Platinum Analogues Research Articles

Retrospective analysis of patients with locally advanced or metastatic gastric cancer in Argentina.

To assess patient and disease characteristics, treatment patterns and associated costs in patients with locally advanced or metastatic gastric cancer in Argentina, in the public and private sectors. A historic cohort of patients who had received first-line chemotherapy treatment (platinum analog and/or a fluoropyrimidine) and were followed-up for at least three months after the last administration of a first-line cytotoxic agent were eligible. Case-report forms were prepared based on medical records from four Argentinian hospitals. Estimates of treatment costs were also calculated using the unit costs of the participating hospitals. Of 101 patients, more than three quarters (79.2%) were male, 41.6% were diagnosed with metastatic stage IV disease (mean age, 57.7years), and 27.7 % had a smoking history. Before locally advanced or metastatic gastric cancer diagnosis, 42.4% of the patients had received total gastrectomy. Ninety-seven percent of the patients received a doublet or triplet therapy, of which epirubicin in combination with oxaliplatin and capecitabine was the most common treatment (38%), followed by capecitabine plus oxaliplatin (29%). Around 36% of the patients responded to first-line treatment (complete and partial response). Out of the 76.2% of the patients who followed a second-line treatment, 37.7% were still administered a platinum analog and/or fluoropyrimidine. During the reported follow-up period, 50% of the patients progressed, and 32.8% had stable disease. The best supportive care consisted mostly of outpatient visits after last-line therapy (16.8%), palliative radiotherapy (16.8%), and surgery (30.7%). We observed significant differences between public and private hospital costs. Understanding treatment patterns in patients with locally advanced or metastatic gastric cancer may help address unmet medical needs for better patient management and improvement of their clinical outcome in Argentina.

ALDH-Dependent Glycolytic Activation Mediates Stemness and Paclitaxel Resistance in Patient-Derived Spheroid Models of Uterine Endometrial Cancer.

SummaryUterine endometrial cancer is associated with poor survival outcomes in patients with advanced-stage disease. Here, we developed a three-dimensional cell cultivation method of endometrioid cancer stem-like cells with high aldehyde dehydrogenase (ALDH) activity from clinical specimens. ALDH inhibition synergized with paclitaxel to block cancer proliferation. In the clinical setting, high ALDH1A1 expression was associated with poor survival. A high level of ALDH correlated with an increase of glucose uptake, activation of the glycolytic pathway, and elevation of glucose transporter 1 (GLUT1). Blockade of GLUT1 inhibited characteristics of cancer stem cells. Similarly to ALDH inhibition, GLUT1 inhibition synergized with paclitaxel to block endometrial cancer proliferation. Our data indicated that ALDH-dependent GLUT1 activation and the resulting glycolytic activation are of clinical importance for both prognostic evaluation and therapeutic decision-making in endometrial cancer patients. In addition, the synergistic effects of taxane compounds and ALDH or GLUT1 inhibitors may serve as a new clinical treatment option for endometrial cancer.

New Platinum-Based Prodrug Pt(IV)Ac-POA: Antitumour Effects in Rat C6 Glioblastoma Cells.

Gliomas are the most frequent primary tumours of the nervous system, characterised by high degree of malignancy, widespread invasion and high-rate proliferation. Cisplatin and analogue are currently employed in clinical trials as active chemotherapeutic agents for the systemic treatment of this type of malignancy. Despite therapy benefits, clinical use of these agents is hampered by severe side effects including neurotoxicity. Therefore, the aim of the present study was to analyse the effect of a new compound of platinum(IV) conjugate, named Pt(IV)Ac-POA, which can generate a synergistic antineoplastic action when released along with cisplatin, after a specific reduction reaction within tumour cells. To assess the effects of the novel compound on rat C6 glioma cells, cell cycle and cell death activation analyses were carried out using flow cytometry. Morphological changes and activation of different cell death pathways were evaluated by both transmission electron microscopy and immunofluorescence microscopy. Protein expression was investigated by western blotting analysis. The novel compound Pt(IV)Ac-POA, bearing as axial ligand (2-propynyl)octanoic acid (POA), which is a histone deacetylase inhibitor (HDACi), acts as a prodrug in tumour cells, inducing cell death through different pathways at a concentration lower than those tested for other platinum analogues. The current results showed that Pt(IV)Ac-POA could represent a promising improvement of Pt-based chemotherapy against gliomas, either inducing a chemosensitisation and reducing chemoresistance.

Retrospective analysis of patients with advanced or metastatic gastric cancer in Colombia

Aims: To assess patient and disease characteristics, treatment patterns, and associated costs in patients with advanced or metastatic gastric cancer (A/MGC) in Colombia, in both the public and private hospitals.Materials and methods: A total of 145 patients who had received first-line chemotherapy treatment (platinum analog and/or a fluoropyrimidine) and were followed for at least 3 months after the last administration of a first-line cytotoxic agent were eligible for inclusion. Case-report forms were elaborated based on the patients’ medical records from three Colombian hospitals. Estimates of treatment costs were calculated using unit costs from the participating hospitals.Results: Of the 145 patients, more than half (64.83%) were male, 79.56% were diagnosed with metastatic stage IV disease (mean age = 58.14 years). Prior to MGC diagnosis, 31.71% of the patients being operated on received a total gastrectomy; 66.9% of the patients received a doublet therapy, of which 5-fluorouracil (5-FU) in combination with cisplatin was the standard treatment (14%), followed by combination with leucovorin (12%). Only around 10% of the patients responded to first-line treatment. Out of 41.38% of the patients who received a second-line treatment, 71.67% were still administered a platinum analog and/or fluoropyrimidine. During the follow-up period, 52% of the patients progressed and 20% achieved stable disease. Best supportive care mostly consisted of outpatient visits after last line-therapy (72.41%), palliative radiotherapy (18.6%), and surgery (37.2%).Limitations and conclusions: Gastric cancer is one of the main causes of cancer-related death in Colombia, as most of the patients are diagnosed at an advanced stage, when prognosis is poor. Treatment patterns are highly heterogeneous. Second-line treatments were mostly initiated with paclitaxel, capecitabine, irinotecan, or cisplatin.

Medical interventions for the prevention of platinum-induced hearing loss in children with cancer.

Medical interventions for the prevention of platinum-induced hearing loss in children with cancer.

Synthesis, solution behaviour and potential anticancer activity of new trinuclear organometallic palladium(II) complex of {S}-1-phenylethyl dithiooxamide: Comparison with the trinuclear heterobimetallic platinum(II) analogue

Addition of H2R2DTO (R = {S}-1-phenylethyl and DTO = dithiooxamide) to the bis(benzonitrile)palladium(II) chloride complex in chloroform afforded the mononuclear Pd(DTO)2·2HCl complex. The complex treated with NaHCO3 for removing of HCl and then reacted with [Pd(ƞ3-allyl)(µ-Cl)]2 for preparation of a new trimetallic organopalladium(II) complex. The molecular structure of the trimetallic complex was determined by X-ray diffraction indicating a planar geometry around each palladium center. Also, variable temperature spectroscopy for this complex was performed in CDCl3 in the range 298–390 K, and simulations of the dynamic spectra were performed using the gNMR program. A comparison between the target-based activity of the Pd(II) complex and its trinuclear heterobimetallic platinum(II) analogue as potential anticancer agents was also conducted. All the biological tests showed that both Pd(II) and Pt(II) complexes can fairly inhibit cathepsin B (Cat-B) and cathepsin L (Cat-L) as well as two out of three activities of 20S proteasome.

Malignant Pleural Mesothelioma: Is Tailoring the Second-Line Therapy Really “Raising the Bar?”

Unresectable or relapsed malignant pleural mesothelioma (MPM) has dismal prognosis. First-line combination therapy with pemetrexed and a platinum analog allows a modest survival benefit, while no clear therapeutic options exist for the second-line therapy. In this setting, pemetrexed seems to be the most active drug; however, the inclusion in front-line treatment limits its use in further lines. Nevertheless, rechallenge with one or both drugs used in first-line remains a feasible strategy for responder patients. Alternatively, only few cytotoxic drugs have demonstrated a mild activity in refractory MPM. Among other options, targeted therapy has unfortunately produced disappointing results as salvage treatment probably due to the lack of a clear understanding of the tumor biology. In contrast, recent data suggest moderate efficacy and mild toxicity of immunotherapy also for the treatment of MPM. The combination of checkpoint inhibitors with chemotherapy or other immunological agents seems promising and could really "raise the bar" in this setting.

Delineation of proapoptotic signaling of anthracene-shelled M2L4 metallacapsules and their synergistic activity with curcumin in cisplatin-sensitive and resistant tumor cell lines.

Since the introduction of cisplatin into clinical practice a few decades ago, the topic of metal-based drugs has expanded significantly. Recent examples emphasize on metallosupramolecules as an emerging class of compounds with diverse properties. They can trigger unique cellular events in malignant cells or serve as molecular hosts for various biologically active compounds, including anticancer agents. The anthracene-shelled M2L4 coordination nanocapsules under research have already proved very high anticancer potency with remarkable selectivity and lack of cross-resistance. In this study, we provide an oncopharmacological evaluation of the Pt(II)- and Pd(II)-clipped M2L4 nanocapsules; we report a thorough analysis of their synergistic effects in combined treatments with the pleiotropic anticancer agent curcumin. We examined changes in cellular expression of several apoptosis-related proteins in a panel of tumor cell lines with different chemosensitivity towards cisplatin, i.e. HT-29, HL-60 and its resistant strains HL-60/CDDP and HL-60/Dox, in order to assess the molecular mechanisms of their antitumor activity The results of the immunoassay concluded activation of the mitochondrial apoptotic pathway in all the screened tumor lines. A prevalent modulation of the extrinsic apoptotic signaling cascade was observed in the chemoresistant variants. Curcumin interactions of the tested compounds were estimated against the cisplatin-refractory cell line HT-29 via the Chou-Talalay method (CTM), whereby the palladium species yielded superior synergistic activity as compared to their platinum analogues.

A retrospective analysis of cisplatin/carboplatin plus paclitaxel in advanced or recurrent cervical cancer

To compare the efficacy and safety of paclitaxel plus carboplatin (TC) and paclitaxel plus cisplatin (TP) in the treatment of advanced or recurrent cervical cancer, this retrospective study included 116 advanced or recurrent cervical cancer cases treated at Beijing Obstetrics and Gynecology Hospital between June 2002 and June 2014. Of these cases, 52 were treated with TC (TC group) and 64 were treated with TP (TP group). We found that the overall survival and response and disease-control rates were not significantly different between the two groups. The TC group had a markedly lower incidence of Grade III–IV gastrointestinal toxicity reactions and a shorter hospitalisation stay than the TP group. The incidences of Grade III–IV bone marrow suppression and renal toxicity were not significantly different between the TP and TC groups. These findings suggest that TC may be a safe and effective alternative to TP for the treatment of advanced or recurrent cervical cancer.Impact StatementWhat is already known on this subject: Paclitaxel plus cisplatin (TP) is regarded as the standard regimen for cervical cancer, nevertheless, cisplatin is always associated with nephrotoxicity and requires hydration therapy. Carboplatin is a platinum analogue with milder nephrotoxicity than cisplatin. It is reported that carboplatin may be a viable and less toxic alternative to cisplatin in the management of advanced or recurrent cervical cancer, but another study shows that the therapeutic efficacy of paclitaxel plus carboplatin (TC) is non-inferior to that of TP.What the results of this study add: This study compared the efficacy and safety of TC and TP, and found that the TC and TP groups had similar overall response and disease-control rates and survival, but the TC group was better tolerated with a markedly lower incidence of Grades III–IV gastrointestinal toxicity reactions and had a shorter hospitalisation stay than the TP group.What the implications are of these findings for clinical practice and/or further research: TC may be a safe and effective alternative to TP for the treatment of advanced or recurrent cervical cancer in clinical practice.

Cisplatin-Membrane Interactions and Their Influence on Platinum Complexes Activity and Toxicity.

Cisplatin and other platinum(II) analogs are widely used in clinical practice as anti-cancer drugs for a wide range of tumors. The primary mechanism by which they exert their action is through the formation of adducts with genomic DNA. However, multiple cellular targets by platinum(II) complexes have been described. In particular, the early events occurring at the plasma membrane (PM), i.e., platinum-membrane interactions seem to be involved in the uptake, cytotoxicity and cell-resistance to cisplatin. In fact, PM influences signaling events, and cisplatin-induced changes on membrane organization and fluidity were shown to activate apoptotic pathways. This review critically discusses the sequence of events caused by lipid membrane-platinum interactions, with emphasis on the mechanisms that lead to changes in the biophysical properties of the membranes (e.g., fluidity and permeability), and how these correlate with sensitivity and resistance phenotypes of cells to platinum(II) complexes.

AC138128.1 an Intronic lncRNA originating from ERCC1 Implies a Potential Application in Lung Cancer Treatment.

Lung cancer is one of the most devastating tumors with a high incidence and mortality worldwide. Polymorphisms and expression of ERCC1 commonly predicted the occurrence and prognosis of lung cancer. However, few studies have focused on long non-coding RNAs related to ERCC1 though some studies reminded the importance of its post-transcriptional regulation. In the present study, an intronic lncRNA AC138128.1 originated from ERCC1 was firstly identified in microarray chip and database, and its possibility as a novel biomarker to predict lung cancer treatment was further discussed. Firstly, the qRT-PCR data showed that AC138128.1 expression was much lower in lung cancer comparing with its para-cancer tissues, which further analyzed by ROC curve. Similarly, the difference was also verified in 16HBE, A549 and LK2 cells. Then AC138128.1 expression was found to have an increasing trend in a dose or time-dependent manner after cisplatin treatment. Finally, the subcellular distribution of AC138128.1 reminded that AC138128.1 was mainly expressed in the nucleus. Interestingly a positive relationship between AC138128.1 and ERCC1 expression was only found in cancer tissues, which reminded AC138128.1 may be involved in the regulation of ERCC1. Therefore, as a preliminary exploration of the lncRNA originated from ERCC1, the present study suggested AC138128.1 is of potential value in predicting platinum analogue benefit in lung cancer.

Cochrane corner: platinum-induced hearing loss after treatment for childhood cancer

This Cochrane Corner features the review entitled “Platinum-induced hearing loss after treatment for childhood cancer” published in 2016. In their review, van As et al. identified 13 cohort studies including 2837 participants with a hearing test after treatment with a platinum-based therapy for different types of childhood cancers. All studies had problems related to quality of the evidence. The reported frequency of hearing loss varied between 1.7% and 90.1% for studies that included a definition of hearing loss; none of the studies provided data on tinnitus. Only two studies evaluated possible risk factors. One study found a higher risk of hearing loss in people treated with the combination of cisplatin plus carboplatin compared to treatment with cisplatin only and for exposure to aminoglycosides. The other found that age at treatment (lower risk in older children) and single maximum cisplatin dose (higher risk with an increasing dose) were significant predictors for hearing loss, while gender was not. This systematic review shows that children treated with platinum analogues are at risk of developing hearing loss, but the exact prevalence and risk factors remain unclear.

Abstract IA17: PARP inhibitor resistance in prostate cancer

Abstract Large-scale genomic studies have demonstrated that approximately 15% of metastatic castration-resistant prostate cancer (mCRPC) harbors genetic and epigenetic alterations in homologous recombination repair (HRR) pathway genes. The most commonly altered HRR genes are BRCA2, BRCA1, and ATM, followed by other Fanconi anemia genes including FANCN/PALB2 and FANCA. Loss of HRR causes genomic instability, hyperdependence on alternative DNA repair mechanisms, and enhanced sensitivity to platinum analogues and PARP inhibitors (PARPi). The synthetic lethal interaction with PARPi is being exploited therapeutically in diverse clinical contexts and most notably in BRCA2-deficient mCRPC where the PARPi olaparib has demonstrated improvements in progression-free survival. PARPi resistance has already emerged as a vexing clinical problem for the treatment of BRCA1/2-deficient tumors. The most prevalent mechanism of PARPi resistance is secondary events that cancel the original HRR alteration and restore HRR proficiency. These somatic reversions of mutant BRCA2 alleles can be monitored by sequencing of ctDNA. However, PARPi resistance may also develop without restoration of HRR proficiency via disruption of multiple proteins, such as PTIP or CHD4, that leads to replication fork (RF) stabilization. Importantly, this latter mechanism—namely, the restoration of RF stability—appears to be a highly prevalent mechanism of PARP inhibitor resistance in vitro and in vivo, particularly in tumor cells with an underlying BRCA2 deficiency. Due to their underlying deficiency in BRCA2 and inability to generate RAD51 nucleofilaments, these tumor cells are unable to restore HRR mechanisms. Instead, these cells acquire may PARPi resistance by limiting the nucleolytic degradation of their stalled replication forks. We have recently made the surprising observation that BRCA2-deficient ovarian and breast cancer cells can become resistant to PARPi by downregulating the expression of the polycomb repressive complex PRC2, a methyltransferase complex containing EZH2, SUZ12, EED, and RbAp48. Importantly, downregulation of PRC2 results in the reduced recruitment of the nuclease MUS81 to the RF, thereby providing a novel mechanism of RF protection and PARPi resistance. Whether or not the downregulation of the PRC2/MUS81 pathway is also a mechanism of PARPi resistance in mCRPC remains to be determined. A molecular understanding of PARPi resistance mechanisms may allow the generation of a new class of drugs, or a repurposing of existing drugs, which may reverse this resistance and extend the use of PARPi to more tumor types. Citation Format: Alan D. D’Andrea. PARP inhibitor resistance in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr IA17.

Abstract IA15: PARP inhibitor resistance and acquired vulnerability in breast cancer

Abstract Large-scale genomic studies have demonstrated that some breast cancers, especially triple-negative breast cancers (TNBCs), harbor genetic and epigenetic alterations in homologous recombination repair (HRR) pathway genes. The most commonly altered HRR genes are BRCA1 and BRCA2, followed by other Fanconi anemia genes including FANCN/PALB2, FANCO/RAD51, FANCJ/BRIP, and FANCA. Loss of HRR causes genomic instability, hyperdependence on alternative DNA repair mechanisms, and enhanced sensitivity to platinum analogues, topoisomerase inhibitors, and PARP inhibitors (PARPi). The synthetic lethal interaction with PARPi is being exploited therapeutically in diverse clinical contexts and most notably in ovarian cancer where the PARPi olaparib is FDA approved for use in patients with germline BRCA1/2 mutations. PARP inhibitor resistance has already emerged as a vexing clinical problem for the treatment of BRCA1/2 deficient tumors. The most prevalent mechanism of PARPi resistance is secondary events that cancel the original HRR alteration and restore HRR proficiency. However, PARPi resistance may still develop without restoration of HRR proficiency via disruption of multiple proteins, such as PTIP or CHD4, that leads to replication fork (RF) stabilization. Importantly, this latter mechanism—namely, the restoration of RF stability—appears to be a highly prevalent mechanism of PARP inhibitor resistance in vitro and in vivo, particularly in tumor cells with an underlying BRCA2 deficiency. Due to their underlying deficiency in BRCA2 and inability to generate RAD51 nucleofilaments, these tumor cells are unable to restore HRR mechanisms. Instead, these cells acquire PARP inhibitor resistance by limiting the nucleolytic degradation of their stalled replication forks. We have recently made the surprising observation that BRCA2-deficient tumors can become resistant to PARPi by downregulating the expression of the polycomb repressive complex PRC2, a methyltransferase complex containing EZH2, SUZ12, EED, and RbAp48. Importantly, downregulation of PRC2 results in the reduced recruitment of the nuclease MUS81 to the RF, thereby providing a novel mechanism of RF protection and PARPi resistance. A molecular understanding of PARP inhibitor resistance mechanisms may allow the generation of a new class of drugs, or a repurposing of existing drugs, which may reverse this resistance and extend the use of PARP inhibitors to more tumor types. Citation Format: Alan D. D’Andrea. PARP inhibitor resistance and acquired vulnerability in breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr IA15.

Different infusion durations for preventing platinum-induced hearing loss in children with cancer.

Platinum-based therapy, including cisplatin, carboplatin or oxaliplatin, or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this ototoxicity, different platinum infusion durations have been studied. This review is the second update of a previously published Cochrane review. To assess the effects of different durations of platinum infusion to prevent hearing loss or tinnitus, or both, in children with cancer. Secondary objectives were to assess possible effects of these infusion durations on: a) anti-tumour efficacy of platinum-based therapy, b) adverse effects other than hearing loss or tinnitus, and c) quality of life. We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library 15 March 2018), MEDLINE (PubMed) (1945 to 15 March 2018) and Embase (Ovid) (1980 to 15 March 2018). In addition, we handsearched reference lists of relevant articles and we assessed the conference proceedings of the International Society for Paediatric Oncology (2009 up to and including 2017) and the American Society of Pediatric Hematology/Oncology (2014 up to and including 2017). We scanned ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; apps.who.int/trialsearch) for ongoing trials (searched on 12 March 2018 and 13 March 2018 respectively). Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing different platinum infusion durations in children with cancer. Only the platinum infusion duration could differ between the treatment groups. Two review authors independently performed the study selection, 'Risk of bias' assessment and GRADE assessment of included studies, and data extraction including adverse effects. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We identified one RCT and no CCTs; in this update no additional studies were identified. The RCT (total number of children = 91) evaluated the use of a continuous cisplatin infusion (N = 43) versus a one-hour bolus cisplatin infusion (N = 48) in children with neuroblastoma. For the continuous infusion, cisplatin was administered on days one to five of the cycle, but it is unclear if the infusion duration was a total of five days. Risk of bias was present. Only results from shortly after induction therapy were provided. No clear evidence of a difference in hearing loss (defined as asymptomatic and symptomatic disease combined) between the different infusion durations was identified as results were imprecise (risk ratio (RR) 1.39, 95% confidence interval (CI) 0.47 to 4.13, low-quality evidence). Although the numbers of children were not provided, it was stated that tumour response was equivalent in both treatment arms. With regard to adverse effects other than ototoxicity, we were only able to assess toxic deaths. Again, the confidence interval of the estimated effect was too wide to exclude differences between the treatment groups (RR 1.12, 95% CI 0.07 to 17.31, low-quality evidence). No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life) or for other (combinations of) infusion durations or other platinum analogues. Since only one eligible RCT evaluating the use of a continuous cisplatin infusion versus a one-hour bolus cisplatin infusion was found, and that had methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. For other (combinations of) infusion durations and other platinum analogues no eligible studies were identified. More high-quality research is needed.

A PROSPECTIVE STUDY OF ADVERSE DRUG REACTIONS DUE TO PLATINUM ANALOGS - CHEMOTHERAPY IN A TERTIARY CARE HOSPITAL

Objective: The objective of this study was to analyze the types of adverse drug reactions (ADRs) associated with platinum analogs (cisplatin, carboplatin and oxaliplatin) used for cancer chemotherapy in a tertiary care hospital and determine their causal relationship with the offending drug.Methods: This prospective, observational, non-interventional study was conducted in a tertiary care hospital at GSVM Medical College Kanpur, India, for 4 months. Patients of all age and either sex were included in the study. ADRs were reported by the physicians of oncology department of the hospital and ADRs were assessed for different parameters -causality, outcome, and seriousness of ADR as per the World Health Organization (WHO), type of ADRs as per expanded Rawlins and Thompson’s classification, predictability using council for international organization of medical sciences guidelines and severity using modified Hartwig’s scale. Descriptive statistics were used for data analysis.Results: A total of 140 ADRs were reported from platinum analogs following treatment of different types of cancer in hospital. The burden of ADRs in each patient was 2.41. Most of the ADRs were observed in the age group of 40–60 years. Vomiting (27 ADRs) was commonly reported reaction. Among platinum analogs, cisplatin leads to 82 ADRs (58.57%) followed by carboplatin with 53 ADRs (37.86%) and least with oxaliplatin 5 ADRs (3.57%). Most of the ADRs on causality assessment were possible (104, 74.29%) and probable (36, 25.71%) in nature. Type -A ADRs account for 4/5th of the total reported ADRs, followed by Type-B and C. Severity of 90.71% ADRs was found to be mild followed by moderate, with no case of severe and serious nature. Nearly, most of the ADRs were of predictable type (97.14%).Conclusion: The potential of platinum analogs to cause ADRs is high; thus, the need of effective ADRs monitoring is highly emphasized.

5. Neurophysiological dysfunction in chemotherapy-treated patients: Comparison of different platinum analogues

Objective Chemotherapy-induced peripheral neuropathy is a prominent side effect of treatment with platinum-based chemotherapies cisplatin and oxaliplatin. Progressive abnormalities in sensory axonal excitability have been linked to neuropathy severity in oxaliplatin-treated patients, but not examined in cisplatin-treated patients. Methods Sensory axonal excitability studies were undertaken in median nerve. Neuropathy was assessed via total neuropathy score reduced (TNSr). Results Clinical severity of neuropathy was greater (TNSr: 6.9 ± 1.2) in oxaliplatin-treated patients (N = 16, Age: 57.1 ± 3 years, cumulative dose: 801 ± 63.5 mg/m 2 , median 6 months post-completion IQR: 4–12.5) than in cisplatin-treated patients (TNSr: 3.2 ± 0.6, p . 01 , N = 17, Age: 48.5 ± 4.3 years, cumulative dose: 316.5 ± 19.3 mg/m 2 , median 7 months post-completion IQR: 3–30.5). Cisplatin and oxaliplatin-treated patients demonstrated deficits in sensory nerve function compared to controls, with increased threshold change in excitability (TEh90-100 ms Cis: −128.7 ± 4.7%; Ox: −140.9 ± 5.9%; control: −116.6 ± 3.1%, p . 01 ) and reduced median sensory amplitudes (Cis: 24.4 ± 3.0 μ V; Ox: 15.7 ± 3.0 μ V; control: 43.9 ± 1.1 μ V, p . 01 ) with greater abnormalities in oxaliplatin-treated patients ( p . 01 ). TEh90-100 ms was correlated to median amplitude (r = .418, p . 05 ), with patients demonstrating greater excitability abnormalities also demonstrating greater reduction in sensory amplitude. Conclusions Changes in axonal excitability parameters are consistent between platinum-based chemotherapies and linked to neuropathy severity. Significance Platinum analogues demonstrate similar pathophysiological mechanisms of nerve dysfunction. Axonal excitability techniques may provide a marker of axonal dysfunction across different platinum chemotherapies.

When Do Strongly Coupled Diradicals Show Strongly Coupled Reactivity? Thermodynamics and Kinetics of Hydrogen Atom Transfer Reactions of Palladium and Platinum Bis(iminosemiquinone) Complexes.

The 2,2'-biphenylene-bridged bis(iminosemiquinone) complexes ( tBuClip)M [ tBuClipH4 = 4,4'-di- tert-butyl- N, N'-bis(3,5-di- tert-butyl-2-hydroxyphenyl)-2,2'-diaminobiphenyl; M = Pd, Pt] can be reduced to the bis(aminophenoxide) complexes ( tBuClipH2)M by reaction with hydrazobenzene (M = Pd) or by catalytic hydrogenation (M = Pt). The palladium complex with one aminophenoxide ligand and one iminosemiquinone ligand, ( tBuClipH)Pd, is generated by comproportionation of ( tBuClip)Pd with ( tBuClipH2)Pd in a process that is both slow (0.06 M-1 s-1 in toluene at 23 °C) and only modestly favorable ( Kcom = 1.9 in CDCl3), indicating that both N-H bonds have essentially the same bond strength. The mono(iminoquinone) complex ( tBuClipH)Pt has not been observed, indicating that the platinum analogue shows no tendency to comproportionate ( Kcom < 0.1). The average bond dissociation free energies (BDFE) of the complexes have been established by equilibration with suitably substituted hydrazobenzenes, and the palladium bis(iminosemiquinone) is markedly more oxidizing than the platinum compound, with hydrogen transfer from ( tBuClipH2)Pt to ( tBuClip)Pd occurring with Δ G° = -8.9 kcal mol-1. The palladium complex ( tBuClipH2)Pd reacts with nitroxyl radicals in two observable steps, with the first hydrogen transfer taking place slightly faster than the second. In the platinum analogue, the first hydrogen transfer is much slower than the second, presumably because the N-H bond in the monoradical complex ( tBuClipH)Pt is unusually weak. Using driving force-rate correlations, it is estimated that this bond has a BDFE of 55.1 kcal mol-1, which is 7.1 kcal mol-1 weaker than that of the first N-H bond in ( tBuClipH2)Pt. The two radical centers in the platinum, but not the palladium, complex thus act in concert with each other and display a strong thermodynamic bias toward two-electron reactivity. The greater thermodynamic and kinetic coupling in the platinum complex is attributed to the stronger metal-ligand π interactions in this compound.

Phase II study of olaparib for BRCAness phenotype in pancreatic cancer.

297 Background: The subtype of pancreatic ductal adenocarcinoma cancer (PDAC) patients with DNA damage repair (DDR) deficiency from BRCA1/2 mutations has a favorable prognosis and is sensitive to platinum analogues and PARP inhibition. About 10-20% of PDAC patients have DDR deficiency without BRCA mutations (BRCA ness). The efficacy of olaparib in this population is unknown. Methods: Two parallel phases II trials (Israel and U.S.) are ongoing to determine the efficacy of olaparib in advanced PDAC with BRCA ness. Inclusion criteria: ≥ 1 prior systemic therapy for advanced PDAC, ECOG 0-1, germline BRCA 1/ 2 ( gBRCA) mutation negative, previously known DDR genetic aberrations (DDR-GA), family history of BRCA-associated cancers in ≥2 first-degree relatives (without DDR-GA), ATM loss by IHC (Israel only). Primary and secondary endpoints are objective response rate and PFS, respectively. With an type I error rate α of 0.1 and a β error rate of 0.2, and assuming P0 and P1 are 5% and 20%, respectively, study will enroll 24 patients at each site. Results: Thus far, 21 and 11 patients treated in Israel and U.S; respectively. DDR phenotype: Family history of BRCA cancer without DDR-GA (n = 14), DDR-GA (n = 12), ATM loss by IHC (n = 5). DDR-GAs were ATM (n = 6), PALB2 (n = 1), BRCA somatic (2), FANCB (1), PTEN (1) and CCNE1 (1). Efficacy data are in Table. Common toxicities were grade 1-2 anemia, fatigue and nausea. No responses were observed in platinum refractory cases. Conclusions: Olaparib was tolerated well in this study population. Olaparib showed encouraging initial antitumor activity in platinum-sensitive, gBRCA negative PDAC patients with DDR GA and in patients with family history of BRCA cancers (without identifiable DDR-GA). Clinical trial information: NCT02677038 ; NCT02511223. [Table: see text]

Bevacizumab Added to Moderate-dose Chemotherapy for Refractory Uterine Cancer.

Bevacizumab (bev), when added to a moderate dose combination of previously failed cytotoxins, as a third- and fourth-line therapy for refractory gastric, cholangiocarcinoma, and ovarian cancers, produced high-quality responses. The regimen was based on preclinical models designed in order to simultaneously partner both bev and each of the cytotoxins with 4-5 synergistic drugs. Eligible patients (n=9) had high-grade endometrial tumors and had failed standard chemotherapy. Bev (10 mg/kg every 2 weeks) and cyclophosphamide (150-250 mg/m2), were added to a combination of gemcitabine, fluorouracil, leucovorin, irinotecan and a platinum analogue -first without and then with docetaxel- each at approximately 1/2 to 1/3 of their standard dosage. Dose modification aimed at a repeated absolute neutrophil count (ANC) of 750-1,500 μl or platelets of 125,000-75,000 μl. Safety measures included stop-go use (intermittent, as needed, brief withholding of bev with resumption when again tolerated), of bev, and both prospective and ongoing dose modification in order to protect the bowels. Induction treatment was free of life-threatening complications. Nine consecutive patients, 3 under second- and 6 under multi-line treatment, had 9 objective responses and 8 produced long clinical benefits, 2 of which were complete responses. Seven responses created opportunities for personalized added treatment and research. Absolute median survival was 21.5 months for the 8 patients with platinum-resistant tumors. One patient was unable to tolerate a first standard adjuvant dose of paclitaxel. After rapid peritoneal progression of disease, treatment has produced 52+ months of unmaintained complete remission. Bev, in the combination that was used in this study, meets response, survival, and toxicity criteria for further testing against second- or multi-line chemotherapy-resistant tumors and also when a standard treatment is not safe.