Jacques Medioni

Visceral pleura invasion by non-small cell lung cancer: an underrated bad prognostic factor

BACKGROUND Visceral pleura invasion (VPI) by non-small cell lung cancer is a factor of poor prognosis. A tumor of any size that invades the visceral pleura is classified as T2. Few studies have been conducted concerning the prognostic significance of VPI relative to other staging factors. METHODS Between April 1984 and December 1996, 1,281 patients with T1 (n = 430) and T2 (n = 851) non-small cell lung cancer underwent curative surgical resection. Adjuvant radiation therapy was performed in 455 patients. There were 176 women and 1,105 men aged 30 to 86 years (mean, 60.9 years). Five hundred nineteen pneumonectomies, 742 lobectomies, and 20 segmentectomies were performed. In all patients, a complete mediastinal lymph node dissection was performed. International staging was stage IA and B (n = 697); stage II A and B (n = 247), and stage III A (n = 337). The patients were divided into two groups according to the existence of VPI (group I without, group II with). Both groups were compared with regard to the size of the tumors, histology, associated lymph node involvement, survival rates, and cause of death. Univariate and multivariate analyses were conducted. RESULTS VPI (group II) was identified in 19.1% of the resected specimens: group I, n = 1036; group II, n = 245. The VPI was present in only 10% of non-small cell lung cancer 3 cm or less in size, reaching 33% of patients with non-small cell lung cancer larger than 5 cm (p = 0.0001). Squamous non-small cell lung cancer were significantly less accompanied by VPI (13.5%) than the other histologic categories. The VPI was associated with a higher frequency of N2 involvement (group I = 24.6%, group II = 33.4%, p = 0.01) and N2 involvement was more extensive (two or more N2 involved stations: group I = 8.2%, group II = 15.6%, p = 0.003). Actuarial survival rates were 51.8% at 5 years and 33.8% at 10 years in group I (median, 66 months), and 34.6% at 5 years and 27.9% at 10 years in group II (median, 30 months) (p = 0.000002). Long-term survival rates significantly decreased for larger tumors. Even in patients with N2 stage tumors, the difference of survival curves between the two groups was statistically significant. Cancer-related deaths were more frequent in group II and were mainly caused by distant metastases. By multivariate analysis, visceral pleura invasion proved to be a significant independent factor of poor prognosis. CONCLUSIONS The VPI is a factor of poor prognosis. Its frequent association with extensive N2 involvement supports the hypothesis that exfoliated tumor cells are drained through the pleural lymphatics by the mediastinal lymphatic pathways and then into the bloodstream. The VPI is an important prognostic factor and, as such should stimulate more studies to better select the patients who could benefit from adjuvant therapy.

A Decrease of Regulatory T Cells Correlates With Overall Survival After Sunitinib-based Antiangiogenic Therapy in Metastatic Renal Cancer Patients

Sunitinib, an antiangiogenic molecule, is one of the first-line standard of care in the treatment of patients with metastatic renal cell carcinoma. However, it only benefits to a subgroup of patients and no predictive markers of sunitinib efficacy have been identified. Twenty-eight metastatic renal cell carcinomas were treated with sunitinib-based therapy and another subgroup of 7 primary renal cell cancer patients were also treated by sunitinib in a neoadjuvant trial. Measurements of CD3+CD4+CD25hi Foxp3+ regulatory T cells, an immunosuppressive cell population, were performed before and after each cycle of treatment in blood and tumor in a prospective study. We observed a decrease in the number of peripheral blood Foxp3+ regulatory T cells after each cycle of sunitinib-based therapy. The overall survival was significantly longer in patients showing a decrease in the number of Foxp3+ regulatory T cells after 2 or 3 cycles of treatment (P<0.05). The decrease in the number of regulatory T cells positively correlated with their number at baseline (P<0.01), but not with modification of tumor volume defined by Response Evaluation Criteria in Solid Tumors criteria. The clinical relevance of these results was also supported by an intratumoral decrease of regulatory T cells in 5 out of 7 patients treated by sunitinib in a neoadjuvant trial. Our study represents the first work reporting that the measurement of regulatory T cells may have a predictive value on antiangiogenic response. Antiangiogenic therapy also reversed immunosuppression in the tumor microenvironment which provides novel argument in human to favor its combination with immunotherapy.

Evolution of renal function in patients treated with antiangiogenics after nephrectomy for renal cell carcinoma.

PURPOSE Side effects of antiangiogenic agents are moderate compared with other therapies. The most frequent adverse events are of a renovascular origin and manifest as hypertension (HTN) and thrombotic microangiopathy. To date, data are scanty on the renal tolerance of such drugs regarding renal function as itself, i.e., glomerular filtration rate (GFR). We report on the evolution of GFR in patients receiving antiangiogenic therapy after unilateral nephrectomy for kidney cancer. PATIENTS AND METHODS Data from 73 patients followed in our oncology department for kidney cancer, who had undergone unilateral nephrectomy, and received any antiangiogenic therapy were reviewed. Their GFR was calculated using the aMDRD formula. RESULTS All patients showed a declining renal function over time (-1.23 and -2.51 mL/min/1.73 m(2) using the slope of the curve or the difference between GFR at baseline and that at the end of treatment, respectively). Among them, patients who were recorded as having HTN before initiation of antiangiogenic therapy showed a higher decrease in their GFR of -13.28 and -12.06 mL/min/1.73 m(2). CONCLUSION We recommend that blood pressure should be measured closely in those patients before initiation of antiangiogenic therapy. When HTN is diagnosed, it should be treated and renal function should be monitored since those patients may be at risk for rapidly decreasing renal function under therapy.

Rechallenge with mTOR Inhibitors in Metastatic Renal Cell Carcinoma Patients Who Progressed on Previous mTOR Inhibitor Therapy

Objective: To determine if mammalian target of rapamycin (mTOR) inhibitor (everolimus or temsirolimus) rechallenge in the third- or fourth-line setting after sequential use of a vascular endothelial growth factor receptor (VEGF)-targeted agent and an mTOR inhibitor is a feasible and effective treatment strategy in patients with metastatic renal cell carcinoma (mRCC). Methods: Patients who received a VEGF-targeted agent, an mTOR inhibitor and rechallenge with a second mTOR inhibitor at 2 institutions (Hôpital Européen Georges-Pompidou and Vienna Medical School) between 30 March 2001 and 15 September 2011 were included. Analyses of radiographic images were performed according to the Response Evaluation Criteria in Solid Tumors, version 1.0, to determine the objective response rate and treatment duration (TD). Results: Twelve patients met the inclusion criteria. Following 1 or 2 VEGF receptor-tyrosine kinase inhibitors, 7 patients firstly received everolimus and 5 patients received temsirolimus. Irrespective of treatment sequence, 6 of 12 patients (50%) responded to everolimus and 4 of 12 patients (33%) responded to temsirolimus; 3 patients (25%) did not respond to either. Median TDs (95% confidence interval) for everolimus → temsirolimus and temsirolimus → everolimus sequences were 10.3 months (8.8-19.2 months) and 5.8 months (2.9-19.3 months), respectively. Conclusions: Despite the limited number of patients, this highlights the feasibility of utilizing mTOR rechallenge as an integral part of sequential treatment strategies in mRCC.

Long-term response and postsurgical complete remissions after treatment with sunitinib malate, an oral multitargeted receptor tyrosine kinase inhibitor, in patients with metastatic renal cell carcinoma

Receptor tyrosine kinase (RTK) inhibitors have revolutionized the treatment of metastatic renal cell carcinoma (mRCC) and significantly extended survival in these patients. Sunitinib is an oral multitargeted inhibitor of vascular endothelial growth factor receptors (VEGFRs-1, -2, and -3), platelet-derived growth factor receptors (PDGFRs-α and -β), stem-cell factor receptor (KIT), FMS-like tyrosine kinase 3 (FLT3), colony-stimulating factor 1 receptor (CSF-1R), and glial cell line-derived neurotrophic factor receptor (REarranged during Transfection; RET). Sunitinib is approved multinationally for the treatment of advanced RCC, and is considered the reference standard of care for first-line treatment. In clinical trials, sunitinib has been associated with a consistent, distinct profile of adverse events. Here we describe three cases that show that it is possible to manage adverse events occurring during sunitinib therapy, and thus allow patients with mRCC to receive an effective dose of sunitinib in order to achieve long-term disease control. These cases also show that surgical resection, performed whenever possible, can help to improve control of metastatic disease and so avoid the unnecessary toxicity and high costs of prolonged antiangiogenic therapy.

SynthèseLe rôle des cohortes d’expansion dans les essais de phase I en cancérologie : des recommandations du HUB phase IThe role of the expansion cohort in phase I trials in oncology: Guidelines of the phase I HUB

At the end of the dose escalation step of phase I trials in oncology, it is increasingly frequent to include patients in expansion cohorts. However, the objective of the expansion cohorts, the number of patients included and their justification are insufficiently explained in the protocols. These cohorts are sometimes of considerable size. The aim of this article is to outline the methodology of expansion cohorts in order to provide recommendations for their planning in practice. This work has been undertaken in collaboration with the statisticians of the early phase investigation centers (CLIP(2)), supported by INCA. First, we have outlined the recent articles published on the expansion cohorts in phase I. We then proposed recommendations, in terms of objectives and number of patients to be included, to guide investigators and facilitate the use of these expansion cohorts in practice. Manji et al. have identified 149 phase I clinical trials using expansion cohorts in oncology with a review of the literature between 2006 and 2011 (Manji et al., 2013). Objectives of the expansion cohort were reported in 111 trials (74%). In these trials, safety was the most reported objective (80% of trials), followed by efficacy (45%). According to this review, the number of patients included in these cohorts was insufficiently justified. This result was confirmed by the study of literature that we conducted over the period 2011-2014. We propose to define the number of patients to be included in expansion cohorts in terms of (1) their objectives, (2) the statistical criteria and (3) the clinical context of the trial. The toxicity study remains the primary objective to evaluate in the expansion phase. In some contexts, the activity study is considered as co-primary objective, either for identifying preliminary signs of activity in studies like screening, or for studying the activity when the target population is known. This study is then considered as phase I/II, and experience plans of phase II can be adapted for planning expansion cohorts. Recommendations for the size of expansion cohorts are proposed. Despite the exploratory character of the expansion cohort, a justification of their size based on assumptions statistically defined is recommended in order to provide an interpretable conclusion and to quantify the risk of errors.

Le rôle des cohortes d’expansion dans les essais de phase I en cancérologie : des recommandations du HUB phase I

At the end of the dose escalation step of phase I trials in oncology, it is increasingly frequent to include patients in expansion cohorts. However, the objective of the expansion cohorts, the number of patients included and their justification are insufficiently explained in the protocols. These cohorts are sometimes of considerable size. The aim of this article is to outline the methodology of expansion cohorts in order to provide recommendations for their planning in practice. This work has been undertaken in collaboration with the statisticians of the early phase investigation centers (CLIP(2)), supported by INCA. First, we have outlined the recent articles published on the expansion cohorts in phase I. We then proposed recommendations, in terms of objectives and number of patients to be included, to guide investigators and facilitate the use of these expansion cohorts in practice. Manji et al. have identified 149 phase I clinical trials using expansion cohorts in oncology with a review of the literature between 2006 and 2011 (Manji et al., 2013). Objectives of the expansion cohort were reported in 111 trials (74%). In these trials, safety was the most reported objective (80% of trials), followed by efficacy (45%). According to this review, the number of patients included in these cohorts was insufficiently justified. This result was confirmed by the study of literature that we conducted over the period 2011-2014. We propose to define the number of patients to be included in expansion cohorts in terms of (1) their objectives, (2) the statistical criteria and (3) the clinical context of the trial. The toxicity study remains the primary objective to evaluate in the expansion phase. In some contexts, the activity study is considered as co-primary objective, either for identifying preliminary signs of activity in studies like screening, or for studying the activity when the target population is known. This study is then considered as phase I/II, and experience plans of phase II can be adapted for planning expansion cohorts. Recommendations for the size of expansion cohorts are proposed. Despite the exploratory character of the expansion cohort, a justification of their size based on assumptions statistically defined is recommended in order to provide an interpretable conclusion and to quantify the risk of errors.

Carcinome rénal : état des lieux de la prise en charge des métastases cérébrales

Prognosis of patients with renal carcinoma has improved since the advent of targeted therapies. These last years, due to the improvement of patients overall survival, the incidence of brain metastasis among renal carcinoma patients has increased. This worsens the prognosis of patients. The present revue aims to do a point on treatment of brain metastasis from renal carcinoma. It will address both locoregional (surgery, radiotherapy and stereotactic radiosurgery) and systemic (targeted therapies) treatments.

Abstract CT070: Innovative design for a phase I trial with intra-patient dose escalation: The Crotoxin study

INTRODUCTION. Crotoxin is a bipartite South America rattle snake neurotoxin. It has broad spectrum antitumor activity in vivo in addition to exerting analgesic effects. Prior clinical reports using i.m. injections resulted in local immune reactions with erythema, itching or pain, in addition to anaphylaxis though encouraging responses were recorded. A clinical study was designed incorporating i.v. administration, dose escalation and pre-treatment antihistamine use, aimed at improving dose limiting toxicity (DLT) and local tolerance. METHOD. This trial was performed in patients with stage IV cancer with the primary endpoints to assess safety and tolerability, measured by Dose-Limiting Toxicity (DLT) and to define the Maximum Tolerated Dose (MTD). The secondary objectives were to document anti-tumor efficacy, evaluated according to radiological RECIST criteria 1.0 and analgesia. Baseline pain assessments were completed for each patient. Cohort I included 6 patients with advanced solid tumors (no further therapy options), with dose escalation from 0.04 to 0.32 mg/m 2 /day administered IV by saline drip over 2h daily (Mon to Fri) over 54 days. RESULTS. One male and 5 females (pts) with prior heavily-treated advanced tumors were enrolled: colorectal adenocarcinoma, epithelioid mesothelioma, non-small-cell lung cancer, carcinoma of unknown primary site, invasive breast ductal carcinoma and ovarian papillary adenocarcinoma. Three patients reached the highest target dose level. DLT or MTD were not attained. In Cohort I grade 1 to 2 drug-related events occurred in 3/6 patients: anorexia, diplopia and nystagmus. There were no drug-related serious adverse events. Tumor assessment was performed after 8 weeks of dose escalation (day 54) and all subjects were determined to have progressive disease. At baseline, pain was reported for 5/6 subjects, surveys revealed a diminution of analgesic scores. CONCLUSION: Crotoxin i.v. dose escalation protocol allowed administering 0.32 mg/m 2 /day without unexpected toxicity. Lack of anti-cancer benefit might be related to the long period of 6-8 weeks to reach this dose. A redesign of the protocol to escalate faster and to higher doses, without weekend breaks, is required. Citation Format: Jacques Medioni, Mara Brizard, Reza Elaidi, Paul F. Reid, Benlhassan5 Khadija, Dorothy Bray. Innovative design for a phase I trial with intra-patient dose escalation: The Crotoxin study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT070.

Carcinome rénal : état des lieux de la prise en charge des métastases cérébralesRenal carcinoma: point on treatment of brain metastasis

Prognosis of patients with renal carcinoma has improved since the advent of targeted therapies. These last years, due to the improvement of patients overall survival, the incidence of brain metastasis among renal carcinoma patients has increased. This worsens the prognosis of patients. The present revue aims to do a point on treatment of brain metastasis from renal carcinoma. It will address both locoregional (surgery, radiotherapy and stereotactic radiosurgery) and systemic (targeted therapies) treatments.