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This study looked at whether epidermal growth factor receptor inhibition by the monoclonal antibody panitumumab could increase the efficacy of standard chemotherapy in advanced urothelial cancer. Results were disappointing, with higher toxicity and no improvement in efficacy in the combination arm. Background: Epidermal growth factor receptor (EGFR) overexpression is frequent and associated with poor outcome in urothelial carcinoma. EGFR inhibition could improve the antitumor activity of chemotherapy. Patients and Methods: Patients with advanced, treatment-naive, histologically confirmed advanced urothelial carcinoma and no HRAS or KRAS mutation in the primary tumor received dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) without or with the anti-EGFR monoclonal antibody panitumumab (Pmab). A randomized (1:2) phase II design was used with progression-free survival (PFS) as the primary endpoint. Results: Ninety-seven eligible patients were randomized; 96 patients were evaluable for toxicity and 87 for efficacy. The median PFS were 6.8 months (95% confidence interval [CI], 6.3-9.2) for dd-MVAC and 5.7 months (95% CI, 4.6-6.4 months) for dd-MVAC+Pmab. For both immunohistochemical and molecular definition of basal/squamous-like (BASQ) tumors, no difference was observed in objective response rates or PFS between the two arms in BASQ and non-BASQ tumors. Conclusion: dd-MVAC+Pmab was associated with more serious adverse events and no improvement in efficacy outcomes.

Simple Summary Kaposi’s sarcoma (KS) in people living with HIV (PLHIV) occurs in the vast majority of cases when viral replication is not controlled and when CD4 immunosuppression is important. However, clinicians are observing more and more cases of KS in PLHIV with suppressed viremia on antiretroviral treatment. These clinical forms seem less aggressive, but cause therapeutic dead ends. Indeed, despite repeated chemotherapy, recurrences are frequent. Immunotherapy and specific treatment regimens should be evaluated in this population. Abstract Since the advent of highly effective combined antiretroviral treatment (cART), and with the implementation of large HIV testing programs and universal access to cART, the burden of AIDS-related comorbidities has dramatically decreased over time. The incidence of Kaposi’s sarcoma (SK), strongly associated with HIV replication and CD4 immunosuppression, was greatly reduced. However, KS remains the most common cancer in patients living with HIV (PLHIV). HIV physicians are increasingly faced with KS in virally suppressed HIV-patients, as reflected by increasing description of case series. Though SK seem less aggressive than those in PLHIV with uncontrolled HIV-disease, some may require systemic chemotherapy. Persistent lack of specific anti-HHV-8 cellular immunity could be involved in the physiopathology of these KS. These clinical forms are a real therapeutic challenge without possible short-term improvement of anti-HHV-8 immunity, and no active replication of HIV to control. The cumulative toxicity of chemotherapies repeatedly leads to a therapeutic dead end. The introduction or maintenance of protease inhibitors in cART does not seem to have an impact on the evolution of these KS. Research programs in this emerging condition are important to consider new strategies.

Immune checkpoint inhibitors (ICPi) have shown major therapeutic successes when used in various cancers. In the HIV field a double benefit of such ICPi should result from their dual ability to restore in-vitro HIV-specific CD8 T-cell functions and to enhance HIV production from reservoir cells, thus fulfilling the goals of the 'shock and kill' concept proposed as an HIV cure therapeutic strategy. We conducted a systematic review to identify studies reporting the tolerance profile of ICPi and their effects on HIV plasma loads (pVL), CD4 cell count, HIV reservoirs (cell-associated HIV-DNA) and/or HIV-specific CD8 T cells in PLWH. Thirty-one articles were included for a total 176 participants. Twelve percent of the participants experienced severe adverse events and 49% nonsevere adverse events. pVL remained stable in 91.9% participant, showed increases in 5.8% participant, and decreases in 2.3%. CD4 cell count remained stable in 60.7% participants, showed increases in 24.6%, and decreases in 14.7%. Regarding ICPi effects on HIV-DNA and HIV-specific immunity, we identified three distinct profiles: profile I, transient pVL increases followed by a boost in HIV-specific CD8 T cells concomitant to a decrease in HIV-DNA, reported in one participant. Profile II: increase in HIV-specific CD8 T cells without changes in pVL or HIV-DNA, reported in three participants. III: no effect, reported in five participants. In conclusion, the clinical, virological and immunological safety profiles of ICPi reported in about 200 PLWH appear to be favorable but there are still modest results in terms of HIV cure strategy.

International audience; IntroductionPeople living with HIV (PLWHIV) are at a higher risk of cancer compared to the general population. With improved cancer treatments and the increased life expectancy of PLWHIV, the incidence of second cancers is also expected to increase.MethodsWe reviewed the cases of PLWHIV with cancer that have been presented to the CANCERVIH national multidisciplinary board since 2014. We included all cases with a history of cancer, and studied the incidence and types of second cancers.ResultsIn total, 719 cases were reviewed, out of which 94 (13%) had a history of at least one cancer. For the first primary cancers, 46 (49%) were AIDS-defining cancers (ADCs) and 48 (51%) were non-AIDS-defining cancers (NADCs). Kaposi sarcoma (33%) and NHL (15%) occurred most frequently as first cancers. Among the first cancers that were ADCs, 15% of the second cancers were NHL, 11% anal canal cancers, 9% bladder and 9% Hodgkin lymphomas. Among the first cancers that were NADCs, 38% of the second cancers were lung cancers, 8% bladder, 8% head and neck and 8% NHL.DiscussionWith the aging of PLWHIV, the incidence of second and subsequent cancers is expected to increase in this population. Immuno-virological control should be maintained. Increased surveillance, early prevention and screening programs should be offered to all PLWHIV, including those with an undetectable HIV viral load and/or immune restoration.; IntroductionLes personnes vivant avec le VIH (PVVIH) ont un risque plus élevé de cancer que la population générale. Avec l’amélioration des traitements carcinologiques et l’augmentation de l’espérance de vie des PVVIH, l’incidence des seconds cancers devrait augmenter.MéthodesNous avons examiné les dossiers des PVVIH atteintes d’un cancer qui ont été présentés en RCP nationale CANCERVIH depuis 2014. Nous avons inclus tous les cas avec antécédents de cancer, et étudié l’incidence et les types de seconds cancers.RésultatsAu total, 719 dossiers ont été examinés dont 94 (13 %) avaient un antécédent d’au moins un cancer. Pour les premiers cancers primitifs, 46 (49 %) étaient des cancers classant-SIDA (ADCs) et 48 (51 %) des cancers non-classant-SIDA (NADCs). Le sarcome de Kaposi (33 %) et le LNH (15 %) étaient les premiers cancers les plus fréquents. Parmi les premiers cancers qui étaient des ADCs, 15 % des seconds cancers étaient des LNH, 11 % des cancers du canal anal, 9 % de vessie et 9 % des lymphomes de Hodgkin. Parmi les premiers cancers qui étaient des NADCs, 38 % des seconds cancers étaient des cancers du poumon, 8 % de vessie, 8 % de la tête et cou et 8 % des LNH.DiscussionAvec le vieillissement des PVVIH, l’incidence des seconds cancers (et ultérieurs) devrait augmenter dans cette population. Le contrôle immuno-virologique doit être maintenu. Surveillance accrue, prévention précoce et programmes de dépistage devraient être proposés à toutes les PVVIH, même avec une charge virale VIH indétectable et/ou une restauration immunitaire.

International audience; IntroductionHIV is an exclusion criterion for most lung cancer (LC) trials, however LC is the most common non-AIDS-defined malignancy in people living with HIV (PLHIV), poorer prognosis than the general population. Circulating tumor DNA (ctDNA) was a prognostic marker in LC patients from the general population. This study assessed ctDNA’s prognostic value in PLHIV from a dedicated phase II trial.MethodsOverall, 61 PLHIV with advanced non-squamous non-small-cell lung cancer (NSCLC) participated in the IFCT Phase II trial evaluating first-line four-cycle carboplatin (Ca) AUC5 pemetrexed (P) 500 mg/m2 induction therapy every 3 weeks, followed by P maintenance therapy. Blood samples collected before treatment were analyzed to detect ctDNA using ultra-deep targeted next-generation-sequencing (NGS).ResultsAppropriate samples were available from 55 PLVIH and analyzed for ctDNA detection. Including 42 males (76.4 %), 52.9 years median age, 51 smokers (92.7 %), five with non-squamous NSCLC Stage III (9%), 50 Stage IV (91 %), and performance status (PS) 0−2. ctDNA was detected in 35 patients (64 %), 22 with high and 13 with low ctDNA levels. Overall, 77 % were positive for TP53, 29 % for KRAS, and 11 % for STK11 mutations, more than one alteration was detected in 43 % of samples. Multivariate analysis showed that positive ctDNA was significantly associated with shorter PFS (HR, 4.31, 95 %CI: 2.06−8.99, p

Importance Therapies targeting immune checkpoints, such as the programmed cell death 1 (PD-1) receptor, have become the standard-of-care for patients with non-small cell lung cancer (NSCLC), but people living with HIV (PLWH) were excluded from these studies. Objective To evaluate the efficacy and tolerability of nivolumab in PLWH with advanced NSCLC. Design The CHIVA2 study was a nonrandomized, open-label, phase 2 clinical trial in PLWH with previously treated advanced NSCLC. Setting National multicenter prospective study. Participants patients had viral load of Intervention Nivolumab was administered in second or third line, as monotherapy intravenously at 3 mg/kg every 2 weeks, until disease progression or limiting toxicity. Main Outcomes and Measures The primary endpoint was disease control rate, evaluated using the Response Evaluation Criteria in Solid Tumors, version 1.1. Adverse events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Results Sixteen patients with advanced NSCLC were enrolled: 14 (88 %) were men, median age was 58 years (range: 44−71), and all were smokers. The median duration of nivolumab treatment was 3.5 months (range: 0.5–26.5). The median follow-up was 23.6 months. Disease control rate was 62.5 % for 15 evaluable patients at 8 weeks (2 with partial response, 8 with stable disease, and 5 with disease progression). Twelve (75 %) patients had treatment-related adverse events, which were mild or moderate, except for one patient experiencing severe pruritus, onycholysis, and pemphigoid. There were no opportunistic infections or unexpected immune-related events. HIV viral load was stable during treatment. An increase in proliferating CD8+ and CD4+ T-cells was observed after 3 nivolumab cycles in a subgroup of 9 patients. Conclusions and Relevance Second/third-line nivolumab treatment was well-tolerated and beneficial in PLWH with NSCLC. Future trials should investigate immune checkpoint inhibitors in first-line settings. Trial Registration EudraCT.ema.europa.eu registration number: 2016−003796-22

Anti-PD-1 antibodies prolong survival of performance status (PS) 0–1 advanced non-small-cell lung cancer (aNSCLC) patients. Their efficacy in PS 3–4 patients is unknown. Conse- cutive PS 3–4 aNSCLC patients receiving compassionate nivolumab were accrued by 12 French thoracic oncology departments, over 24 months. Overall survival (OS) was calculated using the Kaplan-Meier method. Prognostic variables were assessed using Cox proportional hazards models. Overall, 35 PS 3–4 aNSCLC patients (median age 65 years) received a median of 4 nivolumab infusions (interquartile range [IQR], 1–7) as first- (n = 6) or second-line (n = 29) therapy. At a median of 52-month follow-up (95%CI, 41–63), 32 (91%) patients had died. Median progression-free survival was 2.1 months (95%CI, 1.1–3.2). Median OS was 4.4 months (95%CI, 0.5–8.2). Overall, 20% of patients were alive at 1 year, and 14% at 2 years. Treatment-related adverse events occurred in 8/35 patients (23%), mostly of low-grade. After adjustment, brain metastases (HR = 5.2, 95%CI, 9–14.3, p = 0.001) and &lt, 20 pack-years (HR = 4.8, 95%CI, 1.7–13.8, p = 0.003) predicted worse survival. PS improvement from 3–4 to 0–1 (n = 9) led to a median 43-month (95%CI, 0–102) OS. Certain patients with very poor general condition could derive long-term benefit from nivolumab salvage therapy.

Background Cancer patients are thought to have an increased risk of developing severe Coronavirus Disease 2019 (COVID-19) infection and of dying from the disease. In this work, predictive factors for COVID-19 severity and mortality in cancer patients were investigated. Patients and Methods In this large nationwide retro-prospective cohort study, we collected data on patients with solid tumours and COVID-19 diagnosed between March 1 and June 11, 2020. The primary endpoint was all-cause mortality and COVID-19 severity, defined as admission to an intensive care unit (ICU) and/or mechanical ventilation and/or death, was one of the secondary endpoints. Results From April 4 to June 11, 2020, 1289 patients were analysed. The most frequent cancers were digestive and thoracic. Altogether, 424 (33%) patients had a severe form of COVID-19 and 370 (29%) patients died. In multivariate analysis, independent factors associated with death were male sex (odds ratio 1.73, 95%CI: 1.18-2.52), ECOG PS ≥ 2 (OR 3.23, 95%CI: 2.27-4.61), updated Charlson comorbidity index (OR 1.08, 95%CI: 1.01-1.16) and admission to ICU (OR 3.62, 95%CI 2.14-6.11). The same factors, age along with corticosteroids before COVID-19 diagnosis, and thoracic primary tumour site were independently associated with COVID-19 severity. None of the anticancer treatments administered within the previous 3 months had any effect on mortality or COVID-19 severity, except cytotoxic chemotherapy in the subgroup of patients with detectable SARS-CoV-2 by RT-PCR, which was associated with a slight increase of the risk of death (OR 1.53; 95%CI: 1.00-2.34; p = 0.05). A total of 431 (39%) patients had their systemic anticancer treatment interrupted or stopped following diagnosis of COVID-19. Conclusions Mortality and COVID-19 severity in cancer patients are high and are associated with general characteristics of patients. We found no deleterious effects of recent anticancer treatments, except for cytotoxic chemotherapy in the RT-PCR-confirmed subgroup of patients. In almost 40% of patients, the systemic anticancer therapy was interrupted or stopped after COVID-19 diagnosis., Highlights • A total of 1289 patients with solid tumours and COVID-19 were analysed. • Mortality and COVID-19 severity were mainly driven by patient general characteristics. • Overall, we found no deleterious effects of recent anticancer treatments on mortality. . • Systemic anticancer treatment was interrupted or stopped in 39% of patients.

International audience; Direct oral anticoagulants (DOAC) are now recommended for the treatment of cancer-associated thrombosis (CAT) based on the results of dedicated trials demonstrating that DOAC are non-inferior to low molecular weight heparins in preventing recurrent venous thromboembolism (VTE) in this population. The definition of "cancer patient" differs substantially among studies. Whether patients with active cancer and those with a history of cancer (HOC) carry the same risks of recurrent VTE and bleeding remains unclear. Few studies reported data on the efficacy and safety of anticoagulants according to active cancer or HOC categories. While in subgroup analyses of EINSTEIN and HOKUSAI the rates of recurrent VTE and bleeding did not differ between these categories, results from a subgroup analysis of AMPLIFY, from HOKUSAI-Cancer, and from the COMMAND cohort suggest that HOC patients might have a lower bleeding risk than active cancer patients. Whether the inclusion of HOC patients in CAT studies might introduce some bias by decreasing the rates of both recurrent VTE and bleeding remains an unanswered issue since no dedicated prospective study addressed this question. A strict definition of active cancer should be used in further trials.

Since the advent of highly active antiretroviral therapy, cancer incidence is still 2 to 3-fold higher in patients infected by human immunodeficiency virus (HIV) than in the general population, with an increased incidence of malignancies not associated with acquired immunodeficiency syndrome (AIDS). HIV-infected patients cancer treatment does not differ from that in the general population. However, the management of those patients have some particularities due to preexisting comorbid conditions, including metabolic, cardiovascular, renal or hepatic complications and the risk for potential drug - drug interactions in HIV-infected patients. In this review, we described efficacy and tolerance of radiotherapy with or without chemotherapy in this frail population treated for cancer. Utilization of modern radiotherapy techniques such as intensity-modulated radiotherapy may improve the treatment tolerance.

In the recent past, we observed an increased risk of cancer in the population with human immunodeficiency virus (HIV) owing to the development of antiretroviral therapies that decreased mortality caused by HIV-specific infections. This particularly fragile population is frequently excluded from clinical trials, and up-to-date recommendations for these patients are lacking. Only few cases of patients with HIV suffering from cancer and undergoing first-line immunotherapy have been reported so far. Here, we report the largest known study of patients with HIV with NSCLC (five patients) undergoing first-line immunotherapy by pembrolizumab, after CANCERVIH group selection. Our results are consistent with those of previous case reports concerning safety of immunotherapy in patients with HIV, revealing no severe or fatal toxicity, opportunistic infections, or immune reconstitution inflammatory syndrome. Moreover, pembrolizumab did not seem to modify HIV viral parameters. We also evaluated the effectiveness of immunotherapy in these HIV-immunosuppressed patients: the average survival was 9.8 months, with three patients having rapid progression and two partial response. Nevertheless, besides safety and drug-to-drug interactions, the effectiveness of first-line immunotherapy in people living with HIV needs to be supported by larger studies.

Prediction of recurrence is a challenge for the development of adjuvant treatments in clear-cell renal cell carcinoma (ccRCC). In these tumors, expression of long non-coding RNAs (lncRNAs) are deregulated and closely associated with prognosis. Thus, we aimed to predict ccRCC recurrence risk using lncRNA expression. We identified prognostic lncRNAs in a training set of 351 localized ccRCCs from The Cancer Genome Atlas and validated lncRNA-based recurrence classification in an independent cohort of 167 localized ccRCCs. We identified lncRNA MFI2-AS1 as best candidate in the training set. In the validation cohort, MFI2-AS1 expression was independently associated with shorter disease-free survival (Hazard Ratio (HR) for relapse 3.5, p = 0.0001). Combined with Leibovich classification, MFI2-AS1 status improved prediction of recurrence (C-index 0.70) compared to MFI2-AS1 alone (0.67) and Leibovich classification alone (0.66). In patients with aggressive tumors (Leibovich ≥5), MFI2-AS1 expression was associated with dramatically increased risk of relapse (HR 12.16, p MFI2-AS1 who had favorable outcomes. Compared to normal samples, MFI2-AS1 was upregulated in tumor tissue, and higher expression was associated with metastatic dissemination. Overall, MFI2-AS1 status improves patient stratification in localized ccRCC, which supports further integration of lncRNAs in molecular cancer classifications.

Background Indication for adjuvant chemotherapy in ypN0 rectal cancer patients after chemoradiotherapy (CRT) is debated. The clinical significance of the presence of sterilized lymph nodes (LNS) in ypN0 patients remains to be determined. Aims To assess the prognostic value of LNS in ypN0 rectal cancers after neoadjuvant CRT. Methods From 2006-2016, 235 patients underwent TME surgery for non-metastatic mid-low rectal cancer after CRT. A lymph node was considered sterilized if there were signs of treatment response (fibrosis, necrosis or mucus) without residual tumor cells. Results 180 patients (77%) were classified ypN0 and 55 (23%) ypN+. LNS was present in 20 patients (9%). In ypN0 patients, 5-year OS was similar between patients with and without LNS. In contrast, 5-year DFS was significantly lower in ypN0/LNS + patients (58% vs. 78%, p = 0.043) and was similar to those staged ypN+. In multivariate analysis, two factors were independent predictors of DFS: mesorectal grading (OR = 3.14; 95%CI: 1.10-8.34; p = 0.033) and the presence of LNS (OR = 3.93, 95% CI: 1.06-11.81, p = 0.042) Conclusion The presence of LNS in ypN0 rectal cancer after neoadjuvant CRT is associated with an increased risk of recurrence and may be taken into account for the discussion of adjuvant chemotherapy.

PurposeHIV infection is an exclusion criterion in lung cancer trials. This multicenter phase II trial aimed to assess feasibility, efficacy and safety of first-line carboplatin plus pemetrexed (CaP) followed by pemetrexed (P) maintenance in people living with HIV (PLHIV) with advanced non-squamous non-small cell lung cancer (NS-NSCLC).MethodsFour cycles of CaP were followed by P-maintenance therapy in patients with Eastern Cooperative Oncology Group performance status (PS) ≤2. The primary objective was a disease control rate (DCR) ≥30% after 12 weeks.ResultsOf the 61 PLHIV enrolled 49 (80%) had a PS 0–1, 19 (31%) brain metastases. Median CD4 lymphocyte count was 418 cells·µL−1(range: 18–1230), median CD4 lymphocyte nadir 169.5 cells·µL−1(1–822); 48 patients (80%) were virologically controlled. Four-cycle inductions were achieved by 38 patients (62%), and 31 (51%) started P maintenance [median of 4.1 cycles (range: 1–19)]. The 12-week DCR was 50.8% (95%CI: 38.3;63.4) and partial response rate 21.3%. Median PFS and OS were respectively 3.5 (95%CI: 2.7;4.4) and 7.6 months (5.7;12.8). Patients with PS 0–1 had the longest median PFS (4.3 months, 95%CI: 3.1;5.2) and OS (11.9 months, 95%CI: 6.4;14.3). During induction, CaP doublet was well tolerated apart from grade 3–4 hematologic toxicities (neutropenia, 53.8%; thrombocytopenia, 35.0%; anemia, 30.0%). Two fatal treatment-related sepsis were reported. No opportunistic infections were experienced.ConclusionIn PLHIV with advanced NS-NSCLC, first-line 4-cycle CaP induction followed by P maintenance was effective and reasonably well-tolerated. Further studies should evaluate combination strategies of CaP with immunotherapy in PLHIV.

International audience; Breast and prostate cancers are among the most prevalent cancers worldwide. Oestradiol and progesterone are major drivers for breast cancer proliferation, and androgens for prostate cancer. Endocrine therapies are drugs that interfere with hormone-activated pathways to slow cancer progression. Multiple new breakthrough drugs improving overall survival have recently been developed within this class. As the use of these latter drugs grows, incidence of cardiac arrhythmias has emerged as an unappreciated complication. These changes are not surprising given that sex hormones alter ventricular repolarization. Testosterone shortens action potential duration and QT interval duration, while oestradiol has an opposite effect. In patients with breast cancer, selective oestrogen receptor modulators are associated with more reports for long QT and torsade de pointes (TdP) than aromatase inhibitors, likely through an oestradiol-like effect on the heart. Cyclin-dependent kinase 4/6 inhibitors, a new class of anticancer drugs used in combination with endocrine therapies in hormone receptor positive breast cancer, are also variably associated with drug-induced long QT, particularly with ribociclib. In prostate cancer, androgen deprivation therapy is associated with long QT and TdP, and possibly atrial fibrillation for abiraterone. In this review, we have summarized the clinical and preclinical data focusing on cardiac arrhythmia considerations of hormone cancer therapies.

Summary Following the introduction of highly active antiretroviral treatments (HAART), patients infected with HIV have experienced significant survival improvement. Since the beginning of the HIV epidemic, three types of cancer constitute a diagnosis of AIDS (defined as AIDS malignancies) in HIV-positive patients: Kaposi sarcoma, non-Hodgkin lymphoma and, since 1993, cervical cancer. However, in the late 1990s, population-based cohort studies revealed higher rates of certain other cancers (defined as non-AIDS related malignancies). This chapter discusses the incidence, aetiology, screening, pathology, diagnosis, and follow-up of these HIV-related neoplasms. Hodgkin lymphoma, anal carcinoma, lung carcinoma and hepatocellular carcinoma, are the most common non-AIDS-defining malignancies (ADMs). Lung cancer is the only frequent cancer in HIV-infected patients not known to be associated with viral infection. Anal cancer is emerging as an important cause of mortality among people with a longer duration of HIV infection. Keywords: AIDS-defining malignancies; anal carcinoma; cervical cancer; HIV-related neoplasms; Hodgkin lymphoma; Kaposi sarcoma; lung cancer; non-Hodgkin lymphoma

Purpose Renal toxicities are common with angiogenesis multikinase inhibitors (AMKI), and can be limiting in phase I trials. Factors associated with such toxicities are poorly known. The aims of this exploratory study were to describe renovascular toxicities associated with AMKI, impact on drug development and to identify baseline parameters associated with the occurrence of renal toxicities in phase I trials. Methods Consecutive patients treated with AMKI in Gustave Roussy phase I unit between October 2005 and August 2013 were included. We retrospectively collected baseline characteristics and renovascular side effects. Associations were assessed in univariate and multivariate analyses. Results Overall, 168 patients were included: male 53.0 %, mean age 55.5 years old, history of hypertension 26.8 %, diabetes 6.0 %, atherosclerosis 13.6 %, stage 3 Chronic Kidney Disease (CKD, NKF-KDOQI) 17.2 %. Incidences of reno-vascular side effects were: hypertension 47.6 %, proteinuria 19.0 %, renal failure 11.9 % and thrombotic microangiopathy 10.1 %. Eighty percent of dose limiting toxicities (DLTs) were related to a renal toxicity. Multivariate analysis showed that onset of renal failure was associated with history of hypertension (p = 0.0003) and stage 3 CKD (p = 0.032). Conclusions A majority of the DLTs associated with AMKI in phase 1 trials are renal toxicities. Baseline hypertension and stage 3 CKD (NKF-KDOQI) might help to better identify patients at risk of AMKI-related renal toxicities.

International audience; Background: In addition to restoring anti-tumor immune responses, immune checkpoint inhibitors (ICI) may also induce immune-related adverse events (irAE) that can affect any organ. We aim to determine the spectrum, timing, clinical features, and fatalities of rheumatic and musculoskeletal immune-related adverse events (RMS-irAE) associated with ICI.Patients methods: We performed an observational, retrospective, pharmacovigilance study using the World Health Organization international pharmacovigilance database, VigiBase, from inception to January 2019. RMS-irAE reporting rate on ICI versus full database was performed using disproportionality analysis with computation of reporting-odds-ratios (ROR) and a Bayesian disproportional estimate (information component, IC). IC025 (lower end of the IC 95% credibility interval) >0 is deemed significant.Results: We identified 1288 RMS-irAE significantly associated with ICI: polymyalgia rheumatica (n = 76, ROR = 14.6 [11.6-18.4], IC025 = 3.34), sarcoidosis (n = 94; ROR = 9.6 [7.9-11.9]; IC025 = 2.85), Sjogren's syndrome (n = 49; ROR = 6.9 [5.2-9.2]; IC025 = 2.24), myositis (n = 465; ROR = 4.9 [4.5-5.4]; IC025 = 2.12), arthritis (n = 606; ROR = 1.4 [1.3-1.5]; IC025 = 0.34) and scleroderma (n = 17; ROR = 2.0 [1.2-3.2]; IC025 = 0.17). Arthritis, myositis, and Sjogren's syndrome were over-reported in patients treated with ICI combination versus those treated with ICI monotherapy (ROR = 1.6-2.9, p < .05) and more frequently reported on anti-PD1/PDL1 monotherapy vs. anti-CTLA4 monotherapy (2.1-4.4, p < .05). Median time to onset occurred early for myositis (31 days [19.2-57.8]) and was the most delayed for scleroderma (395 days [323.8-457.2], p < .0001). The fatality rate for RMS-irAE ranged from 24% for myositis (n = 106/441) (up to 56.7% with concurrent myocarditis) to [0-6.7%] for other RMS-irAE (p < .0001).Conclusions: Clinicians should be aware of the spectrum of RMS-irAE. Myositis can be particularly life-threatening, particularly when associated with myocarditis.

International audience; Objective: To report efficacy and tolerance of nivolumab or pembrolizumab, PD-1 inhibitors, in people living with HIV (PLWHIV) and cancer.Design: Series of PLWHIV cancer patients treated with anti-PD1 agents in real-life clinical practice.Methods: From May 2014 to January 2019, 575 HIV-infected patients have been discussed in the French CANCERVIH national multidisciplinary board and included in the network database. Twenty-three patients were treated with immune checkpoint inhibitors in daily practice. We report the demographic characteristics, CD4+ T-cell counts, HIV viral loads, safety and efficacy data of these 23 PLWHIV treated in routine practice with nivolumab or pembrolizumab for nonsmall cell lung cancer (n = 21), melanoma (n = 1) and head and neck cancer (n = 1) retrospectively collected from the database CANCERVIH network. The median CD4+ T-cell count at treatment initiation was 370 cells/μl (IQR: 125–1485). HIV viral load was undetectable in all patients.Results: As of 29 April 2019, with a median follow-up of 10.8 months (2.0–27.7), the median number of injections was 6 (IQR: 4–18). Only two grade 3 adverse reactions were reported (no toxic deaths or immune-related deaths). Among the 23 patients, a partial response was observed in five patients (22%), a stabilization for five (22%) and a progression in 13 (57%). Only one patient experienced a positive HIV viral load, but this occurred following ART interruption.Conclusion: Treatment with PD-1 inhibitors seems to have an efficacy signal and be well tolerated in PLWHIV, including impact on CD4+ lymphocyte count and HIV load, that should be monitored during treatment course (regarding real-life experience).

IF 7.191 (2017); International audience; BACKGROUND:Previous studies showed that high and low body mass index (BMI) was associated with worse prognosis in early-stage colorectal cancer (CRC), and low BMI was associated with worse prognosis in metastatic CRC (mCRC). We aimed to assess efficacy outcomes according to BMI.PATIENTS AND METHODS:A pooled analysis of individual data from 2085 patients enrolled in eight FFCD first-line mCRC trials from 1991 to 2013 was performed. Comparisons were made according to the BMI cut-off: Obese (BMI ≥30), overweight patients (BMI ≥ 25), normal BMI patients (BMI: 18.5-24) and thin patients (BMI

Although the decline in cancer mortality rates with the advent of combination antiretroviral therapy (cART) in HIV-infected individuals can be mostly explained by a decrease in cancers incidence, we looked here if improved survival after cancer diagnosis could also contribute to this decline. Survival trends were analyzed for most frequent cancers in the HIV-infected population followed in the French Hospital Database on HIV: 979 and 2,760 cases of visceral and non-visceral Kaposi's sarcoma (KS), 2,339 and 461 cases of non-Hodgkin lymphoma (NHL) and Hodgkin's lymphoma (HL), 446 lung, 312 liver and 257 anal cancers. Five-year Kaplan–Meier survival rates were estimated for four periods: 1992–1996, 1997–2000, 2001–2004 and 2005–2009. Cox proportional hazard models were used to compare survival across the periods, after adjustment for confounding factors. For 2001–2004, survival was compared to the general population after standardization on age and sex. Between the pre-cART (1992–1996) and early-cART (1997–2000) periods, survival improved after KS, NHL, HL and anal cancer and remained stable after lung and liver cancers. During the cART era, 5-year survival improved after visceral and non-visceral KS, NHL, HL and liver cancer, being 83, 92, 65, 87 and 19% in 2005–2009, respectively, and remained stable after lung and anal cancers, being 16 and 65%, respectively. Compared with the general population, survival in HIV-infected individuals in 2001–2004 was poorer for hematological malignancies and similar for solid tumors. For hematological malignancies, survival continues to improve after 2004, suggesting that the gap between the HIV-infected and general populations will close in the future.

Systemic treatment of lung cancer patients with brain metastases is based on clinical (presence of symptomatic intracranial lesions), pathological and molecular characteristics of the disease. The efficacy of standard platinum-based chemotherapy is comparable inside and outside the brain, justifying its use as front-line therapy. The intracranial efficacy of targeted therapies (EGFR tyrosine kinase inhibitors, ALK inhibitors) is demonstrated, and is globally superior to the efficacy of standard chemotherapy, justifying their use as front-line therapy in case of EGFR activating mutation or ALK rearrangement (providing the change in the crizotinib label in France). The concomitant use of whole brain radiotherapy and a systemic treatment (chemotherapy or targeted therapy) is not recommended in the absence of a demonstrated better efficacy and/or acceptable safety profile. Several trials are ongoing to assess new whole brain radiotherapy modalities, new targeted therapies alone or in combination, especially exploring immunotherapy.

Background Circulating tumour cell (CTC) counting could be a new biomarker for better evaluation of tumour response to molecules tested in phase I trials. Patients and methods Consenting patients with advanced metastatic cancer referred to various phase I units were enrolled prospectively in this study. CTCs from 7.5 ml of whole blood drawn at baseline and after starting experimental therapy were counted using the CellSearch system, and tumour response was assessed using RECIST 1.1 criteria at baseline and 2 months after treatment initiation. Results Between March 2010 and May 2013, a total of 326 patients were enrolled, among whom 214 were evaluable (49% male, median age = 56; main cancer types: lung [28], colon [53], ovarian [18], breast [28]). At baseline, we detected ≥1 CTC/7.5 ml in 113/214 patients (53%), and at day 30, we observed ≥1 CTC/7.5 ml in 103/214 patients (48%). Two months after treatment initiation, 11 (5%) of the 214 patients were classified as having a partial response, with no CTCs in 9 of them or a decrease in the CTC count after therapy. In contrast, among the 104 patients (49%) classified as having progressive disease, 38 patients had a higher CTC count. The remaining 99 patients (49%), 33 of whom (33%) had a lower CTC count, were classified as having stable disease. The sensitivity and specificity of CTC variation for predicting progressive disease were 41% (32–51%) and 80% (73–88%) respectively. Conclusion An early CTC change following therapy does not correlate with RECIST response in patients with advanced cancer enrolled in phase I trials.

Background Duodenal GISTs represent 3–5% of all GISTs with limited understanding of patient outcomes. We conducted a retrospective analysis of primary localized duodenal GISTs. Methods Patients were identified via a survey from 16 FSG centers ( n = 105), and a group of 9 patients enrolled in the BFR14 trial. Data were collected from the original database and patient files, in agreement with French legislation. Results 114 patients were included, with a median age of 57. Tumors originated mainly in D2 (33%), or D3 (24%), with a median size of 5 cm. 109 patients had resection of the primary tumor; with a Local Resection (LR, n = 82), a pancreaticoduodenectomy (PD, n = 23), and data were missing for 4 patients. Resections were R0 ( n = 87, 79%), R1 ( n = 8, 7%), R2 ( n = 6). Tumor characteristics were: KIT+ ( n = 104), CD34+ ( n = 58). Miettinen risk was low ( n = 43), and high ( n = 52). Imatinib was administered preoperatively ( n = 11) and post-operatively ( n = 20). With a median follow-up of 36 months (2–250), 98 patients are alive, and 33 relapsed. The 5-year OS and EFS rates are 86.5% and 54.5%. EFS was similar for patients in the LR and the PD groups ( P > 0.05 ). In multivariate analysis, ECOG PS, and CD34 expression are independent prognostic factors on OS. Miettinen risk and spindle cell type are independent predictive factors for relapse. Conclusions Patients with resected duodenal GIST have a reasonably favorable prognosis. This study favors a preservation of pancreas when there are no anatomical constraints. LR exhibit similar survival and smaller morbidity then PD.

Introduction Actuellement, les inhibiteurs de check-points immunitaires (ICI) sont recommandes pour le traitement de plus de 16 types de cancers differents et le nombre de patients eligibles ne cesse d’augmenter notamment avec l’approbation recente dans le cancer du sein. La gestion des toxicites immunitaires induites par ces anticorps monoclonaux anti-cytotoxic-T-lymphocyte-associated protein-4 (CTLA4) ou anti-programme cell death 1/programme cell death ligand 1 (PD1/PDL1) devient cruciale. En effet, en restaurant l’immunite cellulaire T antitumorale, les ICI peuvent induire des effets indesirables dont la frequence, le tropisme et la severite dependent notamment des schemas therapeutiques utilises. Une etude recente des toxicites cardiovasculaires immuno-induites a montre un risque de mortalite majeur lie aux myocardites. Cependant, les effets indesirables rhumatologiques sont a ce jour peu decrits. Objectifs Identifier et caracteriser les toxicites rhumatologiques induites par les ICI a l’aide de la base internationale de pharmacovigilance de l’OMS. Materiels et methodes A l’aide de la base de pharmacovigilance de l’OMS, nous avons compare par une analyse de disproportionnalite bayesienne la declaration des effets indesirables rhumatologiques chez les patients exposes aux ICI a la declaration de ces effets dans la base de donnees complete a partir de 2008 (date de la premiere declaration d’evenement indesirable sous ICI). Toutes les pathologies systemiques rhumatologiques (a l’exception de la vascularite) ont ete incluses selon la definition des termes Medical Dictionary for Regulatory Activities (MedDRA). Les molecules suivantes ont ete prises en compte : pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, tremelimumab, cemiplimab et ipilimumab. L’association entre effet indesirable et medicament est calculee par l’information component (IC) ou le reporting odds ratio (ROR). La borne inferieure de l’intervalle de confiance a 95 % de l’IC : IC0,25 est significatif si positif. Resultats Nous avons identifie 54 416 effets indesirables rapportes sous ICI (14 988 450 effets indesirables rapportes dans la base depuis 2008). Comparativement a l’ensemble de la base, une association significative entre ICI et effets indesirables rhumatologiques a ete mise en evidence pour 6 pathologies : les arthrites (n = 606/121 811, ROR 1,4 [1,3–1,5] ; IC0,25 0,45), les myosites (n = 465/26 722, ROR 4,9 [4,5–5,4] ; IC0,25 2,12), la sarcoidose (n= 94/2772, ROR 9,6 [7,9–11,9] ; IC0,25 2,85), la pseudopolyarthrite rhizomelique (n= 76/1504, ROR 14,6 [11,6–18,4] ; IC0,25 3,34), le syndrome de Gougerot-Sjogren (n = 49/2000, ROR 6,9 [5,2–9,2] ; IC0,25 2,24) et le sclerodermie (n =17/2385 vs 17, ROR 2,0 [1,2–3,2] ; IC0,25 0,17). Les patients atteints de myosite etaient plus souvent des hommes (70,4 % ; p Conclusion Parmi les toxicites rhumatologiques, les myosites sont les plus precoces et les plus graves. Le phenotype des toxicites rhumatologiques differe des pathologies auto-immunes spontanees et leur type varie selon l’ICI (PD1 ou CTLA-4), ce qui suggere des mecanismes physiopathologiques distincts. Une meilleure connaissance de ces effets indesirables est necessaire pour si possible les prevenir et ameliorer leur prise en charge therapeutique.

5540 Background: The VENUS study reports on the efficacy/safety of bevacizumab (Bev) in patients (pts) treated in the real-life setting. Methods: In this multicentric observational ambispective VENUS study, all Pts were naive of any antiVEGF and received Bev +/- chemotherapy. Pts were followed until progression or death, for a maximum of 3 years since Bev initiation. De novo side effects were defined as symptoms for which patients were naïve at baseline. Results: 148 OC pts were included (27 centres), 10 excluded and 8 were lost of follow-up. 52 were retrospective. Median age 64 years (55-70). 84.1% were advanced. Median duration of Bev was 8.6 months, min 1 max 36 months. Initial Bev dose was 15 mg/kg Q3W for 65.3%, 10.0 for 22.5%, 7.5 for 10.2% and 5.0 for 2%. 2 pts presented with thrombotic micro-angiopathy (1.4%). Before Bev, hypertension (HTN) was present in 28.9%; proteinuria in 11.3%. Incidence of de novo HTN was 25%. 43 pts (31.2%) experienced de novo Grade 1-2 Pu, for a total of 56 events, no grade 3-4 was observed. A total of 12 Grade 4 events occurred: 9 neutropenia and 3 thrombopenia. Mean overall survival (OS) and progression free survival (PFS) were 30.0 and 13.3 months, respectively. Conclusions: 1) 1/3 of pts were treated at low doses in this real-life study; 2) safety of Bev in real-life was manageable and as expected, 3) OS and PFS were consistent with those reported in the OCEANS study: PFS 12.4 and OS 33.6 months but lower than in the GOG-0213 study: PFS 13.8 and OS 42.6 months. De novo events recorded during follow-up. [Table: see text]

e17587 Background: Metastatic cystic adenoid carcinoma (mCCA) is a rare entity of cancer associated with a poor prognostic. Only limited efficacy data based on case-reports and retrospective analysis are available and there is currently no standard for treatment. The aim of our study is to evaluate the efficacy and prognostic factors in recently diagnosed mCCA. Methods: We retrospectively collected demographic and efficacy data from patients treated for mCCA between September 2012 and January 2019 at the Pitié-Salpêtrière Hospital. Univariate analysis of prognostic factors was performed using the Cox model. Survival was estimated using the Kaplan-Meier method and long rank analysis. Results: Fifteen patients were included: 8 women and 7 men with a median age at diagnosis of 57 years (range 32-71). The primitive sites were accessory salivary glands in 9 patients, major salivary glands in 3 patients, lung, cervix and lacrimal glands in each of the 3 other patients. Histology of the primary tumor was available for 7 patients with 4 cribriform and 3 solid types respectively, an intermediate grade in 5 patients, a high in 2 patients, and a median of Ki67 at 35% (range 8.5-40%). Thirteen patients received a first line therapy, including 10 with platinum – LV5FU2, 2 with cisplatine anthracycline and cyclophosphamide association (CAP) and 1 with sunitinib. A stable disease was found in 7 patients (54%), a partial response in 4 patients (31%) and 2 patients had progression at first evaluation. The median 1st line PFS was 5.8 months (range 2.0-12.7). With a median time of follow-up at 12.9 months (range 4.0-61.3), 5 patients (33%) were dead, 8 patients (53%) were still receiving systemic therapy and 4 patients (27%) received 4 lines. A patient with partial response after 6 CAP cycles,received a liposomal anthracycline combined with carboplatin for 8 cycles with a response time of 12.7 months. In univariate analysis, no statistically significant prognostic factors were found. Conclusions: In our retrospective study, 1st line of systemic therapy is efficient in mACC with a 31% response rate. Furthermore, here we report the first patient treated with liposomal anthracycline associated with duration of response for 12.7 months. These preliminary results should be confirmed before becoming a new option for treatment in mACC.

e17578 Background: Few data exist regarding the use of denosumab in patients with bone metastases from radioactive iodine (RAI) refractory differentiated thyroid cancer (DTC) and advanced medullary thyroid cancer (MTC). We aimed to describe adverse events of specific interest - osteonecrosis of the jaw (ONJ) and severe hypocalcemia - in this rare setting. Methods: We retrospectively reviewed the charts of all the patients treated with denosumab for bone metastases from RAI-refractory DTC and advanced MTC in our institution. All patients had a calcium measurement and a clinical and radiological dental screening before denosumab initiation. All patients without hypercalcemia received a calcium supplementation. We assessed associations between ONJ or severe hypocalcemia ( < 1.75mmol/L) and suspected risk factors by Fisher exact tests. Results: Between 2014 and 2018, 23 patients were treated with denosumab. Two-thirds of patients were male (n = 16), median age was 69 years (range 43-87). Histology was DTC and MTC in 19 (83%) and 4 (17%) patients, respectively. DTC patients had received a median cumulated dose (CD) of 300 mCi of RAI (range 100-700). Ten patients (43%) had at least one cervical surgery for recurrence or persistence, and 6 (26%) had cervical radiotherapy. Four patients had hypoparathyroidism before denosumab initiation. Two-thirds of patients ( n =15) received a tyrosine kinase inhibitor (TKI) in association with denosumab. The median duration of denosumab was 20 months (range 1-47). ONJ occurred in 6 patients (26%) and severe hypocalcemia in 3 patients (13%). Conclusions: Patients with RAI-refractory DTC and advanced MTC are at high risk of ONJ and severe hypocalcemia under denosumab treatment. Benefit/risk ratio should be highly weighted particularly when treatment is prolonged. Patients should be closely monitored for the risk of ONJ and hypocalcemia. [Table: see text]

Incidence of centimetric or infracentimetric node negative (pT1a-b, N0) breast cancer is increasing due to screening procedures. Although considered as having an overall favorable prognosis, several retrospective studies have suggested a higher risk of relapse when HER2 is overexpressed. Since randomized studies evaluating trastuzumab in the adjuvant setting did not include T1a-bN0, there is no level I evidence supporting the administration of a trastuzumab-based post-operative chemotherapy in these cases. However, some recent retrospective data suggest a benefit for such a strategy and current guidelines recommend to consider adjuvant chemotherapy plus trastuzumab in pT1bN0. The final decision, as well as the nature of cytotoxics to be administered in combination with trastuzumab, require a careful evaluation of the benefit/risk ratio in order to minimize the risk of toxic events, notably at the cardiac level.

Objective To evaluate the impact of ‘hereditary-like’ status in upper tract urothelial carcinoma (UTUC) on the survival of patients who have undergone radical nephroureterectomy (RNU) and adjuvant chemotherapy. Patients and Methods A multicentre retrospective study was performed on all patients with high-risk UTUC who underwent RNU and adjuvant cisplatin-based chemotherapy. Using a patient risk identification tool, we distinguished tumours suspected to be hereditary from sporadic tumours and compared survival rates. Results A total of 112 patients with a median age of 67 years were included. Hereditary-like tumour status was detected in 35 patients (31.3%), while 77 patients (68.7%) had sporadic tumours. The median age was significantly younger in the hereditary-like tumour group (56.0 vs 69.8 years, P < 0.001). Overall survival (OS) after chemotherapy was significantly better in the group with hereditary-like tumours than in the group with sporadic tumours (5-year OS: 48.2 vs 32%; P = 0.008). The cancer-specific survival (CSS) rate was significantly better in the group with ‘hereditary-like’ tumours than in the group with sporadic tumours (5-year CSS: 58 vs 35%; P = 0.006). Although there was a trend in favour of the hereditary-like tumours, we observed no significant difference regarding progression-free survival (PFS) between the two groups (5-year PFS: 71 vs 52%; P = 0.07). Conclusion Adjuvant chemotherapy after RNU improves survival outcomes in patients with hereditary-like UTUC compared with those with sporadic tumours.

Current advances in the biology of cancer and emergence of new tools for genome analysis have opened clinical perspectives in oncology, generally termed as ‘personalized medicine’. This broad term must encompass previous well-proven strategies, such as pharmacogenetics- and pharmacokinetics-based dosing, with more recently introduced pharmacogenomics approaches, all applied as a means to tailor treatment to a given patient presenting with a given tumor. Despite outstanding results in lung cancer, colorectal cancer and melanoma, only a few predictive biomarkers are currently justified in routine clinical practice. Overall, there is a persistent gap between the growing number of identified deregulated pathways or genetic mutations, both at the tumor and the constitutional levels, and their actual implementation at the bedside as part of clinical routine. This article underlines these limitations and covers several issues that may explain the discrepancy between the plethora of published data about emerging biomarkers, and the relative scarcity of tests eventually reaching a clinically validated application. The main identified difficulties concern invasive and costly prospective biomarker studies and the issue of tumor heterogeneity. Finally, early trial designs for targeted therapies as well as those for conventional cytotoxics may not necessarily address the right questions by skipping critical end points. Proposed solutions point out the use of liquid biopsies and systems biology approaches, for an easier implementation of personalized medicine at the bedside.

International audience; Hormone-naïve prostate cancer and its castration-resistant state (CRPC) are clinically and genetically heterogeneous diseases. From initiation of prostate carcinogenesis to its evolution towards therapeutic resistance, various combinations of genetic and epigenetic events occur. Schematically, progression to CRPC could be divided in two distinct pathways, either dependent or independent of the androgen receptor activity. Nevertheless, because the better knowledge of the genetic landscape of CRPC is under way, limited clinical applications are available at the moment, underlying the usefulness of prognostic and predictive biomarkers in daily practice. Despite the promising prognostic value of circulating tumor cells, no biomarker has been currently validated as a surrogate for overall survival in CRPC patients. Inversely, considerable interest has been generated with the recent finding of the splice variant AR-V7 that allows to predict resistance to abiraterone acetate and enzalutamide. However, other predictive biomarkers would be necessary to accurately guide personalized sequencing of CRPC treatment, which now includes numerous possibilities based on the six validated drugs, without accounting for those currently under investigation in the ongoing randomized controlled trials. As a consequence, only rational sequencing, which consists in choosing an agent that is not expected to have cross-resistance with previous therapy, can be currently advised.

The success of endocrine therapies for hormone receptor-positive breast cancer and trastuzumab and lapatinib for targeting human epidermal growth factor receptor 2 (HER2)-positive tumors has paved the way for the clinical development of several other metastatic breast cancer (MBC)-targeted therapies. Although the benefit of the anti-VEGF (vascular endothelial growth factor) monoclonal antibody bevacizumab in the MBC setting has become a topic of debate, clinical trial results are accumulating, and phase 3 evaluations are ongoing for newer HER2-targeted agents (pertuzumab and trastuzumab-maytansine immunoconjugate) and VEGF-targeted agents (aflibercept), as well as dual, epidermal growth factor receptor/HER2-targeted agents (afatinib [BIBW 2992] and neratinib), multitargeted tyrosine kinase inhibitors (sunitinib and pazopanib), and mammalian target of rapamycin (everolimus) and poly (ADP-ribose) polymerase 1 inhibitors (iniparib, olaparib). These agents as well as other novel classes of anticancer agents are being tested in clinical trials with the potential of addressing unmet therapeutic needs in the MBC patient population. Cancer 2012;118: 3014–25. © 2011 American Cancer Society.

Learning Objectives After completing this course, the reader will be able to: Include geriatric assessment into oncologic practice to describe patients and to evaluate the real benefit/risk ratio of any adjuvant treatment.Describe the actual risk of association of erythropoiesis-stimulating agents with bevacizumab. This article is available for continuing medical education credit at CME.TheOncologist.com The incidence of breast cancer is two to three times higher in women aged ≥65 years than in the whole population, whereas their mortality rate is threefold to fourfold higher. Targeted therapies allow significantly longer disease-free survival times. Nevertheless, in an elderly population, these treatments need to be prescribed with caution. This paper reviews the treatments of breast cancer in the elderly, and the issues of targeted therapies and their toxicities. Patients with human epidermal growth factor receptor (HER)-2+ breast cancer benefit from trastuzumab; although cardiotoxic effects are observed in The life expectancy of breast cancer patients should be taken into account to determine the appropriateness of treatments. The quality of life of elderly cancer patients must be assessed with an appropriate tool. Older patients exhibit greater vulnerability, suggesting identification and exclusion of patients at high cardiac risk. Future recommendations for the treatment of elderly women with breast cancer should include a multidisciplinary approach and a global geriatric assessment before treatment with anti–HER-2 therapy or bevacizumab.

Purpose Axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3, is under investigation for treatment of various solid tumors. The safety and pharmacokinetics of axitinib in combination with gemcitabine in patients with advanced pancreatic cancer was evaluated in the phase I portion of this trial. The randomized phase II portion was reported separately. Patients and methods Patients with advanced pancreatic cancer who had received no prior chemotherapy were eligible for this study. Pharmacokinetic profiles of the drugs were obtained on cycle (C) 1 day (D) 1 (gemcitabine alone 1,000 mg/m2), C1D14 (steady state, axitinib alone 5 mg twice daily [BID]), and C1D15 (gemcitabine plus steady-state axitinib). Adverse events were monitored weekly at the clinic. Results Eight patients participated in the phase IB portion of the trial. Patients received gemcitabine on D1, D8, and D15 and continuous axitinib in a 28 day-cycle beginning C1D3. There was no dose-limiting toxicity. Common treatment-related adverse events included fatigue, diarrhea, dysphonia, and hypertension. Myelosuppression was similar to gemcitabine monotherapy. No apparent major pharmacokinetic interactions between gemcitabine and axitinib were observed. Of six patients evaluable for efficacy, three had confirmed partial responses. Conclusions Axitinib (5 mg BID) and gemcitabine (1,000 mg/m2) were well tolerated when administered together, without any pharmacokinetic interactions, and showed encouraging antitumor activity.

Physicians who are responsible for the delivery of systemic treatment in lung cancer should be aware of the potential risk of drug-induced pulmonary toxicity (DIPT), because such toxicity may develop in the context of a multifactorial clinical condition. First, most patients with lung cancer may suffer from other non-neoplastic, smoking-related lung diseases, such as emphysema and chronic obstructive lung disease, which may generate pathologic changes in lung parenchyma. In addition, lung cancer itself may worsen the respiratory function, inducing atelectasis and lymphangitic carcinomatosis. The superimposed iatrogenic damage may lead to respiratory failure and, sometimes, death. The risk of DIPT from chemotherapeutic agents has been widely examined in the past; and, currently, the potential for lung toxicity has been extended by the introduction of molecular targeted therapies. Because there are no univocal criteria with which to recognize DIPT, the diagnosis often is made by exclusion; consequently, it is hard to establish an early diagnosis. The objective of this review was to describe the major DIPTs associated with antineoplastic agents against nonsmall cell lung cancer to help physicians with this difficult diagnostic challenge.

The number of melanoma cases worldwide is increasing faster than any other cancer and remains one of the most treatment-refractory malignancies. Despite decades of clinical trials testing chemotherapy and immunotherapy, a standard first-line treatment for metastatic melanoma has not yet been established; tough single agent dacarbazine represents the most common option. This review will focus on metastatic malignant melanoma treatment from single agent until new therapies. An overview of established chemotherapies and immunotherapies, followed by a summary of trials testing the potential combination and new agent are explored.

It is now clearly established that anti-vascular endothelial growth factor (VEGF) drug class induces hypertension and proteinuria sometimes related to thrombotic microangiopathy and/or various glomerulopathies, according to capillary and glomerular VEGF and VEGF-receptor expressions. As reported in the literature, anti-epidermal growth factor receptor (EGFR) therapies seem to be less nephrotoxic. Indeed, many reports of anti-EGFR nephrotoxicity are tubular dependent such as acute tubular necrosis, electrolyte disorders (hypophosphatemia, hypomagnesemia, etc.) or both. This is explained by elective tubular expression of renal EGF/EGFR. In this paper, we focus on electrolyte disorders related to anti-EGFR treatment and discuss the tubular involvement of these drugs based on their renal expression.

Hodgkin lymphoma (HL) represents one of the most common types of a non-AIDS-defining tumour that occurs in the HIV population, and its incidence is increasing in the post Highly Active Anti-retroviral Therapy (HAART) era. Despite the aggressiveness of that disease, the outcome of patients with HIV-HL has improved with better, combined antineoplastic and antiretroviral approaches. New and effective antiretroviral drugs, in conjunction with nucleoside analogs, improve the control of the underlying HIV infection when used during treatment of HL with chemotherapy. The inclusion of hematopoietic growth factors in the treatment of patients with HIV-HL may allow for the administration of higher dose-intensity chemotherapy and the prolonged use of antiretroviral drugs, with the aim of improving the survival. In addition, new functional imaging tools, like the Positron Emission Tomography (PET), may help to guide treatment and minimize long term toxicity.

The importance of targeted therapies has been emphasized by clinical trials using antiangiogenic or HER2 inhibitors in breast cancer. First with trastuzumab, it was demonstrated that targeted therapies may improve outcome in patients with HER overexpressing breast cancer in metastatic or adjuvant settings. The emerging role for angiogenesis inhibitors has also been demonstrated with bevacizumab. Unfortunately, there is growing clinical and biological evidence that tumour cells may develop unexpected and complex mechanisms of resistance to those targeted therapies. This review outlines the mechanisms by which tumour cells may resist to new targeted agents. Most recent developments are also highlighted.

Proteinuria is a dose-related side-effect occurring after inhibition of vascular endothelial growth factor (VEGF) signalling and may reflect severe glomerular damage. The inhibition of the VEGF signalling axis induces downexpression or suppression of nephrin, an important protein for the maintenance of the glomerular slit diaphragm, sometimes leading to nephritic syndrome and/or glomerular thrombotic microangiopathy, the main-associated kidney disease. A MEDLINE search was carried out using the following criteria: (1) all MEDLINE listings as of 01-01-2000 with abstracts; (2) English language; and (3) Humans. The following phrases were used to query the database: (proteinuria) AND (anti-VEGF OR VEGF inhibition OR bevacizumab OR sunitinib OR sorafenib OR VEGF Trap OR axitinib OR pazopanib OR AZ 2171). The references of each article identified were carefully reviewed for additional reference. The incidence of mild and asymptomatic proteinuria ranges from 21% up to 63%, but heavy proteinuria has been reported in up to 6.5% of renal cell carcinoma patients. Although discontinuation of anti-VEGF agent induced significant reduction, persistence of proteinuria is common. Although angiotensinconverting-enzyme inhibitors and/or angiotensin receptor blockers seem to be preferred, no specific recommendation for an antiproteinuric agent can be made in this context because there are no controlled studies addressing the subject. Periodic monitoring of urinary protein should be carried out in anti-VEGF-treated patients and patients showing proteinuria need special referral to nephrologists.

Background The Renal Insufficiency and Anticancer Medications (IRMA) study reported a renal insufficiency (RI) prevalence of 50%–60% in a population of almost 5000 patients with solid tumors, 80% of whom were being treated with anticancer drugs that either necessitated dosage adjustment or were potentially nephrotoxic drugs. A national multicenter study from 15 cancer centers in France analyzed IRMA data on patients with prostate cancer. Patients and Methods Data on patients with prostate cancer from the IRMA study were analyzed. Renal function was calculated using Cockcroft-Gault and abbreviated Modification of Diet in Renal Disease (aMDRD) formulas to estimate the prevalence of RI. Anticancer drugs' potential renal toxicity and need for dosage adjustment were detailed. Results Of the 222 IRMA patients with prostate cancer, 14.9% had a serum creatinine (SCr) level of > 110 μmol/L. When using Cockcroft-Gault and aMDRD formulas, 62.6% and 55.9%, respectively, of the patients had RI. Of the 228 anticancer drug prescriptions, 82.9% required dose adjustments for RI or were drugs with no available data on their administration in patients with RI. Of the patients treated, 86.9% received ≤ 1 such drug, but only 29.1% received nephrotoxic drugs. Conclusion The prevalence of RI in patients with prostate cancer was very high in spite of a normal SCr level in most cases. Some anticancer drugs, particularly some bisphosphonates and platinum salts, might be nephrotoxic and/or need dosage adjustment. However, other important drugs in prostate cancer, such as docetaxel, neither require dose reduction nor present with potential nephrotoxicity. Both issues were significantly more important in the patients with bone metastases compared with those with nonmetastatic disease.

The Renal Insufficiency and Anticancer Medications (IRMA) study is a French national, observational study which demonstrated the high prevalence of abnormal renal function in a population of 4684 solid tumor patients. Among them, 50-60% had decreased renal function, and 80% were treated with anticancer drugs that either necessitated dosage adjustment in case of renal insufficiency (RI) or were potentially nephrotoxic drugs. Since elderly patients are well-known to have reduced renal function, either due to physiological aging or their disease/medication history, a subgroup analysis of this particular population of patients was performed. In 1553 IRMA patients whose age was > or =65 years, the prevalence of RI was very high in spite of normal serum creatinine values in most cases. Anticancer drugs used may be nephrotoxic or need dosage adjustment in a high number of cases.

We report a patient with unknown primary undifferentiated carcinoma who developed acute renal failure associated with interstitial fibrosis following pemetrexed therapy. Despite drug withdrawal, renal function remained altered and the patient experienced chronic renal insufficiency. Pemetrexed disodium (Alimta™) is a multitargeted antifolate agent approved by the Food and Drug Administration (FDA) for patients diagnosed with mesothelioma and non-small cell lung cancer. This drug is almost exclusively cleared by renal excretion [1]. The most common side effects are hematologic dose-limiting toxicities and nonhematologic toxicities including fatigue, diarrhea, nausea, mucositis and rash. Although few cases of renal failure have been published, no study has reported on the renal pathological findings in this setting. We present a case of acute tubular necrosis associated with interstitial fibrosis after pemetrexed therapy.

Erythropoiesis-stimulating agents are indicated for the treatment of chemotherapy induced-anemia in cancer patients. Controlled clinical studies have shown that epoetin alfa consistently and significantly increases levels of hemoglobin (Hb), decreases the need for RBC transfusion, and improves the quality of life that is of such importance in cancer patients with a limited life expectancy. The rise achieved in Hb level correlates with an improvement in quality of life. Studies have also demonstrated that earlier initiation of epoetin therapy (i.e., starting treatment at an Hb level of 10–11 g/dl rather than waiting for Hb to fall to

Since the mid-1980s, it has been known that the epidermal growth factor receptor, an immunoglobulin G cytoplasmic membrane protein and member of the type I subfamily of tyrosine kinase receptors, plays a key role in tumor growth and metastasis. Cetuximab is the first immunoglobulin G1 monoclonal antibody that blocks the epidermal growth factor receptor, resulting in an inhibition of tumor growth, angiogenesis, tumor spread and metastasis. Cetuximab is active in heavily pretreated colorectal cancer, as a single agent or in combination with irinotecan, a conclusion that is strongly suggested by the Bowel Oncology with Cetuximab Antibody (BOND) study in terms of response rate (11% monotherapy vs 23% in combination; p < 0.007) and time to progression (1.5 vs 4.1 months; p < 0.001). The main adverse event related to cetuximab is skin reaction, the intensity of which is correlated with efficacy. The Monoclonal Antibody Erbitux in a European Pre-License (MABEL) study has confirmed these results, recently generating a median survival of 9.2 months, comparable to 8.6 months achieved in the BOND study. Cetuximab has shown efficacy (with or without irinotecan) as second-line treatment in patients who have failed irinotecan in combination with bevacizumab, an antivascular endothelial growth factor monoclonal antibody. The combination is currently being tested in the first-line management of advanced colorectal cancer, as well as in the adjuvant setting. The evaluation of other combinations either with oxaliplatin or capecitabine, is ongoing, with preliminary reports of promising activity.

Background: The purpose of the study was to prospectively evaluate the efficacy and tolerability of the FOLFIRI.3 regimen in patients with unresectable pancreatic adenocarcinoma. Patients and methods: Chemotherapy-naive patients with histologically proven advanced pancreatic adenocarcinoma were treated with the FOLFIRI.3 regimen, consisting of irinotecan 90 mg/m2 as a 60-min infusion on day 1, leucovorin 400 mg/m2 as a 2-h infusion on day 1, followed by 5-fluorouracil (5-FU) 2000 mg/m2 as a 46-h infusion and irinotecan 90 mg/m2, repeated on day 3, at the end of the 5-FU infusion, every 2 weeks. Results: Forty patients were enrolled, of whom 29 (73%) had metastatic disease. A total of 441 cycles were delivered (1–53). Grade 3–4 neutropenia occurred in 35% of the patients, accompanied by fever in two cases. Other relevant grade 3–4 toxic effects were nausea-vomiting (27%) and diarrhea (25%). Grade 2 alopecia occurred in 48% of the patients. There were no treatment-related deaths. The confirmed response rate was 37.5%. Stable disease was observed in 27.5% of the patients. The median progression-free and overall survivals were 5.6 months and 12.1 months, respectively. The 1-year survival rate was 51%. Conclusion: The FOLFIRI.3 regimen seems to be active on advanced pancreatic cancer and to have a manageable toxicity profile. The lack of cross-resistance between FOLFIRI.3 and gemcitabine-based regimens allows efficient second-line therapies.