Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer.

BACKGROUND: No treatment has surpassed platinum-based chemotherapy in improving overall survival in patients with previously untreated locally advanced or metastatic urothelial carcinoma. METHODS: We conducted a phase 3, global, open-label, randomized trial to compare the efficacy and safety of enfortumab vedotin and pembrolizumab with the efficacy and safety of platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. Patients were randomly assigned in a 1:1 ratio to receive 3-week cycles of enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight intravenously on days 1 and 8) and pembrolizumab (at a dose of 200 mg intravenously on day 1) (enfortumab vedotin-pembrolizumab group) or gemcitabine and either cisplatin or carboplatin (determined on the basis of eligibility to receive cisplatin) (chemotherapy group). The primary end points were progression-free survival as assessed by blinded independent central review and overall survival. RESULTS: A total of 886 patients underwent randomization: 442 to the enfortumab vedotin-pembrolizumab group and 444 to the chemotherapy group. As of August 8, 2023, the median duration of follow-up for survival was 17.2 months. Progression-free survival was longer in the enfortumab vedotin-pembrolizumab group than in the chemotherapy group (median, 12.5 months vs. 6.3 months; hazard ratio for disease progression or death, 0.45; 95% confidence interval [CI], 0.38 to 0.54; P<0.001), as was overall survival (median, 31.5 months vs. 16.1 months; hazard ratio for death, 0.47; 95% CI, 0.38 to 0.58; P<0.001). The median number of cycles was 12 (range, 1 to 46) in the enfortumab vedotin-pembrolizumab group and 6 (range, 1 to 6) in the chemotherapy group. Treatment-related adverse events of grade 3 or higher occurred in 55.9% of the patients in the enfortumab vedotin-pembrolizumab group and in 69.5% of those in the chemotherapy group. CONCLUSIONS: Treatment with enfortumab vedotin and pembrolizumab resulted in significantly better outcomes than chemotherapy in patients with untreated locally advanced or metastatic urothelial carcinoma, with a safety profile consistent with that in previous reports. (Funded by Astellas Pharma US and others; EV-302 ClinicalTrials.gov number, NCT04223856.).

Neoadjuvant chemotherapy with dose-dense MVAC in muscle-invasive bladder cancer: a tertiary center experience

Purpose Neoadjuvant chemotherapy in muscle-invasive bladder cancer (MIBC) patients has proven beneficial in overall survival. However, the optimal regimen is still a matter of debate. Materials and method In this retrospective analysis, we evaluate the results obtained in 42 patients treated in our center with 4 cycles of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) followed by radical cystectomy from August 2015 to October 2020. All patients had cT2 or higher non-metastatic MIBC. Clinical and pathological outcomes are reported. Results Of the 42 patients, 90.5% were men (n = 38) and the mean age was 65 years. All of them had ECOG 0–1 at diagnosis and most tumors had an initial clinical stage T2N0 (76%). Thirty-six patients (85.7%) completed 4 cycles of neoadjuvant treatment, and 21.4% required a dose reduction. The most frequent adverse event (AE) was grade 1–2 asthenia (81%), while neutropenia was the most frequent grade 3 or higher AE (38%). Complete pathological response (ypT0, ypN0) was achieved in 50% of patients (n = 21), and down-staging was observed in 57.1% (n = 24). Only one patient presented radiological progressive disease during neoadjuvant treatment (2.4%), and after a mean follow-up time of 31.5 months, 33.3% of patients experienced disease recurrence. Conclusions Neoadjuvant chemotherapy with 4 cycles of dd-MVAC is an effective regimen with high rates of pathological complete responses and down-staging along with an acceptable toxicity profile. DD-MVAC should be considered as an alternative to cisplatin and gemcitabine in patients with good clinical performance status (AU)

Toripalimab Plus Chemotherapy for Recurrent or Metastatic Nasopharyngeal Carcinoma: The JUPITER-02 Randomized Clinical Trial.

Importance: There are currently no therapies approved by the US Food and Drug Administration for nasopharyngeal carcinoma (NPC). Gemcitabine-cisplatin is the current standard of care for the first-line treatment of recurrent or metastatic NPC (RM-NPC). Objective: To determine whether toripalimab in combination with gemcitabine-cisplatin will significantly improve progression-free survival and overall survival as first-line treatment for RM-NPC, compared with gemcitabine-cisplatin alone. Design, Setting, and Participants: JUPITER-02 is an international, multicenter, randomized, double-blind phase 3 study conducted in NPC-endemic regions, including mainland China, Taiwan, and Singapore. From November 10, 2018, to October 20, 2019, 289 patients with RM-NPC with no prior systemic chemotherapy in the RM setting were enrolled from 35 participating centers. Interventions: Patients were randomized (1:1) to receive toripalimab (240 mg [n = 146]) or placebo (n = 143) in combination with gemcitabine-cisplatin for up to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxicity, or completion of 2 years of treatment. Main Outcome: Progression-free survival as assessed by a blinded independent central review. Secondary end points included objective response rate, overall survival, progression-free survival assessed by investigator, duration of response, and safety. Results: Among the 289 patients enrolled (median age, 46 [IQR, 38-53 years; 17% female), at the final progression-free survival analysis, toripalimab treatment had a significantly longer progression-free survival than placebo (median, 21.4 vs 8.2 months; HR, 0.52 [95% CI, 0.37-0.73]). With a median survival follow-up of 36.0 months, a significant improvement in overall survival was identified with toripalimab over placebo (hazard ratio [HR], 0.63 [95% CI, 0.45-0.89]; 2-sided P = .008). The median overall survival was not reached in the toripalimab group, while it was 33.7 months in the placebo group. A consistent effect on overall survival, favoring toripalimab, was found in subgroups with high and low PD-L1 (programmed death-ligand 1) expression. The incidence of all adverse events, grade 3 or greater adverse events, and fatal adverse events were similar between the 2 groups. However, adverse events leading to discontinuation of toripalimab or placebo (11.6% vs 4.9%), immune-related adverse events (54.1% vs 21.7%), and grade 3 or greater immune-related adverse events (9.6% vs 1.4%) were more frequent in the toripalimab group. Conclusions and Relevance: The addition of toripalimab to chemotherapy as first-line treatment for RM-NPC provided statistically significant and clinically meaningful progression-free survival and overall survival benefits compared with chemotherapy alone, with a manageable safety profile. These findings support the use of toripalimab plus gemcitabine-cisplatin as the new standard of care for this patient population. Trial Registration: ClinicalTrials.gov Identifier: NCT03581786.

Nivolumab plus Gemcitabine-Cisplatin in Advanced Urothelial Carcinoma.

BACKGROUND: No new agent has improved overall survival in patients with unresectable or metastatic urothelial carcinoma when added to first-line cisplatin-based chemotherapy. METHODS: In this phase 3, multinational, open-label trial, we randomly assigned patients with previously untreated unresectable or metastatic urothelial carcinoma either to receive intravenous nivolumab (at a dose of 360 mg) plus gemcitabine-cisplatin (nivolumab combination) every 3 weeks for up to six cycles, followed by nivolumab (at a dose of 480 mg) every 4 weeks for a maximum of 2 years, or to receive gemcitabine-cisplatin alone every 3 weeks for up to six cycles. The primary outcomes were overall and progression-free survival. The objective response and safety were exploratory outcomes. RESULTS: A total of 608 patients underwent randomization (304 to each group). At a median follow-up of 33.6 months, overall survival was longer with nivolumab-combination therapy than with gemcitabine-cisplatin alone (hazard ratio for death, 0.78; 95% confidence interval [CI], 0.63 to 0.96; P = 0.02); the median survival was 21.7 months (95% CI, 18.6 to 26.4) as compared with 18.9 months (95% CI, 14.7 to 22.4), respectively. Progression-free survival was also longer with nivolumab-combination therapy than with gemcitabine-cisplatin alone (hazard ratio for progression or death, 0.72; 95% CI, 0.59 to 0.88; P = 0.001). The median progression-free survival was 7.9 months and 7.6 months, respectively. At 12 months, progression-free survival was 34.2% and 21.8%, respectively. The overall objective response was 57.6% (complete response, 21.7%) with nivolumab-combination therapy and 43.1% (complete response, 11.8%) with gemcitabine-cisplatin alone. The median duration of complete response was 37.1 months with nivolumab-combination therapy and 13.2 months with gemcitabine-cisplatin alone. Grade 3 or higher adverse events occurred in 61.8% and 51.7% of the patients, respectively. CONCLUSIONS: Combination therapy with nivolumab plus gemcitabine-cisplatin resulted in significantly better outcomes in patients with previously untreated advanced urothelial carcinoma than gemcitabine-cisplatin alone. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 901 ClinicalTrials.gov number, NCT03036098.).

Optimal cisplatin cycles in locally advanced cervical carcinoma patients treated with concurrent chemoradiotherapy

Purpose To analyze the effect of cisplatin cycles on the clinical outcomes of patients with locally advanced cervical cancer (LACC) treated with concurrent chemoradiotherapy (CCRT). Methods This study included 749 patients with LACC treated with CCRT between January 2011 and December 2015. A receiver operating characteristic (ROC) curve was used to analyze the optimal cut-off of cisplatin cycles in predicting clinical outcomes. Clinicopathological features of the patients were compared using the Chi-square test. Prognosis was assessed using log-rank tests and Cox proportional hazard models. Toxicities were compared among different cisplatin cycle groups. Results Based on the ROC curve, the optimal cut-off of the cisplatin cycles was 4.5 (sensitivity, 64.3%; specificity, 54.3%). The 3-year overall, disease-free, loco-regional relapse-free, and distant metastasis-free survival for patients with low-cycles (cisplatin cycles < 5) and high-cycles (≥ 5) were 81.5% and 89.0% (P < 0.001), 73.4% and 80.1% (P = 0.024), 83.0% and 90.8% (P = 0.005), and 84.9% and 86.8% (P = 0.271), respectively. In multivariate analysis, cisplatin cycles were an independent prognostic factor for overall survival. In the subgroup analysis of high-cycle patients, patients who received over five cisplatin cycles had similar overall, disease-free, loco-regional relapse-free, and distant metastasis-free survival to patients treated with five cycles. Acute and late toxicities were not different between the two groups. Conclusion Cisplatin cycles were associated with overall, disease-free, and loco-regional relapse-free survival in LACC patients who received CCRT. Five cycles appeared to be the optimal number of cisplatin cycles during CCRT (AU)

Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer.

BACKGROUND: Among patients with resectable early-stage non-small-cell lung cancer (NSCLC), a perioperative approach that includes both neoadjuvant and adjuvant immune checkpoint inhibition may provide benefit beyond either approach alone. METHODS: We conducted a randomized, double-blind, phase 3 trial to evaluate perioperative pembrolizumab in patients with early-stage NSCLC. Participants with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC were assigned in a 1:1 ratio to receive neoadjuvant pembrolizumab (200 mg) or placebo once every 3 weeks, each of which was given with cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant pembrolizumab (200 mg) or placebo once every 3 weeks for up to 13 cycles. The dual primary end points were event-free survival (the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence, or death) and overall survival. Secondary end points included major pathological response, pathological complete response, and safety. RESULTS: A total of 397 participants were assigned to the pembrolizumab group, and 400 to the placebo group. At the prespecified first interim analysis, the median follow-up was 25.2 months. Event-free survival at 24 months was 62.4% in the pembrolizumab group and 40.6% in the placebo group (hazard ratio for progression, recurrence, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.72; P<0.001). The estimated 24-month overall survival was 80.9% in the pembrolizumab group and 77.6% in the placebo group (P = 0.02, which did not meet the significance criterion). A major pathological response occurred in 30.2% of the participants in the pembrolizumab group and in 11.0% of those in the placebo group (difference, 19.2 percentage points; 95% CI, 13.9 to 24.7; P<0.0001; threshold, P = 0.0001), and a pathological complete response occurred in 18.1% and 4.0%, respectively (difference, 14.2 percentage points; 95% CI, 10.1 to 18.7; P<0.0001; threshold, P = 0.0001). Across all treatment phases, 44.9% of the participants in the pembrolizumab group and 37.3% of those in the placebo group had treatment-related adverse events of grade 3 or higher, including 1.0% and 0.8%, respectively, who had grade 5 events. CONCLUSIONS: Among patients with resectable, early-stage NSCLC, neoadjuvant pembrolizumab plus chemotherapy followed by resection and adjuvant pembrolizumab significantly improved event-free survival, major pathological response, and pathological complete response as compared with neoadjuvant chemotherapy alone followed by surgery. Overall survival did not differ significantly between the groups in this analysis. (Funded by Merck Sharp and Dohme; KEYNOTE-671 ClinicalTrials.gov number, NCT03425643.).

Pharmacological boosting of cGAS activation sensitizes chemotherapy by enhancing antitumor immunity.

Enhancing chemosensitivity is one of the largest unmet medical needs in cancer therapy. Cyclic GMP-AMP synthase (cGAS) connects genome instability caused by platinum-based chemotherapeutics to type I interferon (IFN) response. Here, by using a high-throughput small-molecule microarray-based screening of cGAS interacting compounds, we identify brivanib, known as a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor, as a cGAS modulator. Brivanib markedly enhances cGAS-mediated type I IFN response in tumor cells treated with platinum. Mechanistically, brivanib directly targets cGAS and enhances its DNA binding affinity. Importantly, brivanib synergizes with cisplatin in tumor control by boosting CD8+ T cell response in a tumor-intrinsic cGAS-dependent manner, which is further validated by a patient-derived tumor-like cell clusters model. Taken together, our findings identify cGAS as an unprecedented target of brivanib and provide a rationale for the combination of brivanib with platinum-based chemotherapeutics in cancer treatment.

Time dependent cisplatin dosing differences on hypoalgesia focusing on oxidative stress.

Although cisplatin is a key drug in cancer chemotherapy, it often causes sensory peripheral neuropathy, presenting as allodynia in the early stage and hypoalgesia in the serious stage. Chronotherapy has previously been shown to ameliorate cisplatin-induced peripheral neuropathy that was severe enough to cause hypoalgesia in rats. It also has adverse effects such as renal dysfunction and ototoxicity, which are induced by oxidative stress. Here, we show that oxidative stress causes severe cisplatin-induced peripheral neuropathy, and that differences in oxidative stress occur depending on the dosing time of cisplatin. Cisplatin was administered to rats at 5:00 or 17:00 every seven days for four weeks. The antioxidant agent, 1,3-Dimethylthiourea (DMTU), was administered before and after the administration of cisplatin. The hot plate test was used to assess hypoalgesia. Oxidative stress in the sciatic nerve was assessed from thiobarbituric acid reactive substances (TBARs) and superoxide dismutase (SOD) activity. Nerve apoptosis was analysed with qRT-PCR. We observed an increase in TBARs and a decrease in SOD activity with the development of cisplatin-induced hypoalgesia, which was ameliorated by DMTU treatment. Furthermore, differences in the dosing time of cisplatin caused differences in oxidative stress which were correlated with cisplatin-induced hypoalgesia. Severe oxidative stress caused cisplatin-induced hypoalgesia, and chronotherapy with cisplatin ameliorated hypoalgesia by reducing oxidative stress. In the future, chronotherapy with cisplatin may contribute to the treatment of cancer in humans.

Holographically Activatable Nanoprobe via Glutathione/Albumin-Mediated Exponential Signal Amplification for High-Contrast Tumor Imaging.

Glutathione (GSH)-activatable probes hold great promise for in vivo cancer imaging, but are restricted by their dependence on non-selective intracellular GSH enrichment and uncontrollable background noise. Here, a holographically activatable nanoprobe caging manganese tetraoxide is shown for tumor-selective contrast enhancement in magnetic resonance imaging (MRI) through cooperative GSH/albumin-mediated cascade signal amplification in tumors and rapid elimination in normal tissues. Once targeting tumors, the endocytosed nanoprobe effectively senses the lysosomal microenvironment to undergo instantaneous decomposition into Mn2+ with threshold GSH concentration of ≈ 0.12 mm for brightening MRI signals, thus achieving high contrast tumor imaging and flexible monitoring of GSH-relevant cisplatin resistance during chemotherapy. Upon efficient up-regulation of extracellular GSH in tumor via exogenous injection, the relaxivity-silent interstitial nanoprobe remarkably evolves into Mn2+ that are further captured/retained and re-activated into ultrahigh-relaxivity-capable complex by stromal albumin in the tumor, and simultaneously allows the renal clearance of off-targeted nanoprobe in the form of Mn2+ via lymphatic vessels for suppressing background noise to distinguish tiny liver metastasis. These findings demonstrate the concept of holographic tumor activation via both tumor GSH/albumin-mediated cascade signal amplification and simultaneous background suppression for precise tumor malignancy detection, surveillance, and surgical guidance.

Genetic variations in ABC transporter genes as a predictive biomarker for toxicity in North Indian lung cancer patients undergoing platinum-based doublet chemotherapy.

ATP-binding cassette (ABC) transporters are expressed in various human tissues and play a vital role in the efflux of various chemotherapeutic drugs. The current study has assessed genetic variants of ABCB1, ABCC1, ABCC2, and ABCG2 genes in 407 lung cancer patients undergoing platinum-based doublet chemotherapy. The association of ABCB1 (C1236 T, C3435 T, and G2677 T/A), ABCC1 (G3173 A and G2168 A),ABCC2 (G4544 A), and ABCG2 (C421 A) polymorphisms with chemotherapy-induced adverse events were assessed, and statistical analysis was conducted. Our data showed that patients harboring heterozygous (GA) genotype for ABCC1 G3173 A had an increased risk of developing leukopenia (odds ratio [OR] = 1.88, p = 0.04) and anemia (adjusted odds ratio [AOR] = 2.70, p = 0.03). For ABCC2 G4544 A polymorphism, patients harboring one copy of the mutant (GA) allele showed an increased risk of developing anemia (OR = 4.24, p = 0.03). After adjusting with various confounding factors, the heterozygous (GA) genotype showed a 5.63-fold increased risk of developing anemia (AOR = 5.63, p = 0.03). The ABCB1 G2677 A (OR = 0.37, p = 0.008) and ABCC1 G3173 A (OR = 0.54, p = 0.04) polymorphism showed a lower incidence of developing nephrotoxicity. In ABCG2 C421 A polymorphism, patients harboring heterozygous (CA) genotype had a lower incidence of having diarrhea (OR = 0.25, p = 0.04). An increased risk of having diarrhea was observed in the heterozygous genotype (GA) for ABCC1 G3173 A polymorphism (AOR = 2.78, p = 0.04). An increased risk of liver injury was found in the patients carrying heterozygous genotype of the ABCC1 G3173 A (OR = 2.06, p = 0.02) and ABCB1 C1236 T (OR = 1.85, p = 0.01). This study demonstrates the role of polymorphic variations in ABCB1, ABCC1, ABCC2, and ABCG2 in predicting hematological, nephrotoxicity, gastrointestinal, and hepatotoxicity.

NUT Carcinoma in Children and Adolescents: The Expert European Standard Clinical Practice Harmonized Recommendations.

BACKGROUND AND AIMS: Nuclear protein of the testis ( NUT ) carcinoma (NC) is a rare and highly aggressive tumor mainly occurring in adolescents and young adults, defined by the presence of a somatic NUTM1 rearrangement. The aim is to establish internationally harmonized consensus recommendations for the diagnosis and treatment of adolescents and young adults with NC in the framework of the European Reference Network for Paediatric Oncology. METHODS: The European Cooperative Study Group for Pediatric Rare Tumors developed recommendations according to the Consensus Conference Standard Operating procedure methodology and reviewed by external "experts." No evidence of level I to II exists. Recommendations were developed based on published prospective (level III), but more frequently retrospective series (level IV), case reports (level V), and personal expertise (level V). In addition, "strength" of recommendations were categorized by grading (grade A to E). RESULTS: Histology is mandatory for the diagnosis of NC, including immunolabeling with anti-NUT antibodies and molecular biology ( NUTM1 rearrangement) (level V; grade A). Treatment of NC usually combines aggressive approaches in multimodal regimens. Chemotherapy should be considered as first-line treatment (neoadjuvant vincristine-adriamycin-ifosfamide/cisplatin-adriamycin-ifsofamide or vincristine-doxorubicin-cyclophosphamide/ifosfamide-etoposide) for unresectable or metastatic tumor (ie, 3 courses), rapidly followed by local treatment (level IV; grade B). Referral to a specialized surgical oncology center is highly recommended (level V; grade A). In localized NC, a complete microscopic surgical resection should be attempted whenever and as soon as possible, followed by primary irradiation (60 to 70 Gy) and involved lymph nodes area (level IV; grade B). For head and neck tumors, a systematic neck dissection might be considered, even if N0 (level V; grade C). Adjuvant postirradiation chemotherapy is recommended, for a total of 9 to 12 courses (level IV; grade B). For first-line resected tumors, concomitant adjuvant chemotherapy to radiotherapy may be discussed (level IV; grade B). Targeted therapies and immunotherapeutic regimens should be delivered in the setting of prospective trials (level V; grade B). CONCLUSIONS: This project leads to a consensus strategy based on international experience with this very rare disease.

Suppression of cisplatin-induced ovarian injury in rats by chrysin: an experimental study.

The aim of this study was to investigate the potential therapeutic efficacy of chrysin (CHS) against ovotoxicity caused by intraperitoneal administration of cisplatin (CDDP) in rats. In this experimental study, 24 female rats were randomly divided into four groups: control, CHS (2 mg/kg), CDDP (5 mg/kg) and CDDP (5 mg/kg) + CHS (2 mg/kg). The levels of malondialdehyde (MDA), total oxidant status (TOS), total antioxidant status (TAS), superoxide dismutase (SOD), interleukin-6 (IL-6) and myeloperoxidase (MPO) were determined in the ovarian tissues using spectrophotometric methods. In addition, the ovarian samples were evaluated histopathologically by hematoxylin&eosin staining. The results revealed that the levels of MDA, TOS, IL-6 and MPO significantly increased by CDDP administration compared with control group (p < 0.05). Also, it was found that CDDP significantly decreased TAS and SOD levels (p < 0.05). CHS ameliorated CDDP-induced the increased levels of MDA, TOS, IL-6, MPO and increased the levels of TAS and SOD significantly (p < 0.05). Histological findings also supported the therapeutic effect of CHS against CDDP-induced ovarian damage parameters. In conclusion, our results showed that CHS exhibits a therapeutic effect against CDDP-induced ovotoxicity and therefore the use of CHS after chemotherapy may improve the side effets of CDDP. IMPACT STATEMENTWhat is already known about this subject? Cisplatin (CDDP) is an effective and widely used chemotherapeutic agent to treat various malignancies, but its therapeutic use is limited due to dose-related tissue toxicity. Chrysin (CHS), a natural flavone, exhibits various beneficial activities, including antioxidant, anti-inflammatory and anticancer. There are increasing evidences in the literature that CHS reduces the toxicity of various chemotherapeutic agents, such as CDDP, doxorubicin and cyclophosphamide, in colon, kidney and liver tissues through its antioxidant and anti-inflammatory potential.What do the results of this study add? This study demonstrated that CHS can abolish CDDP-induced in vivo ovarian injury by decreasing MDA, TOS, IL-6 and MPO levels and increasing SOD and TAS levels through its antioxidant and anti-inflammatory potential.What are the implications of these findings for clinical practice and/or further research? This study revealed the therapeutic potential of CHS against CDDP-induced acute ovotoxicity, for the first time. Further pre-clinical studies are necessary to prove the beneficial effect of CHS on the prevention of CDDP-induced ovarian toxicity.

Inflammatory markers S100A8/A9 and metabolic alteration for evaluating signs of early phase toxicity of anticancer agent treatment.

Anticancer agents can cause various side effects, including tissue damages/inflammatory reactions. Drug-responsive biomarkers are essential for evaluating drug toxicity in disease processes. S100 calcium-binding proteins A8/A9 (S100A8/A9) are highly expressed in neutrophils and monocytes/macrophages accumulated at inflammatory sites and are known to be related to tissue damage/inflammation; however, their response to drug toxicity has not been reported. Herein, we investigated the effects of anticancer agents (doxorubicin, cisplatin, and docetaxel) on S100A8/A9 gene expression profiles in four representative tissues (heart, kidney, liver, and lung) in normal C57BL/6J mice. Both S100A8/A9 expression was transiently or time-dependently elevated in four tissues within 48 h after dosing of the three anticancer agents under toxicity-inducing conditions. S100A8/A9 patterns differed among agents and tissues. This result suggests that S100A8/A9 is useful for evaluating anticancer agent-induced tissue damage. Metabolomic analysis revealed that some metabolites showed temporal patterns similar to that of S100A8/A9 expression. The amounts of fumarate (doxorubicin-treated heart), tyrosine (cisplatin-treated kidney), acetylcarnosine (doxorubicin-treated liver), and 2-phosphoglycerate (docetaxel-treated lung) showed similar patterns to that of S100A8/A9 expression. Although these metabolites showed different behaviors between tissues and serum, they may be useful marker candidates for evaluating anticancer agent-induced tissue damage at an earlier stage after dosing.

Carfilzomibe no tratamento de pacientes com mieloma múltiplo recidivado ou refratário, que receberam terapia prévia / Carfilzomib in the treatment of patients with relapsed or refractory multiple myeloma who have received prior therapy

INTRODUÇÃO: O mieloma múltiplo (MM) é uma neoplasia hematológica maligna caracterizada pela proliferação descontrolada de plasmócitos alterados na medula óssea, resultando na produção aumentada de imunoglobulinas não funcional (proteína monoclonal). O acúmulo destas imunoglobulinas e a interação dos plasmócitos com outras células da medula óssea resultam em anemia, lesões ósseas, infecções, hipercalcemia, injúria renal, fadiga e dor. A incidência mundial informada pelo Globocan é de 2,2 novos casos por 100.000 habitantes em homens e 1,5/100.000 em mulheres, com ocorrência, a nível mundial, de 176 mil novos casos e 117 mil mortes em 2020. Carfilzomibe é um agente antineoplásico, inibidor de proteassoma que se liga seletiva e irreversivelmente nos sítios ativos. Tem atividade antiproliferativa e pró-apoptóticas. PERGUNTA DE PESQUISA: Kyprolis® (carfilzomibe) em combinação com dexametasona é eficaz e seguro no tratamento de pacientes com mieloma múltiplo recidivado ou refratário que receberam uma terapia prévia quando em comparação a bortezomibe, ciclofosfamida, dexametasona, cisplatina, doxorrubicina, doxorrubicina lipossomal, etoposídeo, melfalana, vincristina ou talidomida? EVIDÊNCIAS CLÍNICAS: O demandante realizou as buscas na literatura utilizando as seguintes bases de dados: The Cochrane Library, Medline via PubMed, Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), Centre for Reviews and Dissemination (CRD), o que resultou na inclusão de 14 publicações. Na análise conduzida pela Secretaria Executiva foram consideradas 12 publicações referentes a um ensaio clínico randomizado e uma publicação de revisão sistemática. O estudo ENDEAVOR foi um ensaio clínico de fase III, multicêntrico, aberto, que incluiu 929 participantes randomizados para receber carfilzomibe+dexametasona ou bortezomibe+dexametasona. A mediana de SLP foi 18,7 meses (IC 95%, 15,6 a não estimável) no grupo que recebeu carfilzomibe comparado a 9,4 meses (IC 95%, 8,4 a 10,4) no grupo que recebeu bortezomibe, resultando em uma magnitude de benefício absoluto de 9,3 meses (HR 0,53 [IC95% 0,44 a 0,65]; p< 0,0001). A duração mediana de resposta foi 21,3 meses (IC95% 21,3 a não estimável) no grupo carfilzomibe e 10,4 meses (IC95% 9,3 a 13,8) no grupo bortezomibe. Em ambos os grupos, 98% dos participantes apresentaram eventos adversos (qualquer grau), sendo a anemia (43% versus 28%), diarreia (36,7% versus 40,6%) e febre (32,6% versus 15,4%) os eventos mais frequentes nos grupos carfilzomibe e bortezomibe, respectivamente. Os eventos adversos mais comuns grau 3 ou maior foram reportados em 81,9% dos participantes do grupo carfilzomibe (n=379) e 71,1% no grupo bortezomibe (n=324), sendo a anemia (17,3% no grupo carfilzomibe e 10,1% no grupo bortezomibe), hipertensão (14,9% versus 3,3%), trombocitopenia (12,5% versus 14,7%),os três eventos mais frequentes. Insuficiência cardíaca grau 3 ou superior, foi mais frequente no grupo carfilzomibe (6%) que no grupo bortezomibe (2%.). AVALIAÇÃO ECONÔMICA: O demandante apresentou uma análise de custo-efetividade. Na análise do cenário base, em um horizonte temporal de 30 anos, carfilzomibe acrescentou ganhos incrementais de 1,19 QALY, resultando em uma razão de custo utilidade incremental (RCEI) de R$ 195.310,00 por QALY. No cenário proposto pela Secretária-Executiva (horizonte temporal de 10 anos e valor de utilidade derivada do estudo ENDEAVOR), carfilzomibe gerou benefício de 0,63 QALY, com RCEI de R$ 365.830,00 por QALY. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: Com o desconto apresentado pelo demandante, a incorporação de carfilzomibe ao SUS implica em custos adicionais ao sistema de saúde no montante de aproximadamente R$ 365 milhões em cinco anos. A principal limitação da análise foi a estimativa da população. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram identificadas 10 tecnologias potenciais para compor o esquema terapêutico de pacientes adultos com mieloma múltiplo recidivado ou refratário: Belantamabe mafodotin, Ciltacabtageno autoleucel, Elranatamab, Iberdomida, Idecabtagene vicleucel, Isatuximabe, nivolumabe, selinexor, teclistamab, venetoclax. Tais medicamentos são anticorpo monoclonal ligado a um antineoplásico, anticorpo biespecífico, anticorpo monoclonal, imumodulador, terapias baseadas em células T autólogas geneticamente modificadas (CAR-T), inibidor SINE, ou inibidor de Bcl-2. A maioria não possui registro na FDA, EMA ou Anvisa. CONSIDERAÇÕES FINAIS: Os resultados sugerem eficácia e segurança do carfilzomibe na população elegível, porém, no horizonte temporal de 10 anos, com QALY < 1, RCEI de R$ 365.830,00 por QALY e impacto orçamentário de aproximadamente R$ 17 milhões no primeiro ano de incorporação e R$ 131 milhões no 5º ano da incorporação, totalizando R$ 365 milhões em cinco anos. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do Plenário presentes na 109ª Reunião Ordinária da Conitec, realizada no dia 08 de junho de 2022, sem nenhuma declaração de conflito de interesse, deliberaram por unanimidade, encaminhar o tema para consulta pública com recomendação preliminar desfavorável à incorporação de carfilzomibe para o tratamento de mieloma múltiplo recidivado ou refratário no SUS. Os membros consideraram a evidência científica boa e favorável ao carfilzomibe, porém, a RCEI e o impacto orçamentário foram considerados muito altos para o tratamento de uma doença que já tem outras opções terapêuticas disponíveis no SUS. CONSULTA PÚBLICA: Entre os dias 08/07/2022 e 27/07/2022 foram recebidas 421 contribuições, sendo 152 pelo formulário para contribuições técnico-científicas e 269 pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. A maioria foi a favor da incorporação de carfilzomibe no SUS (97% via formulário técnico-científico e 100%). O principal benefício apontado nas contribuições técnico-científicas foi sobre a eficácia, aumento da sobrevida e qualidade de vida, além da disponibilidade de mais uma opção terapêutica e promoção da igualdade no tratamento nos sistemas público e privado de saúde. A empresa detentora do registro do medicamento atualizou o preço do medicamento, e consequentemente os valores do impacto orçamentário e avaliação econômica. No impacto orçamentário o valor ficou em R$ 95,3 milhões em cinco anos. Nas contribuições de experiência e opinião, a totalidade dos respondentes discordou da recomendação preliminar da Conitec. No âmbito das opiniões e experiências positivas, foi mencionada a necessidade de garantir o acesso ao carfilzomibe, especialmente por representar uma alternativa para pacientes recidivados e refratários. Também foi citada a eficácia da tecnologia. Como dificuldades, destacou-se a falta de acesso pelo SUS. Em relação a outros medicamentos, foram mencionados benefícios, mas, também, a eficácia limitada no caso de pacientes recidivados. RECOMENDAÇÃO FINAL DA CONITEC: Os membros do Plenário da Conitec, em sua 112ª Reunião Ordinária, realizada no dia 31 de agosto de 2022, deliberaram por maioria simples, recomendar a não incorporação no SUS de carfilzomibe para o tratamento de pacientes com mieloma múltiplo recidivado ou refratário, que receberam terapia prévia, no SUS. Não houve apresentação de dados clínicos adicionais. Com o preço do medicamento atualizado, ainda assim não se mostrou custo-efetivo. Foi assinado o Registro de Deliberação nº 765/2022. DECISÃO: Não incorporar, no âmbito do Sistema Único de Saúde - SUS, o carfilzomibe para o tratamento de pacientes com mieloma múltiplo recidivado ou refratário, conforme a Portaria nº 107, publicada no Diário Oficial da União nº 184, seção 1, página 75, em 27 de setembro de 2022.

Effect of Radiotherapy Alone vs Radiotherapy With Concurrent Chemoradiotherapy on Survival Without Disease Relapse in Patients With Low-risk Nasopharyngeal Carcinoma: A Randomized Clinical Trial.

Importance: Concurrent chemoradiotherapy has been the standard treatment for stage II nasopharyngeal carcinoma (NPC) based on data using 2-dimensional conventional radiotherapy. There is limited evidence for the role of chemotherapy with use of intensity-modulated radiation therapy (IMRT). Objective: To assess whether concurrent chemotherapy can be safely omitted for patients with low-risk stage II/T3N0 NPC treated with IMRT. Design, Setting, and Participants: This multicenter, open-label, randomized, phase 3, noninferiority clinical trial was conducted at 5 Chinese hospitals, including 341 adult patients with low-risk NPC, defined as stage II/T3N0M0 without adverse features (all nodes <3 cm, no level IV/Vb nodes; no extranodal extension; Epstein-Barr virus DNA <4000 copies/mL), with enrollment between November 2015 and August 2020. The final date of follow-up was March 15, 2022. Interventions: Patients were randomly assigned to receive IMRT alone (n = 172) or concurrent chemoradiotherapy (IMRT with cisplatin, 100 mg/m2 every 3 weeks for 3 cycles [n = 169]). Main Outcomes and Measures: The primary end point was 3-year failure-free survival (time from randomization to any disease relapse or death), with a noninferiority margin of 10%. Secondary end points comprised overall survival, locoregional relapse-free survival, distant metastasis-free survival, adverse events, and health-related quality of life (QOL) measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30; range, 0-100 points; minimum clinically important difference ≥10 for physical function, symptom control, or health-related QOL; higher score indicates better functioning and global health status or worse symptoms). Results: Among 341 randomized patients (mean [SD] age, 48 [10] years; 30% women), 334 (98.0%) completed the trial. Median follow-up was 46 months (IQR, 34-58). Three-year failure-free survival was 90.5% for the IMRT-alone group vs 91.9% for the concurrent chemoradiotherapy group (difference, -1.4%; 1-sided 95% CI, -7.4% to ∞; P value for noninferiority, <.001). No significant differences were observed between groups in overall survival, locoregional relapse, or distant metastasis. The IMRT-alone group experienced a significantly lower incidence of grade 3 to 4 adverse events (17% vs 46%; difference, -29% [95% CI, -39% to -20%]), including hematologic toxicities (leukopenia, neutropenia) and nonhematologic toxicities (nausea, vomiting, anorexia, weight loss, mucositis). The IMRT-alone group had significantly better QOL scores during radiotherapy including the domains of global health status, social functioning, fatigue, nausea and vomiting, pain, insomnia, appetite loss, and constipation. Conclusions and Relevance: Among patients with low-risk NPC, treatment with IMRT alone resulted in 3-year failure-free survival that was not inferior to concurrent chemoradiotherapy. Trial Registration: ClinicalTrials.gov Identifier: NCT02633202.

Variants of ERCC5 and the outcome of platinum-based regimens in non-small cell lung cancer: a prospective cohort study.

Excision repair complementary complex 5 (ERCC5) is an important component in the repair pathway of platinum-induced damage. The current study evaluated the effect of ERCC5 variants (rs751402 and rs1047768) on the clinical outcome of platinum-based regimens in non-small cell lung cancer (NSCLC) patients. A prospective, cohort study was conducted on 57 newly diagnosed NSCLC Egyptian patients. Patients received either cisplatin or carboplatin-based chemotherapy. DNA was extracted and the variants were analyzed using real time PCR. This study found no significant difference between the studied variants and patients' response to chemotherapy, progression-free survival (PFS) or overall survival (OS). However, a statistically significant association was found between the histologic subtypes and the studied variants (p = 0.028 and 0.018 for rs751402 and rs1047768, respectively). A statistically significant association was evident between the type of the allele present in the studied polymorphisms, p value = 0.000040. Moreover, the minor allele frequency (MAF) of the studied variants rs751402 and rs1047768 were similar to those of African and European populations, respectively. Results of this study have concluded that ERCC5 variants did not affect the clinical outcome of platinum-based chemotherapy in NSCLC. A significant coinheritance was found between the two variants of ERCC5. Moreover, the similarity between the MAF of the studied variants and the African or European population can guide future research when extrapolating data from African European populations to their Egyptian counterparts.

A randomized phase 3 trial of Gemcitabine or Nab-paclitaxel combined with cisPlatin as first-line treatment in patients with metastatic triple-negative breast cancer.

Platinum is recommended in combination with gemcitabine in the treatment of metastatic triple-negative breast cancer (mTNBC). We conduct a randomized phase 3, controlled, open-label trial to compare nab-paclitaxel/cisplatin (AP) with gemcitabine/cisplatin (GP) in mTNBC patients (ClinicalTrials.gov NCT02546934). 254 patients with untreated mTNBC randomly receive AP (nab-paclitaxel 125 mg/m² on day 1, 8 and cisplatin 75 mg/m² on day 1) or GP (gemcitabine 1250 mg/m² on day 1, 8 and cisplatin 75 mg/m² on day 1) intravenously every 3 weeks until progression disease, intolerable toxicity or withdrawal of consent. The primary endpoint is progression-free survival (PFS); secondary endpoints are objective response rate (ORR), safety and overall survival (OS). The trial has met pre-specified endpoints. The median PFS is 9.8 months with AP as compared to 7.4 months with GP (stratified HR, 0.67; 95% CI, 0.50-0.88; P = 0.004). AP significantly increases ORR (81.1% vs. 56.3%, P < 0.001) and prolongs OS (stratified HR, 0.62; 95% CI, 0.44-0.90; P = 0.010) to GP. Of grade 3 or 4 adverse events, a significantly higher incidence of neuropathy in AP and thrombocytopenia in GP is noted. These findings warrant further assessment of adding novel agents to the nab-paclitaxel/platinum backbone due to its high potency for patients with mTNBC.

Low-dose cisplatin exposure and SNAIL, Vimentin, E-cadherin expression in HEPG2 cell line / Exposición a dosis bajas de cisplatino y expresión de SNAIL, Vimentina, E-cadherina en línea celular HEPG2

Cisplatin, the first platinum compound approved for cancer treatment, is widely used in the treatment of various cancers including hepatocellular carcinoma (HCC). HCC incidence rates rise globally. Epithelial mesenchymal transition (EMT) is implicated in cancer invasion and metastasis, which are associated with increased mortality. Cisplatin dose might influence cancer invasion and metastatic behavior of the cells. The aim of the study was to investigate the effect of low-dose cisplatin treatment on EMT- related changes in HepG2 cells. Following treatment with 4 µM cisplatin, HepG2 cells were evaluated morphologically. Gene expression of E-cadherin, Vimentin, Snail1 was assessed by quantitative PCR. Immunofluorescence analyses of NA-K ATPase were performed. Although the low-dose cisplatin treated cells exhibited a more stretched morphology, no statistical difference was detected in gene expression of E-cadherin, Vimentin, Snail1 and immunofluorescence of NA-K ATPase. Findings on low-dose cisplatin effects in HepG2 might contribute to the knowledge of antineoplastic inefficacy by further understanding the molecular mechanisms of drug action.

El cisplatino, el primer compuesto de platino aprobado para el tratamiento del cáncer, es ampliamente utilizado en el tratamiento de varios tipos de cáncer, incluido el carcinoma hepatocelular (CHC). Las tasas de incidencia de CHC aumentan a nivel mundial. La transición mesenquimal epitelial (EMT) está implicada en la invasión del cáncer y la metástasis, que se asocian con un aumento de la mortalidad. La dosis de cisplatino podría influir en la invasión del cáncer y el comportamiento metastásico de las células. El objetivo del estudio fue investigar el efecto del tratamiento con dosis bajas de cisplatino en los cambios relacionados con la EMT en las células HepG2. Tras el tratamiento con cisplatino de 4 µM, se evaluaron morfológicamente las células HepG2. La expresión génica de E-cadherina, vimentina, caracol1 se evaluó mediante PCR cuantitativa. Se realizaron análisis de inmunofluorescencia de NA-K ATPasa . Aunque las células tratadas con cisplatino en dosis bajas exhibieron una morfología más estirada, no se detectaron diferencias estadísticas en la expresión génica de E-cadherina, vimentina, Snail1 e inmunofluorescencia de NA-K ATPasa. Los hallazgos sobre los efectos del cisplatino en dosis bajas en HepG2 podrían contribuir al conocimiento de la ineficacia antineoplásica al comprender mejor los mecanismos moleculares de la acción del fármaco.

Dose Modification of Etoposide plus Platinum in Elderly Patients with Extensive-Disease Small-Cell Lung Cancer.

BACKGROUND: Elderly patients with extensive-disease small-cell lung cancer (ED-SCLC) have a high risk of chemotherapy toxicity due to multiple comorbidities and poor performance status. Although dose modification is often used to avoid toxicity in elderly patients with ED-SCLC, there is little data on the effect of initial dose-reduced chemotherapy on survival outcomes. METHODS AND PATIENTS: We retrospectively reviewed 100 elderly patients (≥70 years) with ED-SCLC who received first-line etoposide plus platinum chemotherapy between January 2006 and December 2020. RESULTS: The median age was 74 years. Eighty-nine patients (89%) had a history of smoking, and 38 (38%) had chronic lung disease. Thirty-four patients (34%) received dose-reduced etoposide plus platinum in the first cycle. The dose-reduced group had significantly higher age, lower body mass index, and poor Eastern Cooperative Oncology Group Performance Score. There were no significant differences in survival outcomes between the dose-reduced and full-dose chemotherapy (median overall survival [OS], 4.9 vs. 6.5 months, p = 0.440; median progression-free survival [PFS], 3.7 vs. 4.6 months, p = 0.272). In multivariate analyses, DR in the first cycle (hazard ratio 0.519, 95% CI: 0.269-1.000, p = 0.050) was significantly associated with OS. Following a subgroup analysis of 59 patients who received minimum four cycles, no significant differences in survival outcomes between the two groups (median OS, 10.9 vs. 9.4 months, p = 0.817; median PFS, 6.3 vs. 6.5 months, p = 0.902) were noted. CONCLUSIONS: The dose-reduced chemotherapy with first-line etoposide plus platinum had non-inferior survival outcomes compared to the full-dose chemotherapy in elderly patients with ED-SCLC.