Second-line therapy for disseminated small-cell lung cancer: optimal management remains to be defined

International audienceLung cancer remains an important public health concern for both men and women, with significant morbidity and mortality. Small-cell lung cancer (SCLC) represents between 14% and 18% of all lung cancers. Two thirds are disseminated stages at diagnosis. Management of main SCLC is based on chemotherapy and platin-etoposide combination represents the therapeutic cornerstone for both localized and extensive disease (1). More recently, two pivotal phase 3 trials obtained promising results with the association of platinum-based chemotherapy and immunotherapy, either atezolizumab (2) or durvalumab (3). These chemotherapies or combination of immunotherapy and chemotherapies provide high objective response rates (ORR), but the majority of patients relapse. Second-line treatment for SCLC remains a challenge (4,5). In this second line setting, particular attention must be paid, in these patients who have a poor prognosis, to the quality of life but also to economic issues. In most randomized-controlled trials, ORR was observed in less than a quarter of patients and median overall survival (OS) range from 3.2 to 8.7 months. The factors associated with outcomes appeared to be associated with the type of firstline chemotherapy, the response to it (resistant, refractory or sensitive), treatment-free period and performance status at relapse (5). Few real-life studies have provided data on treatment efficacy in non-selected patients (6). Filling that gap, Zhao et al. (7) analyzed the results of 116 SCLC patients treated after a first line platin chemotherapy progression. The main chemotherapy regimens analyzed were irinotecan, topotecan, paclitaxel or docetaxel. Their respective progression-free survival (PFS) durations were comparable, at 3, 2.5, 2.7 or 1.7 months, but OS differed significantly for irinotecan, with 19 vs. 5, 5.6, or 6.1 months, respectively. In that analysis, the ORR to second-line therapy was positively associated with the response to first-line therapy (P=0.012). According to their multivariate analyses, treatmentfree interval <90 days, lactate dehydrogenase ≥225 U/L and neutrophil-to-lymphocyte ratio (NLR) ≥3.5 were independent risk factors for poor OS. That study had numerous limitations, particularly its retrospective design and monocenter setting. Even though it was a real-life study, the inclusion modalities did not allow us to know the number of patients who did not receive second-line therapy because of poor general conditions and, thus, the degree of selection of those analyzed. In real life setting, many SCLC patients do not receive second-line therapy. According to a German study (8), among the 432 consecutively included patients with advanced disease at diagnosis, only 50% of them received second-line therapy. In a Swedish mono-centric analyse (9) of 544 patients-408 metastatic and 136 with localized at diagnosis-only a quarter of the former received secondline therapy, with the rest given best supportive care (BSC). Median OS after starting second-line therapy was 10.2 and 4.4 months, respectively, for patients with sensitive or resistant SCLC. For patients with localized disease at diagnosis, only one-third of patients with received secondline treatment, which achieved a median PFS of 4.8 months and median OS of 8.2 months

Long-term survival of patients downstaged by oxaliplatin and 5-fluorouracil combination followed by rescue surgery for unresectable colorectal liver metastases

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Fatigue visual analogue scale score correlates with quality of life in cancer patients receiving epoetin alfa (Sandoz) for chemotherapy-induced anaemia: The CIROCO study

Purpose: Available tools to measure fatigue and health-related quality of life (HRQoL) in cancer patients are often difficult to use in clinical practice. The fatigue visual analogue scale (VAS) provides a simple method to assess fatigue. This study evaluated the correlation between HRQoL and fatigue perceived by cancer patients undergoing chemotherapy. Methods: This was a non-interventional prospective study of adult cancer patients in France presenting with chemotherapy-induced anaemia (CIA) treated with epoetin alfa (Sandoz). Data were collected using an electronic case report form at study inclusion (T0), after 2-3 chemotherapy cycles (T1) and after 4-6 cycles (T2). Results: The study included 982 patients from September 2015 to October 2017. Overall, there was a negative correlation between fatigue VAS and HRQoL. The overall haemoglobin (Hb) change between T0 and T2 was +17.8 % (± 18.1 %). Fatigue assessed by both patients and physicians showed a clinically significant improvement during the study. Global HRQoL also increased. Conclusion: Treatment of CIA with epoetin alfa (Sandoz) improved Hb levels, fatigue, and HRQoL, with a correlation observed between fatigue VAS score and HRQoL. Fatigue VAS could act as a simple alternative to more complex methods to measure HRQoL; however, further analyses are required to confirm this association

The combination of everolimus and zoledronic acid increase the efficacy of gemcitabine in a mouse model of pancreatic adenocarcinoma

International audienceBackground: Gemcitabine is a standard treatment for pancreatic adenocarcinoma. Many mechanisms are involved in gemcitabine resistance, such as reduced expression of the human equilibrative nucleoside transporter 1 (hENT1) membrane transporter, deoxycytidine kinase deficiency, and changes in the signal transmission of mitogen-activity protein kinase (MAPK) and the phosphoinositide 3-kinase (PI3K) pathways.Aim:To evaluate the anti-tumor efficiency of blocking signaling pathways using combined action of gemcitabine, everolimus and zoledronic acid versus gemcitabine alone in a mouse subcutaneous xenograft.Methods: Implantations of two human pancreatic adenocarcinoma cells lines (PANC1, K-ras mutated and gemcitabine-resistant; and BxPc3, wild-type K-ras and gemcitabine-sensitive) were performed on male athymic nude mice. The mice received different treatments: gemcitabine, gemcitabine plus everolimus, everolimus, gemcitabine plus zoledronic acid, everolimus plus zoledronic acid, or gemcitabine plus everolimus and zoledronic acid, for 28 days. We measured the tumor volume and researched the expression of the biomarkers involved in the signaling pathways or in gemcitabine resistance.Results: In wild-type K-ras tumors, the combinations of gemcitabine plus everolimus; zoledronic acid plus everolimus; and gemcitabine plus zoledronic acid and everolimus slowed tumor growth, probably due to caspase-3 overexpression and reduced Annexin II expression. In mutated K-ras tumors, gemcitabine plus everolimus and zoledronic acid, and the combination of zoledronic acid and everolimus, decreased tumor volume as compared to gemcitabine alone, inhibiting the ERK feedback loop induced by everolimus.Conclusion: The combination of zoledronic acid and everolimus has an antitumor effect and could increase gemcitabine efficacy

Blue Dye Embolization of Renal Tumor: A New Technique to Improve Tumor Localization During Laparoscopic Partial Nephrectomy

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A phase I/IIa study to evaluate the safety and efficacy of blood-brain barrier (BBB) opening with the SonoCloud-9 implantable ultrasound device in recurrent glioblastoma patients receiving IV carboplatin.

International audience2049 Background: Low intensity pulsed ultrasound (LIPU) in conjunction with intravenous microbubbles can transiently and reversibly disrupt the blood-brain barrier (BBB), allowing for an increase in the tissue concentration of chemotherapy agents in the brain. Mass spectrometry data from preclinical models (mouse, swine) showed a > 5x enhancement in carboplatin brain concentrations, which correlated well with the spatial distribution of a Gadolinium (Gd) contrast agent used for magnetic resonance imaging (MRI). Methods: The primary objective of this phase I/IIa study (NCT03744026) was to demonstrate the safety of BBB disruption using LIPU in patients with recurrent glioblastoma. This study was a 3+3 design using escalating numbers (3, 6, 9) of activated 1 MHz ultrasound emitters. Nine patients were treated in the escalation phase and another 12 patients were treated with 9 emitters in the expansion phase. Eligibility included recurrent GBM (any recurrence) with a maximum tumor size of < 70 mm. The SonoCloud-9 device (CarThera, Paris, France) was implanted during tumor debulking/resection surgery and replaced the bone flap, with the device targeting the tumor and surrounding peritumoral brain. The device was activated every four weeks for a duration of 270 seconds, concomitantly with IV DEFINITY microbubbles (10 ml/kg), to disrupt the BBB prior to administration of carboplatin (AUC 4-6). MRI was performed to verify safety and evaluate efficacy of BBB disruption with Gd enhancement. Results: No DLTs were observed. The overall tolerance of the SonoCloud-9 implant was good, with two transient, manageable grade 3 wound infections and one grade 1 acquired meningocele event considered as probably related to the overall procedure. The most frequent neurologic adverse events were grade 1 blurred vision (5%) and dizziness (5%). Conclusions: Significant Gd enhancement was observed after more than 90% of sonication sessions, suggesting effective BBB disruption and carboplatin enhancement. Clinical trial information: NCT03744026

No impact of passive smoke on the somatic profile of lung cancers in never-smokers

International audienceEGFR and HER2 mutations and ALK rearrangement are known to be related to lung cancer in never-smokers, while KRAS, BRAF and PIK3CA mutations are typically observed among smokers. There is still debate surrounding whether never-smokers exposed to passive smoke exhibit a "smoker-like" somatic profile compared with unexposed never-smokers. Passive smoke exposure was assessed in the French BioCAST/IFCT-1002 never-smoker lung cancer cohort and routine molecular profiles analyses were compiled. Of the 384 patients recruited into BioCAST, 319 were tested for at least one biomarker and provided data relating to passive smoking. Overall, 219 (66%) reported having been exposed to passive smoking. No significant difference was observed between mutation frequency and passive smoke exposure (EGFR mutation: 46% in never exposed versus 41% in ever exposed; KRAS: 7% versus 7%; ALK: 13% versus 11%; HER2: 4% versus 5%; BRAF: 6% versus 5%; PIK3CA: 4% versus 2%). We observed a nonsignificant trend for a negative association between EGFR mutation and cumulative duration of passive smoke exposure. No association was found for other biomarkers. There is no clear association between passive smoke exposure and somatic profile in lifelong, never-smoker lung cancer

Assessment of palliative care for advanced non-small-cell lung cancer in France: A prospective observational multicenter study (GFPC 0804 study).

International audienceINTRODUCTION: Few studies assessed, in real life, symptoms, specific interventions and factors influencing palliative care (PC) initiation for patients with advanced non-small-cell lung cancer (NSCLC). The objective of this study was to examine, in a prospective cohort of advanced NSCLC patients, PC use and factors associated with early (≤3 months after diagnosis) PC initiation. METHODS: It was an observational multicenter study. Each center included 10 consecutive patients with PC initiation. RESULTS: 514 patients were enrolled by 39 centers (age: 62.3±10.7 years, performance status: 0/1; 68.6% cases). At baseline, the most frequent symptoms concerned pain (43.6%), malnutrition (37%) and psychological disorders (25.3%). Specific interventions were infrequent for pain control and malnutrition, but were more numerous for psychological and social problems and terminal care. Median time between diagnosis and PC initiation was 35 [13-84] days, median PC duration was 4.2 [0.6-9.3] months. Median overall survival was 8.6 [6.6-10.7] months; median survival after PC initiation was 3.6 [3.2-4.5] months. In multivariate analysis, only PS ≥2 was linked to early PC. CONCLUSION: This study showed that early PC initiation is not a standard for patients with advanced NSCLC

Repeated blood–brain barrier opening with a nine-emitter implantable ultrasound device in combination with carboplatin in recurrent glioblastoma: a phase I/II clinical trial

Abstract Here, the results of a phase 1/2 single-arm trial (NCT03744026) assessing the safety and efficacy of blood-brain barrier (BBB) disruption with an implantable ultrasound system in recurrent glioblastoma patients receiving carboplatin are reported. A nine-emitter ultrasound implant was placed at the end of tumor resection replacing the bone flap. After surgery, activation to disrupt the BBB was performed every four weeks either before or after carboplatin infusion. The primary objective of the Phase 1 was to evaluate the safety of escalating numbers of ultrasound emitters using a standard 3 + 3 dose escalation. The primary objective of the Phase 2 was to evaluate the efficacy of BBB opening using magnetic resonance imaging (MRI). The secondary objectives included safety and clinical efficacy. Thirty-three patients received a total of 90 monthly sonications with carboplatin administration and up to nine emitters activated without observed DLT. Grade 3 procedure-related adverse events consisted of pre syncope (n = 3), fatigue (n = 1), wound infection (n = 2), and pain at time of device connection (n = 7). BBB opening endpoint was met with 90% of emitters showing BBB disruption on MRI after sonication. In the 12 patients who received carboplatin just prior to sonication, the progression-free survival was 3.1 months, the 1-year overall survival rate was 58% and median overall survival was 14.0 months from surgery