Alain Livartowski

Survival of breast cancer patients with meningeal carcinomatosis

BACKGROUND Breast cancer is the leading nonhematologic cause of meningeal carcinomatosis (MC). The aim of this study was to report the outcome of patients diagnosed with breast cancer MC and treated in single institution by a high-dose intrathecal methotrexate (MTX) regimen. METHODS Ninety-one patients were diagnosed with breast cancer MC from 2000 to 2007. Intrathecal treatment was MTX 15 mg/day (days 1-5), hydrocortisone acetate (day 1) and oral folinic acid (days 1-5), repeated every 2 weeks. Patients and tumor characteristics were associated with the early clinical and biological outcome and with the overall survival (OS). RESULTS The median survival was 4.5 months (range 0-53). In multivariate analysis, adverse prognostic factors at diagnosis were performance status >2 [P = 0.006, response rate (RR) = 0.33 (0.15-0.71)], more than three chemotherapy regimens before MC diagnosis [P = 0.03, RR = 0.40 (0.19-0.93)], negative hormone receptor status [P = 0.02, RR = 0.4 (0.19-0.90)] and high Cyfra 21-1 level [P = 0.048, RR = (0.09-0.99)]. Clinical progression after one cycle and biological response after two cycles were independently associated with OS [P < 0.001, RR = 0.09 (0.02-0.37) and P = 0.003, RR = 3.6 (1.5-8.5), respectively]. We propose a prognostic score in order to define three distinct groups of prognosis. CONCLUSIONS MC presents a poor prognosis, but 1-year survival rate was 25%. This score may become a useful tool for treatment decision and clinical trials.

Resection of pulmonary metastases in osteosarcoma. A retrospective analysis of 44 patients

Between 1977 and 1985,44 patients with osteosarcoma and pulmonary metastases were treated at Institut Curie and Marie‐Lannelongue. Twenty patients were able to undergo operations according to our criteria. Of 17 patients who immediately after surgery were clinically and radiologically free of disease, six are alive with no evidence of disease and one suffered recurrent pulmonary disease; their 5‐year survival is 37%. In 24 patients, various schemes for aggressive chemotherapy for measurable lung disease could be assessed. Only one patient had a complete response; there was one partial response, and three patients experienced stabilization of their disease for 6 to 8 months. Of five patients who had second line postoperative adjuvant chemotherapy, four relapsed within 2 months of stopping treatment. Surgical resection of lung metastases appears definitely to improve the outcome in osteosarcoma patients. Chemotherapy offers no advantage in treating bulk disease, but the prevention of new micrometastatic disease remains a possibility and should be assessed in randomised multicenter trials.

Cabazitaxel in patients with advanced solid tumours: results of a Phase I and pharmacokinetic study.

BACKGROUND Although the taxanes paclitaxel and docetaxel are among the most active agents for the treatment of a wide range of cancers, tumours often develop resistance to these treatments. Cabazitaxel is a novel taxane active in both preclinical models of chemotherapy-sensitive and -resistant human tumours and patients with advanced prostate cancer that progressed following docetaxel treatment. AIM To establish the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel. PATIENTS AND METHODS Cabazitaxel was administered every 3 weeks to patients with advanced solid tumours. The design allowed intrapatient dose escalation. The primary objective was to determine the MTD. Secondary objectives were to describe the safety profile, establish an appropriate dose, determine the pharmacokinetic (PK) profile of cabazitaxel, and assess antitumour activity. RESULTS Twenty-one patients were recruited. The MTD was reached at 30 mg/m(2), at which three of five patients experienced haematologic DLTs during the first cycle. DLTs during subsequent cycles were mainly haematologic and reported at 25 and 30 mg/m(2) dosing levels. Nail disorders and severe alopecia were not reported, and neurotoxicity, fluid retention and hypersensitivity were mild and infrequent. Cabazitaxel demonstrated linear PK, a triphasic elimination profile, with a long half-life and high clearance. Of the 19 patients evaluable for response, one unconfirmed partial response and six occurrences of stable disease were reported. CONCLUSIONS The 25mg/m(2) dose of cabazitaxel was recommended for use in future clinical studies. In this study, cabazitaxel had an acceptable tolerability profile and activity in cervical, colorectal, endometrial and lung cancers.

In vivo efficacy of STI571 in xenografted human small cell lung cancer alone or combined with chemotherapy.

STI571, or imatinib, selectively inhibits BCR/ABL, PDGFR and c‐kit kinase activity. It has been reported that a large proportion of small cell lung cancer (SCLC) cell lines and tumors express c‐kit and that STI571 inhibits tumor cell growth. We therefore investigated the therapeutic efficacy of STI571, alone or combined with chemotherapy, in human SCLC cells or tumors xenografted into nude mice. The level of c‐kit mRNA expression was variable in SCLC tumors (positive for 2 of 4 xenografts), and c‐kit protein was not detected by immunohistochemistry. On the 4 xenografted tumors, PDGFRα and PDGFRβ were not detected by immunohistochemistry. STI571 induced inhibition of proliferation of the SCLC6 cell line without inducing apoptosis; in contrast, in combination with etoposide or topotecan, the growth inhibition of SCLC6 cells induced by STI571 was increased, with apoptotic DNA fragmentation. Four human SCLC xenografts (SCLC6, SCLC61, SCLC74 and SCLC108) were transplanted into mice. After intraperitoneal injection of STI571, we observed 80%, 40% and 78% growth inhibition of SCLC6, SCLC61 and SCLC108 tumors, respectively, without any significant inhibition of SCLC74 tumor growth. In mice bearing responsive SCLC tumors, we observed an increase of growth inhibition induced by chemotherapy (etoposide + ifosfamide or topotecan) by concomitant and continuous administration of STI571, associated with an increase of toxic deaths. In SCLC6‐bearing mice receiving sequential treatments, we observed a reduction of toxic deaths but a decrease of synergistic antitumor efficacy. In conclusion, the efficacy of STI571 alone in SCLC xenografted tumors was variable and did not depend on c‐kit expression. Moreover, a significant increase of chemotherapy‐induced growth inhibition was obtained by concomitant administration of STI571 that should be carefully investigated in SCLC patients.

Circulating tumor DNA changes for early monitoring of anti-PD1 immunotherapy: a proof-of-concept study

Background Recent clinical results support the use of new immune checkpoint blockers (ICB), such as anti-PD-1 (e.g. nivolumab and pembrolizumab) and anti-PD-L1 antibodies. Radiological evaluation of ICB efficacy during therapy is challenging due to tumor immune infiltration. Changes of circulating tumor DNA (ctDNA) levels during therapy could be a promising tool for very accurate monitoring of treatment efficacy, but data are lacking with ICB. Patients and methods This prospective pilot study was conducted in patients with nonsmall cell lung cancer, uveal melanoma, or microsatellite-instable colorectal cancer treated by nivolumab or pembrolizumab monotherapy at Institut Curie. ctDNA levels were assessed at baseline and after 8 weeks (w8) by bidirectional pyrophosphorolysis-activated polymerization, droplet digital PCR or next-generation sequencing depending on the mutation type. Radiological evaluation of efficacy of treatment was carried out by using immune-related response criteria. Results ctDNA was detected at baseline in 10 out of 15 patients. At w8, a significant correlation (r = 0.86; P = 0.002) was observed between synchronous changes in ctDNA levels and tumor size. Patients in whom ctDNA levels became undetectable at w8 presented a marked and lasting response to therapy. ctDNA detection at w8 was also a significant prognostic factor in terms of progression-free survival (hazard ratio = 10.2; 95% confidence interval 2.5-41, P < 0.001) and overall survival (hazard ratio = 15; 95% confidence interval 2.5-94.9, P = 0.004). Conclusion This proof-of-principle study is the first to demonstrate that quantitative ctDNA monitoring is a valuable tool to assess tumor response in patients treated with anti-PD-1 drugs.

Clinical relevance of human cancer xenografts as a tool for preclinical assessment: example of in-vivo evaluation of topotecan-based chemotherapy in a panel of human small-cell lung cancer xenografts

Prediction of human tumor response based on preclinical data could reduce the failure rates of subsequent new anticancer drugs clinical development. Human small-cell lung carcinomas (SCLC) are characterized by high initial sensitivity to chemotherapy but a low median survival time because of drug resistance. The aim of this study was to evaluate the therapeutic relevance of a panel of human SCLC xenografts established in our laboratory using one compromising drug in SCLC, topotecan (TPT). Six SCLC xenografts derived from six patients were used: three were sensitive to a combination of etoposide (VP16), cisplatin (CDDP), and ifosfamide (IFO), and three were resistant, as published earlier. Growth inhibition was greater than 84% for five xenografts at doses of 1–2 mg/kg/day. TPT was combined with IFO, etoposide (VP16), and CDDP. IFO improved the efficacy of TPT in three of the five xenografts and complete responses were obtained even with the less TPT-sensitive xenograft. VP16 increased the efficacy of two of four xenografts and complete responses were obtained. The combination of TPT and CDDP did not improve TPT responses for any of the xenografts tested. Semiquantitative reverse transcriptase-PCR of genes involved in drug response, such as topoisomerase I, topoisomerase II&agr;, multidrug resistance 1 (MDR1), multidrug resistance-associated protein (MRP), lung resistance-related protein (LRP), and glutathione S-transferase π (GSTπ), did not explain the variability in drug sensitivity between SCLC xenografts. In conclusion, these preclinical data mirror those from published clinical studies suggesting that our panel of SCLC xenografts represents a useful tool for preclinical assessment of new treatments.

Gefitinib and chemotherapy combination studies in five novel human non small cell lung cancer xenografts. Evidence linking EGFR signaling to gefitinib antitumor response.

The epidermal growth factor receptor (EGFR) signaling pathway is often activated in NSCLC, and thus represents a promising therapeutic target. We studied the antitumor activity of gefitinib (Iressa™), an orally active EGFR‐tyrosine kinase inhibitor, alone and in combination with standard chemotherapy in 5 recently established human NSCLC xenografts with wild‐type EGFR. Mice were treated with 2 protocols of chemotherapy based on cisplatin (CDDP) combined with either gemcitabine (GEM) or vinorelbine (VNR). Gefitinib alone significantly inhibited tumor growth (TGI) in 4 of the 5 tumor xenografts (mean TGI of 58%, range: 25–70%). CDDP+VNR alone failed to achieve any significant responses, while CDDP+GEM achieved significant responses in 2 xenografts (TGI of 93 and 47%). Addition of gefitinib to CDDP+GEM potentialized chemotherapy in the 3 CDDP+GEM‐resistant xenografts, but did not potentialize the CDDP+VNR combination. The effect of gefitinib treatment on the activity of extra cellular‐regulated kinase (Erk), Akt, JNK and p38 kinases was assessed in IC9LC11 and IC1LC131, two NSCLC xenografts selected for their sensitivity and resistance to gefitinib, respectively. In IC9LC11, gefitinib strongly inhibited Erk, Akt and Jnk phosphorylation, but P38 remained active. Inversely, in IC1LC131, Erk and Akt pathways remained active, while Jnk and P38 pathways were inhibited by gefitinib. The data indicate that the antitumor activity of gefitinib in NSCLC, alone or in combination with chemotherapy, is tumor‐dependent and is influenced by downstream signaling events independent of EGFR status.

Cost comparison of axillary sentinel lymph node detection and axillary lymphadenectomy in early breast cancer. A national study based on a prospective multi-institutional series of 985 patients ‘on behalf of the Group of Surgeons from the French Unicancer Federation’

BACKGROUND Our objective was to assess the global cost of the sentinel lymph node detection [axillary sentinel lymph node detection (ASLND)] compared with standard axillary lymphadenectomy [axillary lymph node dissection (ALND)] for early breast cancer patients. PATIENTS AND METHODS We conducted a prospective, multi-institutional, observational, cost comparative analysis. Cost calculations were realized with the micro-costing method from the diagnosis until 1 month after the last surgery. RESULTS Eight hundred and thirty nine patients were included in the ASLND group and 146 in the ALND group. The cost generated for a patient with an ASLND, with one preoperative scintigraphy, a combined method for sentinel node detection, an intraoperative pathological analysis without lymphadenectomy, was lower than the cost generated for a patient with lymphadenectomy [€ 2947 (σ = 580) versus € 3331 (σ = 902); P = 0.0001]. CONCLUSION ASLND, involving expensive techniques, was finally less expensive than ALND. The length of hospital stay was the cost driver of these procedures. The current observational study points the heterogeneous practices for this validated and largely diffused technique. Several technical choices have an impact on the cost of ASLND, as intraoperative analysis allowing to reduce rehospitalization rate for secondary lymphadenectomy or preoperative scintigraphy, suggesting possible savings on hospital resources.BACKGROUND Our objective was to assess the global cost of the sentinel lymph node detection [axillary sentinel lymph node detection (ASLND)] compared with standard axillary lymphadenectomy [axillary lymph node dissection (ALND)] for early breast cancer patients. PATIENTS AND METHODS We conducted a prospective, multi-institutional, observational, cost comparative analysis. Cost calculations were realized with the micro-costing method from the diagnosis until 1 month after the last surgery. RESULTS Eight hundred and thirty nine patients were included in the ASLND group and 146 in the ALND group. The cost generated for a patient with an ASLND, with one preoperative scintigraphy, a combined method for sentinel node detection, an intraoperative pathological analysis without lymphadenectomy, was lower than the cost generated for a patient with lymphadenectomy [€2947 (σ = 580) versus €3331 (σ = 902); P = 0.0001]. CONCLUSION ASLND, involving expensive techniques, was finally less expensive than ALND. The length of hospital stay was the cost driver of these procedures. The current observational study points the heterogeneous practices for this validated and largely diffused technique. Several technical choices have an impact on the cost of ASLND, as intraoperative analysis allowing to reduce rehospitalization rate for secondary lymphadenectomy or preoperative scintigraphy, suggesting possible savings on hospital resources.

Use of a Subcutaneous Implantable Pleural Port in the Management of Recurrent Malignant Pleurisy: Five-Year Experience Based on 168 Subcutaneous Implantable Pleural Ports

INTRODUCTION The authors report their experience in the use of subcutaneous implantable pleural port (SIPP) catheters for the treatment of symptomatic recurrent malignant pleurisy. MATERIALS AND METHODS Single-center, prospective follow-up of 137 patients (168 SIPPs). RESULTS No SIPP placement failures were observed. All but 3 of the 125 evaluable patients obtained complete or partial relief of their dyspnea. Seventy-six patients (60.3%) were receiving chemotherapy. Spontaneous pleurodesis was observed within 2 months in 46 patients (36.8%). Twenty-six patients (20.8%) died during the month following SIPP placement. Forty-one patients (32%) survived for more than 6 months. The overall median survival time was 344 days. Three infectious complications (1 empyema, 2 cellulitis) and 3 mechanical complications were observed. The role of pleurodesis as prognostic factor was assessed. Seventy-one patients survived for more than 2 months, 36 with pleurodesis, 35 without pleurodesis, requiring repeated pleural aspiration. The difference observed between the two groups by the 120th day was no longer significant when chemotherapy was taken into account. CONCLUSION SIPP is a safe and effective option for the outpatient management of recurrent malignant effusions and could be considered as first-line treatment in all patients with bilateral, compressive pleural effusion or poor lung reexpansion.

Preclinical assessment of cisplatin-based therapy versus docetaxel-based therapy on a panel of human non-small-cell lung cancer xenografts.

The success of treatment of advanced non-small-cell lung cancer (NSCLC) remains very poor. The aim of this study was, on a series of NSCLC xenografts, to compare the efficacy of standard cisplatin-based or docetaxel-based chemotherapy. Seven human xenografts were obtained from six patients (two xenografts were derived from primary or metastatic tumors of the same patient). Three xenografts were adenocarcinomas and four were squamous cell carcinomas. All xenografts reproduced the same histology as that of the patients original tumor. Docetaxel, administered as single-agent chemotherapy, induced a significant response in five of the seven NSCLC xenografts (71%), without significant increase after combination with cisplatin, vinorelbine, or gemcitabine. Relative expression of genes putatively involved in drug response was also studied in all xenografts and did not explain the variability of drug sensitivity. In conclusion, this panel of human NSCLC xenografts reliably reproduces the data obtained in patient tumors and the relative sensitivity to docetaxel reported in NSCLC patients.