Cumulative Cisplatin Dose Research Articles

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 > 90 mL/min, while 42% <90 mL/min (only 4 patients with eGFR < 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 > 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 > 90 mL/min and patients with eGFR < 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.

Three Weekly Versus Weekly Cisplatin: Comparison of two Different Chemotherapy Protocols with Concurrent Radiotherapy in Locally Advanced Head and Neck Cancer

Introduction: Chemoradiotherapy (CRT) with concurrent cisplatin-based chemotherapy is the treatment of choice of locally advanced head and neck cancers (LAHNC), but the optimal regimen of cisplatin remains contentious. Though 3-weekly cisplatin is the recommended schedule, it is associated with severe adverse reactions. A lower dose weekly schedule is generally accepted to be more tolerable and is widely used in our country. Methodology: Our study retrospectively compares the 3-weekly and the weekly concurrent cisplatin schedules in patients of LAHNC treated with CRT. Patients were selected for either schedule based on the treating physician’s preference. The two schedules were compared for treatment-related toxicities, radiotherapy interruptions, cumulative cisplatin doses delivered and overall survival (OS) as well as disease-free survival (DFS) at 2 years. Results: In our study, 43 patients received the 3-weekly schedule while 40 received the weekly schedule. Age, gender, disease stage or site did not affect selection for either regimen, except cancers of the nasopharynx and salivary glands, who almost exclusively received the 3-weekly schedule (90.1%). Patients who received adjuvant CRT after radical surgery were more likely to receive the weekly schedule (66.7%) while patients treated with up-front CRT were more often given the 3-weekly schedule (57.6%). Overall, the 3-weekly arm was associated with more toxicities and treatment breaks, but was more successful in delivering an adequate cumulative dose of cisplatin and had a better OS and DFS at 2 years follow up compared to the weekly arm. It also appeared that treating physicians were more likely to withhold one or more of the weekly cycles to manage treatment toxicity which lead to inadequate cumulative dosing in a high (45%) percentage of patients. Conclusion: Our study reiterates that the 3-weekly cisplatin arm has a better outcome profile than the weekly cisplatin arm at the price of increased toxicity. Weekly schedules have lower toxicities but may not achieve outcomes equivalent to 3-weekly unless adequate cumulative doses are achieved. As our study is retrospective and non-randomized, selection bias may have affected our results.

Prognostic Factors for the Therapeutic Performance of Cisplatin in Head and Neck Malignancies.

IntroductionFor squamous cell carcinoma of the head and neck (HNSCC), cisplatin is used as primary or adjuvant (radio)chemotherapy. In terms of dosage, two main regimens are used, weekly 40mg/m2 or 3-weekly 100mg/m2. For an optimal outcome, the highest possible cumulative total dose of cisplatin is aimed for. The selection of the scheme is patient-specific, but the factors for the selection of the optimal scheme have not yet been conclusively researched. The aim of this study was to find correlations between initial laboratory values and the cumulative total dose of cisplatin, as well as any correlations between early laboratory values or their dynamics and later laboratory values or their dynamics to provide support in the selection of the chemo regimen.Material and MethodsIn this retrospective study, the clinical data and laboratory values, namely glomerular filtration rate (GFR), hemoglobin, albumin, leucocyte, erythrocyte and platelet count, over the course of time of 79 patients with HNSCC who had received chemotherapy with cisplatin in our clinic between 2018 and 2021 were evaluated.ResultsPatients on 3-weekly regimens achieved a higher mean cumulative total dose of cisplatin than patients on weekly regimens (214.18 ± 65.95 vs 183.33 ± 65.2 mg/m2). Significant positive correlations were seen for total cumulative dose of cisplatin with initial GFR (p=0.001, Pearson’s r=0.364), initial hemoglobin (p=0.035, r=0.237), initial erythrocyte (p=0.002, r=0.337), and initial albumin (p=0.002, r=0.337). There were no significant correlations for initial leucocyte or platelets. Regarding the dynamics of the laboratory values under the first chemo administration, no correlation was found with later laboratory values or dynamics.Discussion and ConclusionAs in other prospective studies, our retrospective analysis found a higher cumulative total dose in the 3-weekly regimen. As this seems to correlate positively with patient outcome, superiority of the 3-weekly regimen over the weekly regimen can be assumed. Functioning organ systems, especially of the bone marrow and kidneys, are associated with an increased cumulative total dose and can therefore be regarded as predictive factors. Regular monitoring of laboratory values is nevertheless essential throughout the entire course of chemotherapy.

A Single-Arm Phase 2 Trial on Induction Chemotherapy Followed by Concurrent Chemoradiation in Nasopharyngeal Carcinoma Using a Reduced Cumulative Dose of Cisplatin.

BackgroundWe conducted this study to evaluate if a reduced cumulative dose of induction and concurrent cisplatin conferred similar favorable outcomes when compared to trial NPC-0501.MethodsNewly diagnosed nasopharyngeal carcinoma (NPC) with stage III-IVA were prospectively recruited from January 2015 to September 2019. Induction chemotherapy (IC) consisted of cisplatin 80mg/m2 on day 1 and capecitabine 1000mg/m2 twice daily from day 1 to 14 every 3 weeks for 3 cycles followed by concurrent chemoradiotherapy (CCRT) with 2 cycles of cisplatin 100mg/m2 given every 3 weeks. Tumor response was evaluated according to RECIST v1.1. Acute and late adverse events (AEs) were graded with CTCAE v4.0 and Late Radiation Morbidity Scoring of the RTOG, respectively.Results135 patients were recruited. At 16 weeks after CCRT, all 130 patients who completed the entire course of radiotherapy (RT) had a complete response upon final assessment. With a median follow-up of 36.2 months, 22 treatment failures and 8 deaths were observed. The 3-year progression-free survival, overall survival, locoregional recurrence-free survival, and distant recurrence-free survival were 83.7%, 94.1%, 94.1%, and 85.9%, respectively. Our survival data outcomes were similar to those reported in the cisplatin and capecitabine (PX) induction arm of the 0501 trial. 103 patients (76.3%) reported acute grade 3-4 AEs. Two patients (1.5%) had late grade 3-4 complications, numerically fewer than those reported in the NPC-0501 trial.ConclusionsInduction PX and concurrent cisplatin with a reduced cumulative cisplatin dose yield survival outcomes comparable to those reported in the NPC-0501 trial with excellent tolerability. Therefore, a reduced cumulative dose of cisplatin is a promising treatment scheme for nasopharyngeal carcinoma.

Sensorineural Hearing Loss and Cochlear Outer Hair Cell Function Nasopharyngeal Carcinoma Due to Influence of Cisplatin

Background: Nasopharyngeal carcinoma is a type of tumor sensitive to chemotherapy and radiotherapy.One of the various chemotherapy drugs is cisplatin. However, the cisplatin effects on sensorineuralhearing loss and cochlear outer hair cell dysfunction in patients with nasopharyngeal carcinoma have notbeen evidently discovered. Objective: This research aims to prove the cisplatin effects on sensorineuralhearing loss and cochlear outer hair cell dysfunction in patients with nasopharyngeal carcinoma.Materials and Methods: This research adopted analytical observation by employing a prospectivecohort study approach. In addition, the sampling technique implemented consecutive sampling. Thisresearch was conducted at the ENT-HN Outpatient Unit (URJ) of the Neuro-otology Division ofDr.Soetomo Public Hospital during September-November 2020 period. The auditory test was executedby Pure-Tone Audiometry (ANM) and Distortion Product Otoacoustic Emission (DPOAE). Meanwhile,the statistical analysis was assessed by the Wilcoxon and McNemar test. Results: This research involved22 samples. The cumulative dose of cisplatin up to chemotherapy series III ranged from 260-270 mgwith an average of 265.45+5.10 mg. The results of the ANM test before and after chemotherapy seriesIII employing Wilcoxon test indicated significant differences in frequency of 500 Hz (p-value =0.014),6000 Hz (p-value = 0.011), 8000 Hz (p-value = 0.019),10000 Hz (p-value = 0.000), and 12500 Hz(p-value = 0.002). The frequency of 125 Hz with a p-value = 0.343, the frequency of 250 Hz with ap-value = 0.690, the frequency of 1000 Hz with a p-value = 0.179, the frequency of 2000 Hz with ap-value = 0.459, and the frequency of 4000 Hz with a p-value = 0.125 indicated no significant differencewitha p-value greater than 0.05. Meanwhile, the DPOAE test results before and after chemotherapyseries III utilizing the McNemar test demonstratedthe frequency of 1000 Hz (p-value = 1.000), 2,000Hz (p-value = 0.453), 4000 Hz Hz (p-value = 1.000), 6000 Hz (p-value = 0.388), 8000 Hz (p-value =0.754), and 1000 Hz (p-value = 1.000). The comparative analysis of the DPOAE test results before andafter chemotherapy Series 3 suggested no significant difference, with a p-value greater than 0.05 at allfrequencies. Conclusion: There were cisplatin effects on sensorineural hearing loss in patients withnasopharyngeal carcinoma after chemotherapy series 3 based on ANM test at the frequencies of 500Hz, 6000 Hz, 8000 Hz, 10000 Hz, and 12500 Hz. There were no cisplatin effects on cochlear outer haircell dysfunction in patients with nasopharyngeal carcinoma after chemotherapy series 3.

Institutional Comparison between Radiation with Concurrent Cisplatin Versus Carboplatin/paclitaxel for Squamous Cell Carcinoma of the Head and Neck (SCCHN)

<h3>Purpose/Objective(s)</h3> For SCCHN patients receiving definitive chemoradiation or adjuvant chemoradiation, cisplatin is the standard systemic agent. Carboplatin/paclitaxel has been considered as an alternative in cisplatin-ineligible patients. No head-to-head trials have been conducted comparing the two regimens. We present a retrospective single institution data comparing the two regimens in the definitive and post-operative setting. <h3>Materials/Methods</h3> Patients with SCCHN who received at least one dose of cisplatin or carboplatin/paclitaxel were included. We assessed locoregional control (LRC), overall survival (OS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and safety. Descriptive statistics, Kaplan Meier method, Cox proportional hazards model through both univariate and multivariable analysis (MVA) were used. <h3>Results</h3> Among 308 patients, 157 received carboplatin/paclitaxel and 151 received cisplatin. IMRT (90.6%) was primarily utilized and the median total dose of radiation was 70 Gy. Majority were male (78.6%) and Caucasian (76.3%) with a median age of 63. Oropharynx was the most common primary tumor site (53.2%) with 84.7% being HPV positive. Ninety-seven patients (31.5%) underwent surgery; more carboplatin/paclitaxel (34.0%) patients had positive margins versus cisplatin (16%) patients (p = 0.04). Most of the cisplatin patients received weekly 40 mg/m² (78.8%) and the median cumulative cisplatin dose was 240 mg/m². A majority of patients received carboplatin AUC 2 and paclitaxel 45 mg/m² with a median cumulative paclitaxel dose of 270 mg/m². More patients in the carboplatin/paclitaxel (68.2%) group had T3/T4 disease versus cisplatin (55.6%) patients (p = 0.024). By MVA, no statistically significant differences were observed for LRC or OS. However, carboplatin/paclitaxel significantly improved DMFS [HR 0.49 (0.24-0.99) p=0.048] with a 5 year DMFS of 86.5% versus 77.2% in the cisplatin group. A trend favoring carboplatin/paclitaxel was seen for PFS [HR 0.62 (0.36-1.08) p = 0.09]. In the subgroup of surgical patients, DMFS [HR 0.39 (0.14-1.08) p = 0.071] and PFS [HR 0.41 (0.17-0.94) p=0.036] favored carboplatin/paclitaxel. Carboplatin/paclitaxel had higher grade 3/4 toxicities for leukopenia, anemia, and dermatitis and more feeding tube placements and hospitalizations. <h3>Conclusion</h3> Carboplatin/paclitaxel is comparable to cisplatin and may be more beneficial in the post-operative setting. A prospective, randomized trial is needed to determine whether carboplatin/paclitaxel is non-inferior or even superior to cisplatin and to better characterize its safety profile.

Ototoxicity After Cisplatin-Based Chemotherapy: Factors Associated With Discrepancies Between Patient-Reported Outcomes and Audiometric Assessments.

To provide new information on factors associated with discrepancies between patient-reported and audiometrically defined hearing loss (HL) in adult-onset cancer survivors after cisplatin-based chemotherapy (CBCT) and to comprehensively investigate risk factors associated with audiometrically defined HL. A total of 1410 testicular cancer survivors (TCS) ≥6 months post-CBCT underwent comprehensive audiometric assessments (0.25 to 12 kHz) and completed questionnaires. HL severity was defined using American Speech-Language-Hearing Association criteria. Multivariable multinomial regression identified factors associated with discrepancies between patient-reported and audiometrically defined HL and multivariable ordinal regression evaluated factors associated with the latter. Overall, 34.8% of TCS self-reported HL. Among TCS without tinnitus, those with audiometrically defined HL at only extended high frequencies (EHFs) (10 to 12 kHz) (17.8%) or at both EHFs and standard frequencies (0.25 to 8 kHz) (23.4%) were significantly more likely to self-report HL than those with no audiometrically defined HL (8.1%) [odds ratio (OR) = 2.48; 95% confidence interval (CI), 1.31 to 4.68; and OR = 3.49; 95% CI, 1.89 to 6.44, respectively]. Older age (OR = 1.09; 95% CI, 1.07 to 1.11, p < 0.0001), absence of prior noise exposure (OR = 1.40; 95% CI, 1.06 to 1.84, p = 0.02), mixed/conductive HL (OR = 2.01; 95% CI, 1.34 to 3.02, p = 0.0007), no hearing aid use (OR = 5.64; 95% CI, 1.84 to 17.32, p = 0.003), and lower education (OR = 2.12; 95% CI, 1.23 to 3.67, p = 0.007 for high school or less education versus postgraduate education) were associated with greater underestimation of audiometrically defined HL severity, while tinnitus was associated with greater overestimation (OR = 4.65; 95% CI, 2.64 to 8.20 for a little tinnitus, OR = 5.87; 95% CI, 2.65 to 13.04 for quite a bit tinnitus, and OR = 10.57; 95% CI, 4.91 to 22.79 for very much tinnitus p < 0.0001). Older age (OR = 1.13; 95% CI, 1.12 to 1.15, p < 0.0001), cumulative cisplatin dose (>300 mg/m2, OR = 1.47; 95% CI, 1.21 to 1.80, p = 0.0001), and hypertension (OR = 1.80; 95% CI, 1.28 to 2.52, p = 0.0007) were associated with greater American Speech-Language-Hearing Association-defined HL severity, whereas postgraduate education (OR = 0.58; 95% CI, 0.40 to 0.85, p = 0.005) was associated with less severe HL. Discrepancies between patient-reported and audiometrically defined HL after CBCT are due to several factors. For survivors who self-report HL but have normal audiometric findings at standard frequencies, referral to an audiologist for additional testing and inclusion of EHFs in audiometric assessments should be considered.

Ototoxicity and long-term hearing outcome in pediatric patients receiving cisplatin

Hearing is essential in child development. Cisplatin which is a common chemotherapy used in many pediatric solid-tumor protocols cause various degrees of ototoxicity. Several risk factors for cisplatininduced ototoxicity have been reported, including race and age. This study aimed to evaluate the incidence of ototoxicity and its long-term outcome in Thai pediatric solid-tumor patients receiving cisplatin and to determine the risk factors associated with hearing impairment. A retrospective study was conducted in solid-tumor patients < 15 years old from 2007 to 2019 at Siriraj Hospital, Bangkok, Thailand. Hearing was evaluated by an audiogram and/or auditory steady-state response and the impairment was graded according to the Common Terminology Criteria for Adverse Events version 5. Grade 2 and above was considered significant hearing loss. In total, the hearing of 47 patients was evaluated. At the end of treatment, hearing impairment and significant hearing loss were found in 66% and 48.9% of patients, respectively. A high median cumulative cisplatin dose was significantly associated with worse hearing impairment (p = 0.039) and a more progressive grading of ototoxicity (p = 0.005). A risk factor for significant hearing loss was a cumulative dose ≥400 mg/m2 (p = 0.014). All 9 patients who received a cumulative dose > 600 mg/m2 and 5 patients who received aminoglycoside developed significant hearing loss. One patient had progressive hearing impairment at 8 months after the end of treatment and 1 patient developed grade 3 ototoxicity which required a hearing aid after bone marrow transplantation. The latter patient received a total cisplatin dose of 708.2 mg/m < sup > 2 < /sup > and carboplatin 1400 mg/m < sup > 2 < /sup > . The incidence of hearing impairment in pediatric patients receiving cisplatin is high. Regular hearing evaluation is essential for the early detection of ototoxicity. Long-term follow-up is recommended, especially in patients who have a combination of other risk factors for hearing loss.

Semen and serum platinum levels in cisplatin-treated survivors of germ cell cancer.

BackgroundTesticular cancer survivors often have impaired gonadal function possibly related to chemotherapy. Platinum is a heavy metal that can be detected at low levels in serum many years after treatment, it is not known whether platinum also persists in semen and if platinum persistence in semen is associated with impaired fertility.MethodsAdult cisplatin‐treated testicular cancer survivors were enrolled. High‐Performance Liquid Chromatography‐tandem mass spectrometry was used to measure semen and serum platinum levels. Semen quality and DNA Fragmentation Index (DFI) were assessed.ResultsFrom 11/2017 to 12/2019, 38 patients (median age 32 years; range: 19–52) were enrolled. Median cumulative cisplatin dose was 301 mg/m2 (range: 274–404). Platinum levels were higher in semen than in blood (p = 0.03). Semen platinum levels were not significantly associated with time from last cisplatin dosing (r = −0.34; p = 0.09) nor cumulative dose (r = −0.10, p = 0.63). Sperm concentration was correlated with time from last cisplatin dosing (r = 0.58, p < 0.001) but not with semen platinum level (r = −0.15, p = 0.46). DFI was not significantly associated with time from last cisplatin dosing (r = 0.55, p = 0.08) or semen platinum level (r = −0.32, p = 0.33). In four patients with serial semen samples, platinum level decreased and sperm concentration and motility increased over time.ConclusionsPlatinum is detected in semen of testicular cancer survivors at higher levels than matched blood samples. These preliminary findings may have important implications for the reproductive health of survivors of advanced testicular cancer, further study is needed to assess the relationship between platinum persistence in semen and recovery of fertility postchemotherapy.

Efficiency of high cumulative cisplatin dose in high- and low-risk patients with locoregionally advanced nasopharyngeal carcinoma.

BackgroundThe optimal cumulative cisplatin dose (CCD) during radiation therapy for locoregionally advanced nasopharyngeal carcinoma (LA‐NPC) patients receiving induction chemotherapy (IC) plus CCRT remains controversial. This study aimed to explore the treatment efficiency of CCD for high‐and low‐risk patients with LA‐NPC.MethodsData from 472 LA‐NPC patients diagnosed from 2014 to 2018 and treated with IC plus CCRT were reviewed. After propensity score matching, the therapeutic effects of a CCD > 200 and CCD ≤ 200 mg/m2 were evaluated comparatively. Five factors selected by multivariate analysis were incorporated to develop a nomogram. Subgroup analysis was conducted to explore the role of different CCDs in nomogram‐defined high‐ and low‐risk groups. Additionally, acute toxicities were evaluated comparatively between the high‐ and low‐CCD groups.ResultsAfter matching, there was no difference between different CCD groups for all patients in terms of 3‐year overall survival (OS), distant metastasis‐free survival (DMFS), locoregional recurrence‐free survival (LRRFS), or progression‐free survival (PFS). A nomogram was built by integrating pretreatment EBV DNA, clinical stage, and post‐IC EBV DNA, post‐IC primary gross tumor and lymph node volumes obtained a C‐index of 0.674. The high‐risk group determined by the nomogram had poorer 3‐year PFS, OS, DMFS, and LRRFS than the low‐risk group. A total of CCD > 200 mg/m2 increased the survival rates of 3‐year PFS and DMFS (PFS: 72.5% vs. 54.4%, p = 0.012; DMFS: 81.9% vs. 61.5%, p = 0.014) in the high‐risk group but not in the low‐risk group. Moreover, the high CCD increased treatment‐related acute toxicities.ConclusionsA high CCD was associated with better 3‐year PFS and DMFS rates than a low dose for high‐risk patients but could not produce a survival benefit for low‐risk patients.

Correlation Between Higher Cumulative Dose of Cisplatin for Concurrent Chemoradiation and Acute Kidney Disease Incidence Among Nasopharyngeal Carcinoma Patients: A Comparative Study.

IntroductionNasopharyngeal carcinoma (NPC) is the most malignant cancer in the head and neck area. According to the stage, the management of NPC includes radiation, chemotherapy, or a combination of both. The standard agent for radiosensitizing chemotherapy is cisplatin. Among the several effects of cisplatin administration, nephrotoxicity raises the most concern, especially in high doses. Acute kidney disease (AKD) is a condition in which an acute kidney injury occurs at >7 days but <90 days. This study aimed to assess whether there is a significant difference in the incidence of AKD between NPC patients who received a cumulative dose of cisplatin up to (≤) 200 mg/m2 and patients who received more than (>) 200 mg/m2.MethodsThis is a cohort retrospective study conducted in the radiotherapy unit of Cipto Mangunkusumo General Hospital. Medical records of 540 patients from January 2014 to December 2018 were collected and sorted. After sorting, 120 of the records were analyzed.ResultsThe analysis showed that 38.4% of patients who received >200 mg/m2 cumulative dose of cisplatin experienced AKD, whereas 38.3% of the patients who received ≤200 mg/m2 cumulative dose of cisplatin experienced AKD.ConclusionThis study found that in patients with locally advanced NPC who received cisplatin chemoradiation, there was no significant difference in the incidence of AKD, recovery of renal function, or progression of chronic kidney disease between patients receiving a cumulative dose of cisplatin ≤200 mg/m2 and those receiving >200 mg/m2.

Development of a web-based prognostic model to quantify the survival benefit of cumulative cisplatin dose during concurrent chemoradiotherapy in childhood nasopharyngeal carcinoma

PurposeTo quantify and predict the survival benefits of cumulative cisplatin dose during concurrent chemoradiotherapy (CC-CCD) in children and adolescents with locoregionally advanced nasopharyngeal carcinoma (CA-LANPC). Materials and MethodsPatients with CA-LANPC who received first-line neoadjuvant chemotherapy (NAC) followed by concurrent chemoradiotherapy (CCRT) between September 2007 and April 2018 were evaluated. Recursive partitioning analyses (RPAs) helped identify the ideal thresholds of CC-CCD on disease-free survival (DFS). We then developed a web-based predictive model to quantify the survival benefit of CC-CCD for CA-LANPC. ResultsIn total, 139 patients were eligible for the analysis. The median CC-CCD was 162 mg/m2 (IQR, 138–192 mg/m2). The optimum cut-off point of CC-CCD was 160 mg/m2 for DFS. Hence, we selected 160 mg/m2 as the cut-off to classify CA-LANPC into either high or low CC-CCD groups for survival analysis. The 5-year DFS rates were 91.6% in the high (≥160 mg/m2) CC-CCD group and 77.8% in the low (<160 mg/m2) CC-CCD group (P = 0.011). Multivariate analysis indicated CC-CCD (HR, 0.34; 95%CI, 0.13–0.87; P = 0.024), T stage (HR, 3.72; 95%CI, 1.35–10.22; P = 0.011), and EBV DNA (HR, 3.00; 95%CI, 1.00–8.97; P = 0.049) were independent prognostic factors and were incorporated into the prognostic model. N stage was also included due to its clinical importance. The predictive model was demonstrably accurate (C-index, 0.741) when predicting 5-year DFS rates. ConclusionsWe built a predictive model to quantify the survival benefit of CC-CCD for CA-LANPC treated with NAC plus CCRT. This tool may improve individual treatment consultations and facilitate evidence-based decision-making.

Impact of cumulative cisplatin dose in childhood nasopharyngeal carcinoma based on neoadjuvant chemotherapy response in the intensity-modulated radiotherapy era: a real-world study

BackgroundWe aimed to comprehensively investigate the optimal cumulative cisplatin dose during concurrent chemoradiotherapy (CC-CCD) for locoregionally advanced nasopharyngeal carcinoma (CA-LANPC) with different tumor responses after neoadjuvant chemotherapy (NAC).MethodsPatients with CA-LANPC who underwent NAC followed by cisplatin-based concurrent chemoradiotherapy were retrospectively analyzed. Evaluation of tumor response in patients was conducted by Response Evaluation Criteria for Solid Tumor (RECIST) 1.1 after two to four cycles NAC. Multivariate Cox proportional hazards models were used for prognosis. Recursive partitioning analysis (RPA) was conducted to classify participates and predict disease-free survival (DFS).ResultsOne hundred and thirty-two patients with favorable response after NAC were included. The median CC-CCD was 163 mg/m2 (IQR, 145–194 mg/m2), and 160 mg/m2 was selected as the cutoff point to group patients into low and high CC-CCD groups (< 160 vs. ≥ 160 mg/m2). There was significant improvement in 5-year DFS (91.2% vs. 72.6%; P = 0.003) for patients receiving high CC-CCD compared to those receiving low CC-CCD. Multivariate analysis revealed that CC-CCD, T stage, and Epstein–Barr virus (EBV) DNA were independent prognostic factors for DFS (P < 0.05 for all). Patients were further categorized into two prognostic groups by RPA: the low-risk group (T1-3 disease with regardless of EBV DNA, and T4 disease with EBV DNA < 4000 copy/mL), and the high-risk group (T4 disease with EBV DNA ≥ 4000 copy/mL). Significant 5-year DFS improvement was observed for the high-risk group (P = 0.004) with high CC-CCD. However, DFS improvement was relatively insignificant in the low-risk group (P = 0.073).ConclusionsCC-CCD was a positive prognostic factor for responders after NAC in CA-LANPC. Furthermore, CC-CCD ≥ 160 mg/m2 could significantly improve DFS in the high-risk group with CA-LANPC, but the benefit of high CC-CCD in the low-risk group needs further study.

The association of pretreatment low skeletal muscle mass with chemotherapy dose-limiting toxicity in patients with head and neck cancer undergoing primary chemoradiotherapy with high-dose cisplatin.

BackgroundLow skeletal muscle mass (SMM) is an adverse prognostic factor for chemotherapy dose‐limiting toxicity (CDLT). In patients with locally advanced head and neck squamous cell carcinoma (HNSCC) undergoing chemoradiotherapy (CRT), low SMM is a predictor for CDLT. We aimed to validate these findings.MethodsConsecutive LA‐HNSCC patients treated with primary CRT with high‐dose cisplatin were retrospectively included. SMM was measured on pre‐treatment CT‐imaging. A cumulative cisplatin dose below 200 mg/m2 was defined as CDLT.ResultsOne hundred and fifty three patients were included; 37 (24.2%) experienced CDLT, and 84 had low SMM (54.9%). Patients with low SMM experienced more CDLT than patients with normal SMM (35.7% vs. 10.1%, p < 0.01). Low SMM (OR 3.99 [95% CI 1.56–10.23], p = 0.01) and an eGFR of 60–70 ml/min (OR 5.40 [95% CI 1.57–18.65], p < 0.01) were predictors for CDLT.ConclusionPre‐treatment low SMM is associated with CDLT in LA‐HNSCC patients treated with primary CRT. Routine SMM assessment may allow for CDLT risk assessment and treatment optimization.

Neutrophil to apolipoprotein A-I ratio as an independent indicator of locally advanced nasopharyngeal carcinoma.

PurposeTo explore the peripheral blood cells (neutrophil/monocyte/lymphocyte/platelet) to apolipoprotein AI or high‐density lipoprotein‐cholesterol ratio (NAR, MAR, LAR, PAR, NHR, MHR, LHR, and PHR) as independent prognostic indicators for stage III nasopharyngeal carcinoma (NPC).Patients and methodsBetween 2009 and 2014, 562 patients diagnosed with stage III NPC who were treated with a concomitant chemotherapy and intensity‐modulated radiotherapy with cumulative cisplatin dose ≥200 mg/m2 were included in this retrospective study. Routine blood and biochemical variables and baseline clinical characteristics (T and N stage, age, sex, and induction chemotherapy) were collected. After inserting 19 hematological parameters into a set, we applied the least absolute shrinkage and selection operator (LASSO) algorithm and restricted cubic splines regression to select valuable parameters for predicting 5‐year overall survival (OS). Subsequently, univariate and multivariate survival analyses were used to assess independent indicators of 5‐year OS, distant metastasis survival, regional recurrence‐free survival (RRFS), and disease‐free survival.ResultsNAR, MAR, serum lactated dehydrogenase (LDH), and Epstein‐Barr virus (EBV)‐DNA were selected using LASSO regression, and the optimal cut‐off values for NAR, MAR, EBV‐DNA, and, LDH were 4.39, 0.3, 1590 copies/mL, and 218.4 IU/L, respectively. In multivariate survival analysis, higher NAR was associated with both poor 5‐year OS and RRFS (hazard ratio [HR], 1.88; 95% confidence interval [CI], 1.09‐3.25, P = .024; HR, 3.13; 95% CI, 1.42‐6.91, P = .005, respectively).ConclusionNAR could be an attractive indicator for evaluating the 5‐year OS in patients with stage III NPC, which is closely related to inflammation and circulating lipid metabolism.Level of Evidence: 4

Long-term morbidity and mortality in 2-year hepatoblastoma survivors treated with SIOPEL risk-adapted strategies.

Prognosis of hepatoblastoma patients has increased with cisplatin-based chemotherapy and high-quality resection including liver transplant. Consequently current risk-adapted therapeutic strategy aims to reduce long-term side effects in patients with standard risk disease. We report long-term mortality and morbidity data concerning 151 2-year hepatoblastoma survivors treated with SIOPEL risk-adapted strategies (sex-ratio M/F = 1.6, median age at diagnosis = 2.6years [range 0-17.7], median year at diagnosis = 2008 [1994-2017]). Fifty-three patients had loco-regional risk factors VPEFR, 12 were PRETEXT-IV and 30 were metastatic. All received cisplatin and 84 anthracyclines. Twelve had liver transplant. To assess hearing, renal and cardiac functions, audiograms were performed in 116/151 patients (76.8%), glomerular filtration rate in 113/151 (74.8%) and cardiac ultrasound in 65/84 (77.4%) anthracycline-exposed patients. With a median follow-up of 9.4years (range 2.1-25.8), four late relapses, one second malignancy (Acute Myeloid Leukemia AML-M5) and two deaths (one from hepatoblastoma, one from AML) occurred. The 10-years event free survival and overall survival probabilities were 95.5% (95% CI 91.9-99.1) and 98.7% (95% CI 96.8-100), respectively. Sixty-eight non-oncologic health-events included 57 cases of hearing loss (including 25 Brock 3-4), three liver cirrhosis, three pre-operative portal cavernoma, two focal nodular hyperplasia, two grade-1 chronic kidney diseases and one asymptomatic cardiac dysfunction were reported. Ototoxicity was significantly associated with cisplatin cumulative dose (OR = 2.07, 95% CI 1.32-3.24, p = 0.001) and carboplatin exposure (OR = 3.14, 95% CI 1.30-7.58, p = 0.01) in multivariable analysis adjusted for sex and age at diagnosis. With current risk-adapted strategies, hepatoblastoma is a highly curable disease, with very rare relapses, and few late effects except hearing loss which remains a serious condition in these very young patients.

The cumulative incidence of cisplatin-induced hearing loss in young children is higher and develops at an early stage during therapy compared with older children based on 2052 audiological assessments.

Ototoxicity is a common adverse event of cisplatin treatment. The authors investigated the development of cisplatin-induced hearing loss (CIHL) over time in children with cancer by age and examined the influence of other clinical characteristics on the course of CIHL. Data from Canadian patients with childhood cancer were retrospectively reviewed. Hearing loss was graded according to International Society of Pediatric Oncology criteria. The Kaplan-Meier method was applied to estimate the cumulative incidence of CIHL for the total cohort and according to age. Cox regression models were used to explore the effects of independent variables on CIHL development up to 3 years after the start of therapy. In total, 368 patients with 2052 audiological assessments were included. Three years after initiating therapy, the cumulative incidence of CIHL was highest in patients aged ≤5 years (75%; 95% confidence interval [CI], 66%-84%), with a rapid increase observed to 27% (95% CI, 21%-35%) at 3 months and to 61% (95% CI, 53%-69%) at 1 year, compared with patients aged >5 years (48%; 95% CI, 37%-62%; P < .001). The total cumulative dose of cisplatin at 3 months (per 100 mg/m2 increase: hazard ratio [HR], 1.20; 95% CI, 1.01-1.41) vincristine (HR, 2.87; 95% CI, 1.89-4.36) and the total duration of concomitantly administered antibiotics (>30 days: HR, 1.85; 95% CI, 1.17-2.95) further influenced CIHL development over time. In young children, the cumulative incidence of CIHL is higher compared with that in older children and develops early during therapy. The course of CIHL is further influenced by the total cumulative dose of cisplatin and other ototoxic (co-)medication. These results highlight the need for audiological monitoring at each cisplatin cycle.

Relative contributions of radiation and cisplatin-based chemotherapy to sensorineural hearing loss in head-and-neck cancer patients

Background One of the debilitating complications of head and neck cancer radiotherapy is hearing loss. Objective To quantify the magnitude of sensory neural hearing loss (SNHL) in the head and neck cancer patients undergoing chemoradiation therapy. Design and methods This is a prospective study. Eighty patients with head and neck cancers and undergoing volumetric arc therapy were taken up for the study. Regular audiological evaluation was done. The changes in audiological parameters from baseline are correlated with cochlear dose. Results Cochlea received maximum doses of up to 28.52 Gy without causing SNHL in the absence of chemotherapy. But in concurrent chemoradiotherapy, hearing loss was found at least dose of 9 Gy at frequency range of 4 KHz–8 KHz. The risk of SNHL is independent of cumulative doses of Cisplatin. In 106 ears receiving concurrent chemoradiation, 82.1% and 74.5% ears had sensorineural hearing loss at 4 KHz and 8 KHz respectively, following the completion of treatment. Otoacoustic emissions in the chemoradiation group showed a significant change at the completion of treatment. Conclusion and significance Volumetric arc therapy have facilitated sparing of cochlea (< 40 Gy). This has resulted in better clinical outcome in terms of SNHL. The inclusion of concurrent cisplatin chemotherapy is a significant risk factor for the development of SNHL at higher frequencies.

Evaluation of acute and chronic nephrotoxicity in patients received cisplatin-based chemotherapy: has anything changed over time?

The aim of this study was to determine the frequency and the risk factors of acute and chronic nephrotoxicity in patients who received cisplatin due to malignancy. Medical records of all patients who received cisplatin-based chemotherapy regimen between January 2013 and July 2019 were retrospectively evaluated. The data of 203 patients who met the study criteria were examined. The patients were evaluated for acute nephrotoxicity at 48h and late nephrotoxicity at 3rd month after first course of cisplatin. Early and late nephrotoxicity were defined by NCI CTCAE Version 4.0 criteria. The mean age of the study patients was 56.44 ± 12.69years, 78.8% were males and 21.2% were females. It is revealed that the incidence of cisplatin-induced acute nephrotoxicity was 9.2% and chronic nephrotoxicity was 37.9%. While the development of acute nephrotoxicity was associatedwith female gender, history of diabetes mellitus, history of ischemic heart disease and use of antiplatelet drug, the development of chronic nephrotoxicity was associatedwith older age, female gender and using of diuretics. High serum creatinine, urea and low eGFR value before treatment were found to be associated with both early and late nephrotoxicity (p < 0.05). There was no statistically significant relationship between acute or chronic nephrotoxicity and cumulative dose of cisplatin, hydration or intravenous magnesium supplementation. High initial serum creatinine value and low initial eGFR are the most important determinants of both early and late nephrotoxicity.

Chemoradiotherapy with high-dose cisplatin compared with weekly cisplatin for locally advanced head and neck squamous cell carcinoma.

Concurrent chemoradiotherapy (CRT) using high-dose cisplatin (HDC) is standard for patients with locally advanced head and neck squamous cell carcinoma (HNSCC); weekly cisplatin (WC) is an alternative. We aim to compare retrospectively the survival and disease control outcomes between these regimens in our institutional experience. Patients with stage III-IV HNSCC treated with definitive or postoperative CRT between 2012 and 2018 were identified. Patients were stratified by intent-to-treat CRT. Overall survival (OS) and disease-free survival (DFS) were generated and multivariable Cox models were performed. 193 patients were treated with concurrent HDC (n=69), WC at 40mg/m2 (WC40, n=88) or WC at <40mg/m2 (WC<40, n=36). Treatment intent was definitive in 74% and adjuvant in 26%. Baseline differences included age, performance status and HPV status. Cumulative cisplatin dose ≥200mg/m2 was achieved in 89% (HDC), 86% (WC40) and 25% (WC<40, P<0.0001). For HDC, WC40 and WC<40, 2-year OS rates were 87%, 77%, 60% and 2-year DFS rates were 75%, 68% and 52%, respectively. Multivariable analysis revealed gender, performance status, primary site, T/N stage and chemotherapy as predictive of OS. Primary site, T/N stage and chemotherapy regimen were associated with DFS. Compared with HDC, no differences in locoregional control (LRC) or distant metastasis were observed between groups. Concurrent HDC is associated with increased total cisplatin intensity, OS and DFS compared with weekly cisplatin regimens. LRC was not associated with chemotherapy regimen. HDC remains the standard of care; WC40 is a reasonable alternative that does not appear to sacrifice LRC.