100 (the MTD) and 150 mg. PO parameter values were Tmax 1.3 h, t1/2 1.4 h, CL/F 104 L/h, and Vz/F 214 L. There was no discernable difference between triapine exposure at 100 vs. 150 mg PO (Cmax 520 (2.5) vs. 344 (1.9) µg/L; AUC 1209 (2.53) vs. 1034 (1.41) µg/L•h), and between patient variability at each dose level was substantial. The correlation of PO Vz/F vs Cl/F was high at R2=0.86, suggesting that the apparent clearance and volume variability is primarily due to variability in the oral bioavailability F. PO within patient variability of Cmax and AUC was also large at 43% and 55%. IV PK was less variable with lower geometric standard deviations across all parameters, including within patients where variability of Cmax and AUC was modest at 10 and 12% coefficient of variation, respectively. Oral bioavailability was estimated at 66%. We found a non-significant trend of smoking almost doubling triapine oral clearance from 68 to 156 L/h (p=0.056). There was no apparent relationship between occurrence of DLT and either IV or PO triapine AUC. Methemoglobin levels directly correlated with triapine exposure expressed as AUC or Cmax. Conclusions: Triapine PK parameter values for PO and IV administration and PO bioavailability values observed in this trial were comparable to previous reports. Correlation of methemoglobin with exposure highlights the importance of optimizing triapine exposure. Additional data may support the exploration of a dose specific to current smokers. Citation Format: Jan H. Beumer, Sarah Behr, Holly Gallion, John Vargo, Frederick Ueland, Haider Mahdi, Brian Orr, Eugenia Girda, Susan Christner, Edward Chu, Charles Kunos, Percy S. Ivy, Sarah Taylor. Pharmacokinetics, bioavailability, and pharmacodynamics of oral triapine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2800.

Differential expression of DNA repair genes and treatment outcome of chemoradiotherapy (CRT) in cervical cancer

Cervical cancer (CaCx) is the malignancy of uterine cervix which induce by human papillomavirus (HPV) infections. HPV infection starts with the induction of double-stranded breaks by increasing oxidative stress and modulation of DNA repair pathways. Deficiency in DNA repair pathways and accumulation of DNA damage increases mutation rates resulting in genomic instability and cancer development. Patients with HPV-associated CaCx display increased sensitivity to cisplatin-based chemoradiotherapy (CRT) and improved survival rates. However, the cellular mechanisms responsible for this characteristic difference are unclear. Here, we have evaluated expression of DNA repair genes in peripheral blood cells and correlated them with treatment outcomes. A total of 211 study subjects includes in the study comprised 103 CaCx patients and 108 healthy controls. All the study subjects were analyzed for the expression profile of DNA repair genes by using real-time PCR (RT-PCR). The differentially expressed DNA repair gene was correlated with the treatment outcome of CRT. OGG1, XRCC2, XRCC3, XRCC4 and XRCC6 genes were found to be significant (P = 0.001) down-regulated as compared to controls. While XRCC5 and RAD51 showed significant up-regulated (P = 0.024 and 0.041) in CaCx patients. XRCC6 was associated (P = 0.033) with poor vital while up-regulated RAD51 showed slight association (P = 0.075) with better vital with an increased 2.96- and 2.33-fold risk in the study population. In the case of overall survival, down-regulated XRCC4 was associated (P = 0.042) with poor survival (27 months) with the least hazard ratio (0.56 HR). Down-regulated OGG1 involved BER, XRCC2 and XRCC3 in homologous recombination and XRCC4, XRCC5 and XRCC6 in Non-homologous end-joining repair, which showed a deficiency of DNA repair capacity resulting caused of an accumulation of DNA damage and genome instability. Impaired DNA repair gene expression is responsible for poor prognosis and survival in CaCx. Therefore, these gene expressions can be considered a potential prognostic, diagnostic and therapeutic biomarker for CaCx.

19P Neoadjuvant chemotherapy followed by radical surgery vs chemoradiotherapy in patients with cervical cancer (stage IIB, FIGO 2018)

Improving the results of treatment of patients with stage IIB cervical cancer by introducing the most effective, less toxic chemoradiotherapy at one of the phases of complex or combined treatment. This study based on a prospective analysis of 215 women diagnosed with stage IIB cervical cancer. The median age was 47 years (28-64). The patients were divided into two groups: the NACT+S group, 105 patients who recive 2-3 cycles of neoadjuvant chemotherapy (paclitaxel+carboplatin) followed by surgical treatment. Radiotherapy (1,8 Gy, 45 Gy ± SIB on the metastatically involved lymph nodes 2,2 Gy, 55 Gy) was performed 1-2 months after surgical treatment. Patients also received cycles of cisplatin (40 mg/m2), administered once every week. The second group (CRT group) included 110 patients who underwent radiotherapy (regime was same with NACT+S = 1,8 Gy, 45 Gy ± SIB 2,2 Gy, 55 Gy). Brachytherapy was performed for all patients (6 Gy x 5 fr, to point A 30 Gy). The median follow-up was 23 months (8-38). In the NACT+S group, thrombocytopenia and neutropenia of the 3 - 4 degree were more common than in the CRT group (6.6% and 7.6% vs. 0.9% and 0.9%, respectively; p = 0.026; p = 0.015). However, there was no significant difference between the two groups studied in relation to the 3 - 4 degree of radiation toxicity of the GI and genitourinary system. 26 cases of disease progression (24.8%) occurred in the NACT+S group, and 15 events (13.6%) occurred in the CRT group; the corresponding 3-year DFS rates were 75.2% and 86.4%, respectively (HR 1.83; 95% CI 1.99-3.40; p = 0.05). Nineteen patients (18.1%) died in the NACT+S group, and 18 patients (15.5%) died in the CRT group, with corresponding 3-year indicators of OS was 81.9% and 84.5%, respectively (HR 1.11; 95% CI from 0.58 to 2.14; p = 0.736). Cisplatin-based chemoradiation resulted in superior DFS compared with neoadjuvant chemotherapy followed by radical surgery in locally advanced cervical cancer. In the NACT+S group, thrombocytopenia and neutropenia grade 3 or 4 at a higher rate than in the concomitant CRT group. Despite this, there was no significant difference between the two study groups with 3-year indicators of OS and respect to grade 3 or 4 GI and bladder toxicities.