Cisplatin Chemotherapy Research Articles

The effect of combined TPF and intensity modulated radiotherapy after TPF induction chemotherapy on locally advanced nasopharyngeal carcinoma: a retrospective analysis.

To evaluate the efficacy and toxicity of docetaxel, cisplatin, and fluorouracil (TPF) regimen followed by intensity modulated radiotherapy (IMRT) on locally advanced nasopharyngeal carcinoma (NPC). A total of 150 patients with locally advanced NPC [American Joint Committee on Cancer (AJCC) 2009 stage IIIa-IVb] received 2 or 3 cycles of a TPF regimen as induction chemotherapy. A group of 67 participants (TPF group) continued to receive TPF chemotherapy and radiotherapy, and the remaining 83 participants (P group) received cisplatin chemotherapy and radiotherapy. A median follow-up of 35 months (4-66 months) showed that there was no significant difference between P group and TPF group in progression-free survival (PFS) and overall survival (OS). The incidence rate of myelosuppression at 3-4 degrees was 16.9% and 34.3% in the P group and TPF group (P=0.029), respectively, and the oral mucosa reaction at 3-4 degrees was 18.1% and 37.3% in the P group and TPF group, respectively (P=0.007). The 3-4-degree skin reaction in the P group and TPF group was 15.7% and 29.9% (P=0.030), respectively. The rate of liver function injury in the P group was significantly lower than that in TPF group (P<0.05). Compared with concurrent cisplatin chemotherapy and radiotherapy, the concurrent TPF regimen and IMRT showed no significant improvement in OS and PFS in patients with advanced NPC, but exhibited more severe hematologic toxicity, oral mucosal responses, skin reactions, and liver functional impairment.

MELATONIN ATTENUATES TESTICULAR DYSFUNCTION AND SPERM DAMAGE INDUCED BY CHEMOTHERAPY REGIMEN BASED ON BLEOMYCIN, ETOPOSIDE, AND CISPLATIN (BEP): AN EXPERIMENTAL STUDY

To determine the protective effects of exogenous melatonin following exposure to Bleomycin, Etoposide, and Cisplatin (BEP) chemotherapy on sperm parameters and DNA integrity, testes nitro-oxidative status, as well as on histopathological, inflammatory, and apoptotic alternations in rats testes.

Chronic Kidney Disease in Cancer Survivors.

As breakthroughs in cancer care are leading to improved long-term outcomes in a subset of advanced cancers, there is a growing population of long-term cancer survivors that are at risk of long-term complications. In this review, we summarize what is known about chronic kidney disease in cancer survivors, focusing on the following high-risk groups: survivors of childhood cancers, stem cell transplant recipients, patients with renal cell carcinoma, patients exposed to cisplatin and other nephrotoxic chemotherapies, and patients receiving immunotherapy for cancer. As new anticancer therapies are developed, more research is needed to understand the long-term risks of kidney function decline and to devise methods to prevent chronic kidney disease.

Efficacy and Safety of Gemcitabine Plus Cisplatin as Potential Preoperative Chemotherapy in Locally Advanced Intrahepatic, Perihilar, and Mid-Cholangiocarcinoma: A Retrospective Cohort Study.

In this retrospective cohort study, the potential of gemcitabine (gem)/cisplatin (cis) chemotherapy as future preoperative therapy for patients with unresectable locally advanced or borderline resectable intrahepatic, perihilar, and mid-cholangiocarcinoma was investigated. All patients with intrahepatic, perihilar, and mid-cholangiocarcinoma presented at Amsterdam UMC between January 2016 and October 2019 were included. The radiologic response after 3 and/or 6 cycles of gem/cis chemotherapy in patients with unresectable locally advanced or borderline resectable disease was derived from the original radiologic reports and subsequently re-evaluated for surgical exploration by consensus reading of 2 HPB surgeons and 1 radiologist. Overall, 65 of 364 patients had a locally advanced or borderline resectable disease. Twenty-eight patients were treated with palliative chemotherapy, including 25 (89.3%) patients who received more than 3 cycles. Twenty-two patients (88.0%) and 13 patients (46.4%) showed RECIST stable disease or partial response after 3 and 6 cycles of chemotherapy, respectively. Three patients experienced grade 3 adverse events. Consensus reading concluded that exploration could have been reconsidered in 7 of 28 patients (25.0%). Gem/cis may be a safe and feasible preoperative treatment in initially unresectable locally advanced or borderline resectable cholangiocarcinoma. In addition, the findings of this study support to always rediscuss patients with stable or responsive disease in multidisciplinary team meetings to reconsider resection. Besides, prospective studies are needed to investigate this effect further and, based on these preliminary data, seem feasible in this setting.

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.

ANTIMICROBIAL THERAPY DURING CANCER TREATMENT: A CASE REPORT

Introduction. Penile cancer (pc) is a rare cancer. The standardized incidence rate of pc in russia is 0.82 cases per 100,000 males. On average, 58 % of patients (20–96 %) with pc have a local infection process: tumor decay, the presence of erosion, tumor ulceration, inflammatory changes in regional lymph nodes, etc. During hospitalization nosocomial pathogens may be possible causes of infection in ulcerative lesions.The aim of the study was to present the results of the treatment of tumor ulcer in a patient with penile cancer infected with multiresistant acinetobacter baumannii and klebsiella pneumoniae.Material and methods. We present a clinical observation of 54-year-old patient diagnosed with penile cancer pt4n3m0, with ulceration of the tumor, localized at the root of the penis and ulceration of metastatic lymph nodes in the left inguinal region and subsequent infection with highly resistant nosocomial microorganisms.Results. The patient received 6 courses of paclitaxel, ifosfamide and cisplatin with clinical effect, such as significant reduction of the tumor and therapeutic pathomorphosis of 3-rd degree. Then ileo-inguinal lymphadenectomy was performed on the left. A few months later the tumor continued to grow in the left groin area. During the 2nd line of chemotherapy (cisplatin, docetaxel and capecitabine), the patient had grade iii–iv neutropenia, febrile neutropenia. High fever and localized infection in the area of tumor ulceration with multiresistant hospital microorganisms was detected. Combined antibiotic therapy had temporary effect. After isolation of multiresistant carbapenemresistant k. Pneumoniae from the ulcer, the patient was prescribed ceftazidim/avibactam 2.5 g 3 times a day. Clinical effect, such as defervescence and significant reduction of the ulceration zone was seen subsequently.Conclusion. Etiotropic antibacterial therapy of the infected tumor ulcer resulted in a significant reduction in the manifestation of the infection process, allowing antitumor therapy to be continued, as well as surgery to be performed.

English

BACKGROUND Chemotherapy-induced nausea and vomiting (CINV) is a frequent and feared adverse effect of cancer chemotherapy. International guidelines recommend combinations of 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, dexamethasone, and/or neurokinin-1 (NK1) receptor antagonists for the control of CINV in patients receiving highly emetogenic chemotherapy (HEC) as a part of their treatment. Even though, nausea in delayed period is less controlled and poses a major concern for these patients. METHODS This open label, prospective study was conducted in a rural medical college in Etawah District in Uttar Pradesh, India from November 2017 to November 2018 over a period of 1 year to observe the efficacy of low dose (5 mg OD) olanzapine in combination with standard anti-emetic regimen for the prevention of CINV. Olanzapine is a food and drug administration (FDA) approved antipsychotic drug that has anti-emetic activity and has shown to improve CINV. Low dose olanzapine along with a standard combination of ondansetron, dexamethasone and aprepitant was given to patients receiving highly emetogenic chemotherapy (Cisplatin &gt;70 mg/m2 or doxorubicin-cyclophosphamide combination). CINV was assessed using common toxicity criteria of adverse events (CTCAE) version 5.0. RESULTS Complete response to nausea was observed in 90.90 %, 60.60 % and 54.54 % in acute, delayed and overall period respectively. Complete response to vomiting was observed in 96.96 %, 69.69 % and 66.66 % in acute, delayed and overall period respectively. Complete response to Grade-2 (or above) nausea was observed in 96.96 %, 93.93 % and 90.90 % in acute, delayed and overall period, respectively. Daytime Grade -3 somnolence which was seen in 2/33 patients (6.06 %) was attributable to olanzapine. Patients receiving olanzapine were more likely to have complete response of nausea and emesis in the early, late, and overall assessment periods especially of higher grade (G2 and G3). CONCLUSIONS The authors concluded that low dose olanzapine 5 mg OD combined with an NK1- receptor antagonist, a 5-HT3–receptor antagonist, and dexamethasone is safe and efficacious in the prevention of CINV in patients receiving HEC. KEYWORDS Olanzapine, Low Dose, CINV, HEC

Transformable amyloid-beta mimetic peptide amphiphiles for lysosomal disruption in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is the largest contributor to cancer mortality in the United States. Traditional chemotherapies are toxic and prone to the development of drug-resistance. Recently, several drug candidates were shown to induce lysosomal membrane permeabilization (LMP) in aggressive cancers. This has led to increased interest in lysosome dysregulation as a therapeutic target. However, approaches are needed to overcome two limitations of current lysosomal inhibitors: low specificity and potency. Here, we report the development of a transformable nanomaterial which is triggered to induce LMP of lysosomes in NSCLC. The nanomaterial consists of peptide amphiphiles, which self-assemble into nanoparticles, colocalize with the lysosome, and change conformation to nanofibrils due to lysosomal pH shift, which leads to the disruption of the lysosome, cell death, and cisplatin sensitization. We have found that this cell-penetrating transformable peptide nanoparticle (CPTNP) was cytotoxic to NSCLC cells in the low-micromolar range and it synergized cisplatin cytotoxicity four-fold. Moreover, we demonstrate CPTNP's promising antitumor effect in mouse xenograft models with limited toxicity when given in combination with low dose cisplatin chemotherapy. This is the first example of enhanced LMP via transformable peptide nanomaterial and offers a promising new strategy for cancer therapy.

A meta-analysis comparing the efficacy and safety of gemcitabine plus cisplatin induction chemotherapy in patients with locoregionally advanced NPC.

Nasopharyngeal carcinoma (NPC) is a malignant tumor endangering human health. Gemcitabine or cisplatin chemotherapy has been regarded as effective treatment for patients with locoregionally advanced NPC. However, the effect of gemcitabine plus cisplatin concurrent chemoradiotherapy (CCRT) remained controversial among the studies. Therefore, we conducted this meta-analysis to assess the efficacy and safety of induction chemotherapy by gemcitabine and cisplatin (GP regimen) in patients with locoregionally advanced NPC. A systematic literature search was performed using PubMed, Web of Science, and Embase to evaluate the survival benefit and toxicity profiles of patients with locoregionally advanced NPC who were treated with CCRT. A random-effects model or a fixed-effects model was used to pool the data according to the heterogeneity among the included studies. A total of five studies with 1286 patients met the inclusion criteria and were included in this meta-analysis. Pooled estimate showed that GP regimen was associated with significant improvements in OS (HR = 0.57, 95% CI 0.45, 0.73; P < 0.001), DFS (HR = 0.56, 95% CI 0.47, 0.66; P < 0.001), and DRFS (HR = 0.51, 95% CI 0.36, 0.73; P < 0.001), but not in LRFS (HR = 0.54, 95% CI 0.25, 1.19; P = 0.126) and ORR (RR = 1.30, 95% CI 0.54, 3.09; P = 0.556). Moreover, the incidence of adverse events of all grades (RR = 1.15, 95%CI 0.11, 1.38; P = 0.063) or grade 3-4 (RR = 0.96, 95%CI 0.57, 1.29; P = 0.385), was comparable between GP regimen and control treatments. Our meta-analysis indicated that the patients with locoregionally advanced NPC could benefit from the regimen of gemcitabine plus cisplatin induction chemotherapy.

Effect of Mannitol Hydration as Renoprotective on Cisplatin Induced Nephrotoxicity (CIN) in Head and Neck Cancer Patients

Background: Cisplatin is a cytostatic agent used as treatments in head and neck cancer patients.Nephrotoxicity is one of cisplatin major side effects. This study aimed to evaluate the renoprotectiveeffect of mannitol-hydration administration in head and neck cancer patients who receive cisplatinchemotherapy. Methods: This was a cohort observational study to analyze the renal function of head andneck cancer patients who receives cisplatin before and after mannitol-hydration administration in IRNASurgery and Soekardja Room of Chemotherapy at RSUD Dr. Soetomo Surabaya during June – September2018. The data obtained were BUN, SCr, and eClCr Cockroft-Gault of each cycle. Result: A total of 52patients were evaluated. The average value of creatinine serum, creatinine clearance, and BUN at each cyclewere fluctuate. However, the average value of creatinine serum and BUN were within the normal limit.The result of statistical analysis using paired t-test in those parameters at each cycle were not statisticallysignificant (p &gt; 0,05) after mannitol administration except during first cycle to second cycle the SCr increasedsignificantly and eClCr was decreased significantly (p-value 0,024; 0,006, CI 95% respectively ). At fourthcycle the eClCr also decreased significantly (p value 0,008, CI 95%). Conclusion: The renoprotective effectof mannitol in head and neck cancer patients who receive cisplatin chemotherapy is sufficiently adequatewhich can maintain the value of BUN and creatinine serum of patients at each cycle within the normal limit.

Implications of inhibition of Rev1 interaction with Y family DNA polymerases for cisplatin chemotherapy.

Chemotherapy with cisplatin becomes limiting due to toxicity and secondary malignancies. In principle, therapeutics could be improved by targeting translesion synthesis (TLS) polymerases (Pols) that promote replication through intrastrand cross-links, the major cisplatin-induced DNA adduct. However, to specifically target malignancies with minimal adverse effects on normal cells, a good understanding of TLS mechanisms in normal versus cancer cells is paramount. We show that in normal cells, TLS through cisplatin intrastrand cross-links is promoted by Polη- or Polι-dependent pathways, both of which require Rev1 as a scaffolding component. In contrast, cancer cells require Rev1-Polζ. Our findings that a recently identified Rev1 inhibitor, JH-RE-06, purported to specifically disrupt Rev1 interaction with Polζ to block TLS through cisplatin adducts in cancer cells, abrogates Rev1's ability to function with Y family Pols as well, implying that by inactivating Rev1-dependent TLS in normal cells, this inhibitor will exacerbate the toxicity and tumorigenicity of chemotherapeutics with cisplatin.

Benefits of Nigella sativa Extract Protecting Ovary Due to Cisplatin Chemotherapy

BACKGROUND: Cisplatin (CIS) is an important chemotherapy agent which is widely used for the treatment of many types of solid tumors, which can cause decreased ovarian function. Nigella sativa has been shown to have an anti-inflammatory and anti-oxidant activity that might protect the ovaries from damage due to CIS. AIM: This study aims to understand the benefits of N. sativa protecting the ovaries due to CIS chemotherapy. METHODS: Thirty-two female Rattus norvegicus aged 8 weeks weighing 160–200 g were divided into four groups: Negative control, Positive control, Treatment-1 (CIS 6 mg/KgBW and NS 500 mg/KgBW/day), and Treatment-2 (CIS 6 mg/KgBW and NS 1000 mg/kgBW/day) for 2 weeks. On the 14th day the rats were sacrificed, blood was drawn from the heart, followed by taking ovaries. RESULTS: There was lower mortality and morbidity in CIS + NS 1000 and CIS + NS 500 mg group (p = 0.01 and 0.001). The mean estradiol levels, follicle-stimulating hormone levels, and anti-mullerian hormone levels were not statistically significant among the four groups. The highest number of primary, secondary, tertiary follicles are seen at the CIS + NS 500 mg and CIS + NS 1000 mg groups (p = 0.05). The lowest number of atretic follicles is seen at the CIS + NS 1000 mg group, and the highest number of atretic follicles was in CIS only. CONCLUSION: There is a trend that N. sativa is beneficial in protecting the ovaries from damage caused by CIS.

Curcumin-cisplatin chemotherapy: A novel strategy in promoting chemotherapy efficacy and reducing side effects.

The efficacy of chemotherapy in cancer therapy is limited due to resistance, treatment selectivity, and severe adverse effects. Immunotherapy, chemotherapy, targeted therapy, radiation, and surgery are the most common therapeutic strategies for treatment, with chemotherapy being the most successful. Nonetheless, these treatments exhibit poor effectiveness due to toxicity and resistance. Therefore, combination therapies of natural products may be used as an effective and novel strategy to overcome such barriers. Cisplatin is a platinum-based chemotherapy agent, and when administered alone, it can lead to severe adverse effects and resistance mechanism resulting in therapeutic failure. Curcumin is a polyphenolic compound extracted from turmeric (Curcuma longa) exhibiting anticancer potential with minimal adverse effects. The combination therapy of curcumin and cisplatin is a novel strategy to mitigate/attenuate cisplatin-related adverse effects and improve the barrier of resistance reducing unwanted effects. However, there are uncertainties on the efficacy of curcumin, and more in depth and high-quality studies are needed. This review aims to explain the adverse effects related to individual cisplatin delivery, the positive outcome of individual curcumin delivery, and the combination therapy of curcumin and cisplatin from nano platform as a novel strategy for cancer therapy.

Evaluation of renal function using cystatin C-based estimated glomerular filtration rate in patients with urothelial carcinoma treated with gemcitabine and cisplatin chemotherapy.

Cisplatin-based chemotherapy is a first-line treatment for advanced or metastatic urinary tract urothelial carcinoma (UC). Accurate assessment of renal function is indispensable for determining cisplatin dosing to enhance the safety and effectiveness of cisplatin. The objective of this study was to assess serum cystatin C (sCys C) levels in patients with urothelial carcinoma and to explore its clinical value as a serum marker of glomerular filtration rate (GFR). This study retrospectively enrolled 18 UC patients treated with a combination of gemcitabine and cisplatin between April 2018 and November 2020. We calculated the estimated GFR (eGFR) based on serum creatinine (sCr) or sCys C and estimated Cr clearance (eCCr) based on sCr. The correlation, bias, accuracy and creatinine height index between eGFR or eCCr and measured GFR (mGFR) based on Cr clearance were calculated from urinary Cr and sCr. Estimated GFR based on sCys C correlated most strongly with mGFR. Moreover, the bias, mean error, mean absolute error and root mean square error were significantly lower in eGFRs based on sCyc C than in eGFRs based on sCr and eCCr. The correlation between eGFR based on sCys C/mGFR and creatinine height index was weaker than that between eGFR based on sCr/mGFR and creatinine height index, suggesting that sCys C was less affected by muscle mass. In UC patients, eGFR based on sCys C reflected renal function more accurately than eGFR based on sCr, suggesting that sCys C may be useful for assessing renal function in clinical practice.

SIRT3-mediated mitochondrial unfolded protein response weakens breast cancer sensitivity to cisplatin.

Mitochondrial unfolded protein response plays an important role in the occurrence and development of breast cancer. However, the role of mitochondrial unfolded protein response (UPRmt) in the sensitivity of breast cancer to cisplatin chemotherapy has not yet been cleared. The purpose of this study is to explore the role of mitochondrial unfolded protein response in breast cancer sensitivity to cisplatin. In this study, qRT-PCR, Western blotting, Immunofluorescence, CCK-8, Colony formation, Transwell assay and TUNEL staining assay were used to confirm the role of UPRmt in breast cancer cells treated with cisplatin. Cisplatin increased the levels of UPRmt including CLPP, HSP60, LONP1 in MCF7 and MDA-MB-231 cells. UPRmt inducer Nicotinamide ribose (NR) could promote the proliferation and invasion of breast cancer cells treated with cisplatin. Importantly, SIRT3 was discovered to increase UPRmt in breast cancer cells and silencing of SIRT3 could inhibit the effect of NR in breast cancer. UPRmt regulated by SIRT3 could protect breast cancer cell from cisplatin. Controlling SIRT3-induced UPR may be a potential therapeutic target to increase the sensitivity of breast cancer chemotherapy.

Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study

First-line therapy for advanced oesophageal cancer is currently limited to fluoropyrimidine plus platinum-based chemotherapy. We aimed to evaluate the antitumour activity of pembrolizumab plus chemotherapy versus chemotherapy alone as first-line treatment in advanced oesophageal cancer and Siewert type 1 gastro-oesophageal junction cancer. We did a randomised, placebo-controlled, double-blind, phase 3 study across 168 medical centres in 26 countries. Patients aged 18 years or older with previously untreated, histologically or cytologically confirmed, locally advanced, unresectable or metastatic oesophageal cancer or Siewert type 1 gastro-oesophageal junction cancer (regardless of PD-L1 status), measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1, and Eastern Cooperative Oncology Group performance status of 0-1, were randomly assigned (1:1) to intravenous pembrolizumab 200 mg or placebo, plus 5-fluorouracil and cisplatin (chemotherapy), once every 3 weeks for up to 35 cycles. Randomisation was stratified by geographical region, histology, and performance status. Patients, investigators, and site staff were masked to group assignment and PD-L1 biomarker status. Primary endpoints were overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 combined positive score (CPS) of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients. This trial is registered with ClinicalTrials.gov, NCT03189719, and is closed to recruitment. Between July 25, 2017, and June 3, 2019, 1020 patients were screened and 749 were enrolled and randomly assigned to pembrolizumab plus chemotherapy (n=373 [50%]) or placebo plus chemotherapy (n=376 [50%]). At the first interim analysis (median follow-up of 22·6 months), pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for overall survival in patients with oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more (median 13·9 months vs 8·8 months; hazard ratio 0·57 [95% CI 0·43-0·75]; p<0·0001), oesophageal squamous cell carcinoma (12·6 months vs 9·8 months; 0·72 [0·60-0·88]; p=0·0006), PD-L1 CPS of 10 or more (13·5 months vs 9·4 months; 0·62 [0·49-0·78]; p<0·0001), and in all randomised patients (12·4 months vs 9·8 months; 0·73 [0·62-0·86]; p<0·0001). Pembrolizumab plus chemotherapy was superior to placebo plus chemotherapy for progression-free survival in patients with oesophageal squamous cell carcinoma (6·3 months vs 5·8 months; 0·65 [0·54-0·78]; p<0·0001), PD-L1 CPS of 10 or more (7·5 months vs 5·5 months; 0·51 [0·41-0·65]; p<0·0001), and in all randomised patients (6·3 months vs 5·8 months; 0·65 [0·55-0·76]; p<0·0001). Treatment-related adverse events of grade 3 or higher occurred in 266 (72%) patients in the pembrolizumab plus chemotherapy group versus 250 (68%) in the placebo plus chemotherapy group. Compared with placebo plus chemotherapy, pembrolizumab plus chemotherapy improved overall survival in patients with previously untreated, advanced oesophageal squamous cell carcinoma and PD-L1 CPS of 10 or more, and overall survival and progression-free survival in patients with oesophageal squamous cell carcinoma, PD-L1 CPS of 10 or more, and in all randomised patients regardless of histology, and had a manageable safety profile in the total as-treated population. Merck Sharp & Dohme.

Improvement in Dysphagia Outcomes Following Clinical Target Volume Reduction in the De-ESCALaTE Study

AimsThe De-ESCALaTE study showed an overall survival advantage for the administration of synchronous cisplatin chemotherapy with radiotherapy in low-risk oropharyngeal cancer when compared with synchronous cetuximab. During the trial, a radiotherapy quality assurance protocol amendment permitted centres to swap from the original radiotherapy contouring protocol (incorporating the whole oropharynx into the high-dose clinical target volume (CTV); anatomical protocol) to a protocol that incorporated the gross tumour volume with a 10 mm margin into the CTV (volumetric protocol). The purpose of this study was to examine both toxicity and tumour control related to this protocol amendment. Materials and methodsOverall survival and recurrence at 2 years were used to compare tumour control in the two contouring cohorts. For toxicity, the cohorts were compared by both the number of severe (grades 3–5) and all grades acute and late toxicities. In addition, quality of life and swallowing were compared using EORTC-C30 and MD Anderson Dysphagia Inventory, respectively. ResultsOf 327 patients included in this study, 185 were contoured according to the anatomical protocol and 142 by the volumetric protocol. The two cohorts were well balanced, with the exception of significantly more patients in the anatomical cohort undergoing prophylactic feeding tube insertion (P < 0.001). With a minimum of 2 years of follow-up there was no significant difference in overall survival or recurrence between the two contouring protocols. Similarly, there was no significant difference in the rate of reported severe or all grades acute or late toxicity and no sustained significant difference in quality of life. However, there was a significant difference in favour of volumetric contouring in several domains of the MD Anderson Dysphagia Inventory questionnaire at 1 year, which persisted to 2 years in the dysphagia functional (P = 0.002), dysphagia physical (P = 0.009) and dysphagia overall function (P = 0.008) domains. ConclusionIn the context of the unplanned post-hoc analysis of a randomised trial, measurable improvement in long-term dysphagia has been shown following a reduction in the CTV. Further reductions in the CTV should be subject to similar scrutiny within the confines of a prospective study.

Comparative study on hemato- and nephrotoxicity profile of weekly versus every 3-weekly cisplatin dosage during induction chemotherapy in locally advanced head neck squamous cell carcinoma

BackgroundCisplatin is a frontline anticancer drug routinely used as part of concurrent chemoradiation administered at 3-weekly (100 mg/m2) dose. However, its role as fractionated weekly dose has achieved favorable outcome in patients with locally advanced squamous cell carcinoma of head and neck (LA-SCCHN) during induction chemotherapy (IC). We therefore sought to compare the toxicity outcomes of patients with LA-SCCHN treated with platinum-based IC at a single institution study using split-dose cisplatin chemotherapy. We compared the hematological and renal toxicity profile between the weekly cisplatin (30 mg/m2) (group A) versus 3-weekly (100 mg/m2) (group B) dosage schedule in this setting.ResultsThe median age of the patients in groups A and B were 49.1 years and 48.27 years respectively with male:female ratio of 4:1. Most of the patients were of oropharyngeal cancers. Group A patients showed greater neutropenia (40.2%) than group B (20.6%). There was statistically significant fall in Hb% level in group A (13.9%) than in group B (11.9%). Renal profile showed greater rise in serum urea and serum creatinine (52.7%) in group B than in group A (52.29%) with statistically significant difference.ConclusionsSince toxicities induced by high-dose cisplatin are irreversible and reduce quality of life in patients, the weekly regimen may be preferred owing to less renal toxicity, lesser hospitalization and more feasible in situations with high patient load and limited resources.

Autophagy-dependent ferroptosis contributes to cisplatin-induced hearing loss

Cisplatin-induced hearing loss is a common side effect of cisplatin chemotherapy, for which clinical therapy remains unavailable. Apoptosis of hair cells is considered the primary cause of cisplatin-induced ototoxicity; however, inhibiting apoptosis can only partially restore cisplatin-induced hearing loss. Therefore, auditory cell death caused by cisplatin damage requires further study. Ferroptosis, a novel form of regulated cell death, has been shown to play a role in the mechanism of cisplatin toxicity. In this study, we observed proferroptotic alterations (lipid peroxidation and impaired antioxidant capacity) in the cochleae of C57BL/6 mice after cisplatin damage, verifying the induction of ferroptosis. Using the HEI−OC1 cell line, we observed that cisplatin induced proferroptotic alterations and activated ferritinophagy (specific autophagy pathway). Employing chloroquine, we confirmed that the blockage of autophagy remarkably alleviated cisplatin-induced ferroptosis in HEI−OC1 cells; therefore, the induction of ferroptosis in cisplatin-treated auditory cells was dependent on the activation of autophagy. In addition, the ferroptosis inhibitor ferrostatin-1 and iron chelator deferoxamine significantly attenuated cisplatin-induced cytotoxicity in HEI−OC1 cells and cochlear explants. Moreover, pharmacologically inhibiting ferroptosis using ferrostatin-1 significantly decreased the auditory cell loss and, notably, attenuated hearing loss in C57BL/6 mice after cisplatin damage. Collectively, these findings indicate that autophagy-dependent ferroptosis plays an integrated role in the mechanism of cisplatin-induced hearing loss.

First Report of Oncological Outcome and Prognostic Analysis in a First-Line Setting of Short Hydration Gemcitabine and Cisplatin Chemotherapy for Patients with Metastatic Urothelial Carcinoma

Objectives: The aim of the study was to examine the effectiveness of a modified-short hydration gemcitabine and cisplatin (m-shGC) regimen for patients with metastatic urothelial carcinoma (mUC) and to assess the efficacy of a geriatric nutritional risk index (GNRI) with regard to prognosis. Patients and Methods: From January 2016 to July 2020, 68 patients with mUC underwent first-line m-shGC therapy with 70 mg/m² cisplatin and 1,000 mg/m² gemcitabine (days 1, 8, and 15), with 2,050 mL fluid replaced on the first day of each 28-day cycle. Prior to the start of treatment, the serum neutrophil-to-lymphocyte ratio (NLR), and levels of albumin and C-reactive protein (CRP) in serum, as well as body heights and weights were measured. Patients were grouped according to GNRI <92 (low) or ≥92 (high). The analysis of data was done retrospectively. Results: Median follow-up was found to be 12.9 (range 1.7–50.2) months and the objective response rate (ORR) was 54.4% after m-shGC treatment. The ORR was significantly different when high and low-GNRI groups were compared (ORR: 28.0 vs. 69.8% in low- vs. high-GNRI groups). Median overall survival (OS) was calculated as 8.6 (95% confidence interval [CI]: 5.4–21.3) and 34.5 (95% CI: 20.5–NA) months for low- and high-GNRI groups, respectively (p < 0.0001). Unlike for NLR and CRP, univariate and multivariate analyses revealed that low GNRI and visceral metastases were significant prognostic factors for short OS. Conclusions: First-line m-shGC showed a survival benefit for mUC, with GNRI a useful prognostic biomarker.