Immune checkpoint inhibitors versus second line chemotherapy for patients with lung cancer refractory to first line chemotherapy.

PURPOSE: Anti Programmed Death-ligand (PD1/PD-L1) directed immune-checkpoint-inhibitors (ICI) are widely used to treat patients with advanced non-small cell lung cancer (NSCLC) who progress after first line chemotherapy. The best strategy after early progression under first line has not been specifically studied. PATIENTS AND METHODS: We conducted a multicenter, retrospective study including all consecutive NSCLC patients progressing within the first 3 months following introduction of first-line chemotherapy and being treated with second line ICI monotherapy or chemotherapy between March 2010 and November 2017. We analysed the clinicopathological data and outcome under second line chemotherapy vs. second line ICI: objective response rate (ORR), progression-free survival (PFS), overall survival (OS. RESULTS: We identified 176 patients with refractory disease, 99 who received subsequent immunotherapy and 77 undergoing chemotherapy. The 2 populations were comparable regarding the main prognostic criteria, median age was 60, main histology was adenocarcimoma (68.2%). PFS was not significantly different between both treatments 1.9 [1.8-2.1] versus 1.6 month [1.4-2.0] (P=0.125). Compared to chemotherapy, ICI treated patients had a superior OS (P=0.03) (Median [95% CI] OS 4.6 [2.8-6.7] versus 4.2 months [3.4-5.9] and a non-significant improvement in ORR (17.2% versus 7.9%, respectively, P=0.072). Poor performance status (ECOG PS≥2) and a higher number of metastatic sites (≥3) were associated with poorer prognosis. KRAS-mutated patients did not seem to benefit more from ICI than chemotherapy. CONCLUSIONS: ICI appears to be the preferred second-line treatment for patients who are refractory to first line chemotherapy.

The prognostic impact of immune-related adverse events during anti-PD1 treatment in melanoma and non-small-cell lung cancer: a real-life retrospective study.

Background: Nivolumab and pembrolizumab, two PD1 inhibitors, trigger immune-related adverse events in approximately 50% of patients. Our objective was to determine whether these immune-related adverse events are associated with patient outcomes. Patients and Methods: Retrospective cohort study, realized at the Institut Universitaire du Cancer de Toulouse, of all the patients treated with nivolumab or pembrolizumab off clinical trials. We included patients (i) diagnosed with unresectable stage III or stage IV melanoma or with recurrent stage IIIB or stage IV non-small cell lung cancer (ii) on nivolumab 3mg/kg or pembrolizumab 2mg/kg every 2 or 3 weeks respectively. Results: Of the 311 patients included (of 641 eligible subjects), 120 (38.6%) had melanoma and 191 (61.4%) had non-small cell lung cancer; 241 (77.5%) were treated with nivolumab with a median follow-up of 24 months (20-29). We observed 166 immune-related adverse events in 116 (37.3%) patients, categorized as "early" (onset before 12 weeks in melanoma and before 8 weeks in lung cancer) in 63 (54.3%) patients. Early and late adverse events were significantly associated with an increase in overall survival: adjusted hazard ratio 0.58 [0.41-0.84] (p = .003) and 0.28 [0.16-0.50] (p < .001) respectively. The overall response rate was significantly increased in patients with an immune-related adverse event (53.9% vs 12.9%, p < .001) Conclusions: This study validates the association between immune-related adverse events and anti-PD1 efficacy in real-life, especially if these events are delayed. Our results, along with further studies on the place of immunosuppressive drugs in the therapeutic strategy, could improve the management of these adverse events.

Dose banding as an alternative to body surface area-based dosing of chemotherapeutic agents.

BACKGROUND: Dose banding is a recently suggested dosing method that uses predefined ranges (bands) of body surface area (BSA) to calculate each patient's dose by using a single BSA-value per band. Thus, drugs with sufficient long-term stability can be prepared in advance. The main advantages of dose banding are to reduce patient waiting time and improve pharmacy capacity planning; additional benefits include reduced medication errors, reduced drug wastage, and prospective quality control. This study compares dose banding with individual BSA dosing and fixed dose according to pharmacokinetic criteria. METHODS: Three BSA bands were defined: BSA<1.7 m(2), 1.7 m(2)≤ BSA<1.9 m(2), BSA ≥ 1.9 m(2) and each patient dose was calculated based on a unique BSA-value per band (1.55, 1.80, and 2.05 m(2), respectively). By using individual clearance values of six drugs (cisplatin, docetaxel, paclitaxel, doxorubicin, irinotecan, and topotecan) from 1012 adult cancer patients in total, the AUCs corresponding to three dosing methods (BSA dosing, dose banding, and fixed dose) were compared with a target AUC for each drug. RESULTS: For all six drugs, the per cent variation in individual dose obtained with dose banding compared with BSA dosing ranged between -14% and +22%, and distribution of AUC values was very similar with both dosing methods. In terms of reaching the target AUC, there was no significant difference in precision between dose banding and BSA dosing, except for paclitaxel (32.0% vs 30.7%, respectively; P<0.05). However, precision was significantly better for BSA dosing compared with fixed dose for four out of six drugs. CONCLUSION: For the studied drugs, implementation of dose banding should be considered as it entails no significant increase in interindividual plasma exposure.

Clinical pharmacodynamic factors in docetaxel toxicity.

Neutropenia is the main dose-limiting toxicity occurring in docetaxel treatment. The objective of this study was to identify pharmacodynamic (PD) factors responsible for the neutropaenia caused by docetaxel. Data were obtained from 92 patients treated with docetaxel as a monochemotherapy in two different treatment centres. A semiphysiological population pharmacokinetic-pharmacodynamic (PK/PD) model was applied to describe the time course of neutrophils and the neutropaenic effect of docetaxel. The plasma docetaxel concentration was assumed to inhibit the proliferation of neutrophil precursors through a linear model: Drug effect=Slope x Conc. Slope corresponds to the patients' sensitivity to the neutropaenic effect of docetaxel. Covariate analysis was performed by testing the relationship between the patients' characteristics and Slope using the program NONMEM. The neutropaenic effect of docetaxel showed a high interindividual variability. Three significant PD covariates were identified: serum alpha1-acid glycoprotein levels (AAG), level of chemotherapy pretreatment, and treatment centre. Extensive pretreatment was associated with an increase in Slope values meaning a higher haematotoxicity. An increase in AAG was associated with a decrease of both Slope and docetaxel plasma clearance. Patients treated in one centre had both higher Slope and docetaxel clearance. The centre effect (most likely due to a bias in the PK part of the study between the two centres) reveals the robustness of the PK/PD model. Individual dosing of docetaxel should be based on previous chemotherapy but not on the AAG level since it has a similar influence on PD and PK docetaxel parameters. This methodology should be applied to further investigate elderly patients and to identify more precisely the characteristics of previous chemotherapy that contribute to the cumulative myelotoxicity.

Dexamethasone as a probe for CYP3A4 metabolism: evidence of gender effect.

BACKGROUND: A study was conducted to evaluate prospectively the correlation between docetaxel clearance and pharmacokinetics of dexamethasone previously obtained in 21 patients. PATIENTS AND METHODS: Dexamethasone pharmacokinetics were performed in 17 patients 24 h before docetaxel treatment as monochemotherapy. Dexamethasone and docetaxel plasma concentrations were determined by HPLC methods. Determination of docetaxel unbound fraction in plasma was performed using microequilibrium dialysis. RESULTS: Significant correlation was observed between observed plasma docetaxel clearances (CL(docetaxel)) and values predicted from dexamethasone plasma clearance (CL(dexa)), unbound plasma docetaxel fraction estimated from serum alpha1-acid glycoprotein level (fu(alpha1-AAG)), and hepatic metastasis status. However, after splitting of the prospective data set according to gender, no correlation was observed for males (R(2) = 0.08, NS, n = 10), then strong correlation was observed for females (R(2) = 0.78, P < 0.01, n = 7). Multivariate analysis was performed from data obtained in the women included in the first study and those of this prospective study (n = 18). Docetaxel CL was significantly correlated with CL(dexa) (P = 0.001) and fu(alpha1-AAG) (P = 0.01) according to the relationship (with +/-95% confidence intervals): CL(docetaxel) (l/h) = 1.92 (+/-0.94) x CL(dexa) (l/h) + 2.68 (+/-1.95) x fu(alpha1-AAG) (%) (R(2) = 0.68). CONCLUSION: Dexamethasone may be used to predict docetaxel clearances in females, but not in males.

[Pica: a descriptive study of patients in a speciality medical center]. / Le pica: étude descriptive dans une population de patients hospitalisés en psychiatrie.

According to the DSM IV, pica is a trouble of alimentary behavior, which is characterized by the ingestion of non-nutriment substances during at least on the month. The main objective of this study conducted at the Clermont-de-l'Oise Interdepartmental Medical Center is to evaluate pica's prevalence for hospitalized patients. Secondary objectives are to describe clinical characteristics, complications and outcome upon the different therapeutic approaches. The patients hospitalized in the Adult and/or Pediatric Department of Psychiatry, which fulfilled the 4 criteria of the DSM IV, were considered eligible for the study. In order to better evaluate the severity of behavioral troubles evoked by item D of DSM IV definition, we elaborated specific severity and preoccupation scales. The severity scale reflects the complications due to the ingestion of the non-nutriment substances, the encountered risks in the case of persistence of these troubles as well as the patient's management. The preoccupation scale reflects the medical team's involvement towards the patient in order to prevent life-threatening complications. The two scales are graded from 0 to 5 according to the severity or to the degree of preoccupation, respectively. Only patients with scores 3 were considered as fulfilling the severity criteria. Among the 943 hospitalized patients at a selected time period, 23 adult patients have been considered eligible. According to these data, prevalence of pica was estimated at 2.44%. This value may seem an underestimation when compared to the values reported in the medical literature, which range from 9 to 25%. Additionally, among the 108 hospitalized infant patients, none fulfilled DSM IV criteria, which is surprising, as pica is relatively common in childhood. These results may be explained by the use of the more restrictive criteria of the DSM IV and also by the difficulties encountered in considering pica as an independent medical condition. Indeed, pica is often a secondary diagnosis associated with other psychiatric conditions characterized by profound mental deterioration. Two pathogenic factors were constantly searched in the medical records: iron-deficiency anemia and psychopathology. Cultural factors can be a priori eliminated, as most of these patients are in rupture with their family environment since low ages. Only two patients presented with iron-deficiency anemia and its correction did not result in pica's improvement. These findings do not support the -studies presenting pica as an iron-deficiency anemia induced trouble, which regress after a well-conducted iron replacement. Most patients were found to have precocious lack of affect in their medical history. All patients presented other associated psychiatric troubles including severe mental impairment (48%) and dysharmonic development (26%), as well as autistic troubles and schizophrenia. These data concur with other studies, which associate pica to other psychiatric disorders. Gluttony is a widely represented symptom in our study population (87%) and predisposes to food aspiration. It is the mark of frenetic orality and concerns comestible as well as non-comestible compounds. The ingestion of non-nutriment compounds could therefore be considered as an incapacity of discerning among different mouth-introduced substances. Auto- and hetero-aggressive disorders have been reported in 77% of the patients. These behaviors arise mostly in the phase of seeking of substances, especially if these are particularly attractive. The enhancement of the -anxiety, which often arises in the eventuality of hindering of the act, as well as the soothing effect of the ingestion, suggests a compulsive activity. This compulsive activity could be related to an addictive conduct. Pica could therefore be related to obsessive-compulsive disorders and benefit from its specific therapy, either behavioral or chemotherapy with serotonin-recapture inhibitors. The most common clinical forms of pica were phytophagia and geophagia, probably due to the facility of access to these substances. However, 31 distinct substances have been identified in our study. Pica's evolution often implies severe complications, which are sometimes life threatening in spite of a well-conducted treatment. Severity factors include the iteration of medical and surgical complications, as well as the type of ingested products. Our results show a high incidence of surgical complications, essentially gastro-intestinal. Due to the elevated incidence of complications and to the high rate of mortality, some authors proposed systematical search of pica for any gastro-intestinal troubles arising in patients suffering from mental disorders. For these patients for whom anamnesis is often difficult, a standard X-ray of the abdomen is an essential imaging study. Respiratory complications come in second position and infectious complications are seen mostly for the geo- and coprophagia-suffering patients, which contract intestinal parasitosis. Because of its multifactor causality, treatment of pica is complex, and results are often deceiving. Symptomatic neuroleptic therapy results in transient improvement and is indicated especially in delirious patients. Psychotherapy with behavioral approaches and different institutional approaches can be proposed. Indeed, pica could be considered as an acquired behavior, which could benefit from cognitive and behavioral therapies. Institutional management including supportive and compassionate care, restoration of self-confidence is interesting for these patients. Some authors even suggest that pica might be considered as a good indicator of the institution's care quality.