[Immunotherapy in lung cancer: New concepts]. / Immunothérapie et cancer du poumon : nouveaux concepts.

Improvements in knowledge about the complexity of the tumor microenvironment have paved the way for a revolution in lung cancer treatment with the emergence of immune checkpoint inhibitors. The immune checkpoints negatively regulate immune cells and lead to a dormant state: the immune cells are then unable to interact effectively with their targets. The immune checkpoint inhibitors are monoclonal antibodies that block immune checkpoints and permit reactivation of the immune response against the tumor. Although immune checkpoint inhibitors are effective as monotherapy, several other immune targets exist. The better understanding of the involvement of these new targets in the immune response against tumors is leading to the design of new compounds and new therapeutic approaches.

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.

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.

Uveal metastasis revealing lung cancer.

BACKGROUND: Uveal metastases (UM) are the most common intraocular malignancies and can be the first manifestation of a disseminated disease. The purpose of this study is to determine the frequency with which uveal metastasis results in a diagnosis of lung cancer, to describe the clinical characteristics of patients with lung cancer metastatic to the uvea, as well as diagnostic difficulties that may be encountered. PATIENTS AND METHODS: We carried out a single-center retrospective study of the medical records of all patients who presented with a UM between 1999 and 2010 at the institut Curie in Paris. From these patients, we retrospectively studied UM secondary to lung cancer. A work-up including thoracic-abdominal-pelvic CT was performed for each patient in whom the primary source of choroidal metastasis was unknown. RESULTS: Of 109 patients presenting with UM, 43 were diagnosed with primary lung cancer (39.4%). Of those 43 patients, the UM was observed prior to the lung cancer in 31 patients (72.1%). Demographic data included 61% male and 39% female, mean age 59.1 years (range: 31-78), and mean life expectancy after diagnosis of UM was 7.5 months (range: 0.7-29). Other metastatic sites were associated with UM in 90.7% of the patients. In all, 90.7% of the patients presented with blurred vision, and 25.6% with pain or inflammation. UM were located within the choroid for 39 patients (90.7%), the iris for three patients (7.3%) and the vitreous for one patient. Seventy percent of patients had a solitary lesion, 76.7% had unilateral involvement, and 23.3% of cases were bilateral. Mean thickness on B-scan ultrasonography was 3.61 mm (range: 1-8.5 mm). In all, 81.4% of UM were unpigmented, while 18.6% showed pigment mottling. In all, 20.9% of patients were referred with the diagnosis of choroidal melanoma from their regular ophthalmologist, and three of the 43 patients (6.9%) were initially misdiagnosed and treated for melanoma at Curie. Chest X-ray was unremarkable in 18.9% of patients. CONCLUSION: UM is often the first manifestation of disseminated disease and requires a search for the primary tumor, in particular lung cancer. Standard chest X-ray cannot rule out the diagnosis. Metastases may be solitary with heterogenous pigmentation, and the differential diagnosis from uveal melanoma may be difficult, requiring the expertise of a referral center.

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.

[Pulmonary blastoma in an adult]. / Le pneumoblastome de l'adulte.

The authors report the case of a 24-year-old woman in complete remission 4 years after treatment for a biphasic pulmonary blastoma. After a left lower lobectomy, the patient developed a local recurrence that was treated by chemotherapy. In the light of this case, the authors review the clinical, radiological and therapeutic features of this very rare malignant lung tumour.

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.

[Using a pleural implantable access system for the management of malignant pleural effusions. Experience of Institut Curie]. / Utilisation du cathéter à chambre implantable pleural dans la gestion des pleurésies malignes. Expérience de l'Institut Curie.

PURPOSE: Malignant pleural effusion has a very poor prognosis, raises problems of medical management and impairs quality of life. The authors report the first experience of a pleural implantable access system for the treatment of recurrent symptomatic malignant pleural effusion. DESCRIPTION: Prospective follow-up of 26 patients between 20/8/2005 and 2/11/2006 in a single center. Thirty pleural implantable access systems were placed in 26 patients (22 patients with breast cancers, 3 bilateral placements and one case of replacement) under sedation following the decision of a multidisciplinary meeting. EVALUATION: Twenty-five patients obtained partial or complete relief of their dyspnea. Four patients underwent spontaneous pleurodesis after a maximum of 2 months. Twelve patients were receiving chemotherapy at the time of placement. The number of aspirations performed varied between 1 and 28 over a period of 11 to 330 days. Eight patients died within 1 month after placement of the system and 6 survived more than 6 months. Seven patients died at Institut Curie or in a palliative care unit without returning home. The other 16 patients presented a total of 198 days of hospitalization for 2,305 days of catheter implantation. No placement failures were observed in this series. Two infectious complications (infectious pleuro-pneumonia and skin infection over the puncture site) and two mechanical complications (expulsion of the port and disconnection between the port and the catheter) were observed and easily treated. One patient developed loculation of the pleural cavity after 16 thoracenteses making further thoracentesis ineffective. CONCLUSIONS: The pleural implantable access system is an interesting alternative in terms of efficacy and safety for the outpatient management of malignant pleural effusion. It shows a number of advantages in terms of comfort and infectious risk compared to tunneled pleural catheters.

Vacuum-assisted large-core needle biopsy (VLNB) improves the management of patients with breast microcalcifications - analysis of 1009 cases.

AIMS: To evaluate the surgical management of patients who underwent VLNB for breast microcalcifications. METHODS: This retrospective study compared the histological results and the surgical procedures in two groups of patients, group 1: large-core needle biopsy n=1009, and group 2: surgical biopsy n=270. RESULTS: After VLNB, 54% patients were not operated on after stereotactic large-core needle biopsy, 42% underwent one operation, 4% underwent two operations and 0.2% underwent three operations. No surgery was performed for 95% of benign lesions. Multiples operations were necessary in 12% of patients with malignant lesions of VLNB group compared to 45% in the surgical biopsy group. The rate of underdiagnosis of borderline lesions and ductal carcinomas in situ was 16% by the large-core biopsy technique. CONCLUSION: VLNB constitutes an alternative to surgical biopsy. This procedure avoids surgery for most benign lesions and reduces the number of surgical procedures in malignant lesions.

[New radiotherapy techniques for non-small-cell lung cancer]. / Nouveautés techniques pour une radiothérapie thoracique moderne des carcinomes bronchiques non à petites cellules.

Lung cancer is one of the most difficult challenges for radiotherapy. Problems include ballistic targeting compromised by respiratory movements, poor tolerance of neighboring healthy tissues and difficult dosimetry due to the heterogeneous nature of the thoracic tIssues. New perspectives are offered by recent developments allowing a more comprehensive approach to thoracic radiotherapy integrating new advances in imaging techniques, contention, dosimetry, and treatment devices. Two techniques are particularly promising: conformal radiotherapy and respiration-gated radiotherapy. Conformal radiotherapy, a three-dimensional conformal mode of irradiation with or without intensity modulation, is designed to achieve high-precision dose delivery by integrating advanced imaging techniques into the irradiation protocol. These tools are used to optimize irradiation of target Volumes and avoid recurrence while sparing as much as possible healthy tissues. If healthy tissue can be correctly protected, increased doses can be delivered to the target tumor. Respiration-gated techniques offer promising prospects for the treatment of tumors which are displaced by respiratory movements. These techniques allow better adaptation of the irradiation fields to the target tumor and better protection of healthy tissues (lung, heart...). These new approaches are now routine practices in many centers. Early results have been very promising. We describe here the currently available techniques for thoracic radiotherapy.

[How to finance chemotherapy with new cancer drugs? / Comment financer l'utilisation de nouveaux médicaments de chimiothérapie?

Recently developed drugs are ten to one hundred fold more costly than the chemotherapies of the past while the number of eligible patients and the average duration of treatments are ever increasing. The combined effect of these trends makes budgeting a daunting task, in particular for hospitals with budgetary allocation. Balancing budgets became difficult with the arrival of taxanes, but innovative therapies based on biotechnological advances will further increase the financial slide. Hospital running costs can not be infinitely reduced. Therefore, new rules that govern the financing of innovative therapies become mandatory and budgetary allocations based on DRG evaluations will no longer be feasible.

Distinctive potentiating effects of cisplatin and/or ifosfamide combined with etoposide in human small cell lung carcinoma xenografts.

Combined modalities are currently used for cancer therapy, although their mechanisms of activity remain incompletely deciphered. The design of new drug combinations suffers from our inability to anticipate accurately their efficacy or toxicity. They can be evaluated in vivo, using human tumors grafted into immunodeficient mice, as we did here with combined protocols used in the clinical setting. Xenografts of small cell lung carcinoma (SCLC) from eight patients were used to test the tumor sensitivity to etoposide (VP16; 12-16 mg/kg/days, days 1, 2, and 3), cisplatin (CDDP; 6-9 mg/kg/day, day 1) and ifosfamide (IFO; 90-210 mg/kg/day, days 1, 2, and 3) as single agents and to evaluate the efficacy of the two-drug or three-drug combinations. Five xenografts came from untreated patients (SCLC-61, SCLC-6, SCLC-10, SCLC-41, and SCLC-96) and three after treatment (SCLC-74, SCLC-101, and SCLC-108). p53 was inactivated in all of them. Tumor growth inhibition, growth delay, and the survival rate of tumor-bearing mice reflected individual SCLC chemosensitivity. As single agents, IFO inhibited tumor growth in a dose-dependent manner, whereas CDDP and VP16 had little or no effect. Both CDDP and IFO potentiated VP16, inducing complete regressions in the most sensitive SCLCs; VP16-IFO was more effective than VP16-CDDP, with complete regressions in six versus three of the eight tumors tested, respectively. CDDP-IFO was less effective than VP16-IFO, with three of eight SCLCs giving complete regressions. The three-drug combination led to modest improvement over the best two-drug combination but only for sensitive SCLCs. Because drug-responses distinguished two classes of SCLCs, as sensitive or refractory, MDR1, glutathione S-transferase pi, lung-related multidrug resistance protein, multidrug resistance protein, and topoisomerase IIalpha mRNA expression was studied by semiquantitative reverse transcription. There was no correlation with SCLC sensitivity; topoisomerase IIalpha and multidrug resistance protein was expressed in all cases, lung-related multidrug resistance protein and glutathione S-transferase pie in seven of eight, and MDR1 gene in four of eight. In conclusion, these SCLC xenografts displayed a pattern of chemotherapy response close to that observed in patients. This model confirmed that in two-drug combinations, each component potentiated the effects of the other, with VP16-IFO tending to be the best two-drug combination, both of which were more effective than VP16-CDDP and better tolerated than CDDP-IFO. The addition of a third agent gave a modest, if any, therapeutic benefit in the responders but none in refractory SCLCs. There was no correlation between the extent of response and resistance markers.

Quantitative fluorescence in situ hybridization in lung cancer as a diagnostic marker.

The diagnosis of lung cancer is quite often hampered by the existence of various cell types within samples such as biopsies or pleural effusions. We have established a new marker for image cytometry of interphase tumor cells of the lung by using the most recurrent and early cytogenetic event in lung cancer, the loss of the short arm of chromosome 3. The method is based on the detection of the imbalance between the long and the short arms of chromosome 3 by performing two-color fluorescence in situ hybridization on both arms. Fourteen tumors were analyzed after short-term culture and compared with the corresponding cytogenetic data obtained from metaphase analysis. Results on interphase nuclei and control experiments on metaphases were the same, with imbalance ratios ranging from 1.0 to 2.0 (mean value 1.6, median 1.5). To assess the clinical significance of this approach, three pleural effusions were analyzed. Data showed that normal cells within the sample could have been distinguished from the tumor cells based on different imbalance values between the long and the short arms. Thus, our method allows refined detection of lung tumor cells within samples containing heterogeneous cell populations.

[Surgical excision of pulmonary metastasis of cancer of the breast: apropos of 40 patients]. / Exérèse chirurgicale de métastases pulmonaires de cancer du sein: à propos de 40 patientes.

Between 1987 and 1995, 52 breast cancer patients had a surgical resection of lung secondaries. In 40 patients, the diagnosis of metastatic breast cancer could be confirmed following pathological examination. Five-year survival rates of these 40 patients was 54 +/- 8% and 5-year disease free survival was 30 +/- 8%. The median survival (70 months) of these patients was better than that of 57 patients with isolated lung metastases who had been treated conservatively (chemo- or/and hormonotherapy) during the same time interval. Twenty-six patients benefitted from a radical excision and had a longer disease free interval (42 versus 27 months, p = 0.03) than patients who had had a wedge resection. Overall survival was not significantly different (71 versus 41 months, p = 0.07). We feel that isolated lung nodules may best be treated by radical (segment or lobe) excision, in particular since preoperative differential diagnosis with primary lung cancer may be difficult. In the presence of multiple nodules, first line medical treatment by chemo- or hormonotherapy should be advocated, allowing to reduce the tumor load and to optimize survival in association with surgery.

Surgery of lung metastases of breast cancer: analysis of 40 cases

Between 1987 and 1995, 52 breast cancer patients had a surgical resection of lung secondaries. In 40 patients, the diagnosis of metastatic breast cancer could be confirmed following pathological examination. Five-year survival rates of these 40 patients was 54 8 % and 5-year disease free survival was 30 8%. The median survival (70 months) of these patients was better than that of 57 patients with isolated lung metastases who had been treated conservately (chemo- or/and hormonotherapy) during the same time interval. Twenty-six patients benefitted from a radical excision and had a longer disease free interval (42 versus 27 months, p = 0.03) than patients who had had a wedge resection. Overall survival was not significantly different (71 versus 41 months, p = 0.07). We feel that isolated lung nodules may best be treated by radical (segment or lobe) excision, in particular since preoperative differential diagnosis with primary lung cancer may be difficult. In the presence of multiple nodules, first line medical treatment by chemo- or hormonotherapy should be advocated, allowing to reduce the tumor load and to optimize survival in association with surgery.

Randomized trial comparing protracted infusion of 5-fluorouracil with weekly doxorubicin and cyclophosphamide with a monthly bolus FAC regimen in metastatic breast carcinoma (SPM90).

Infusional 5-fluorouracil in advanced breast cancer has been associated with improved clinical response rates when compared with conventional bolus therapy. As a first line of chemotherapy in proven metastatic breast carcinoma, 258 women were randomly assigned to receive FAC consisting of 5-fluorouracil (F) 600 mg m(-2) intravenously (i.v.) over 1 h on days 1, 2 and 3, doxorubicin (A) 50 mg m(-2) i.v. bolus on day 1 and cyclophosphamide (C), 400 mg m(-2) i.v. bolus on days 1, 2 and 3 or 'FULON' consisting of 5-fluorouracil 250 mg m(-2) day(-1) continuously infused from day 1 to day 22, doxorubicin 15 mg m(-2) i.v. bolus on days 1, 8, 15 and 22 and cyclophosphamide 300 mg m(-2) i.v. bolus on days 1, 8, 15 and 22. Chemotherapy courses were administered 4-weekly for the bolus regimen and 6-weekly for FULON. Pretreatment characteristics were identical between the two groups. Response rates were 54% in the FAC arm and 53% in the FULON arm. Time to progression was 14 months in the FAC arm and 12 months in the FULON arm. Differences were not statistically significant. Median overall survival duration for all patients was 22 months. Haematological toxicity was more severe in the bolus-treated group (P = 0.05), as were nausea and vomiting (P < or = 0.01). We conclude that the two regimens appeared equally effective but have different toxicities.

[A combined radiochemotherapy trial for non-small cell lung cancers: initial results]. / Essai d'association radio-chimiothérapique des carcinomes bronchiques non à petites cellules: résultats préliminaires.

PURPOSE: Analysis of the preliminary results of a phase I study investigating the feasibility of concomitant chemotherapy with daily doses of carboplatin (20 to 25 mg/m2/d over 45 or 10 min) and accelerated chest irradiation (60 to 64 Gy over 4 weeks, 2 Gy per fraction, using the concomitant boost technique). MATERIALS AND METHODS: This combination was given alone or following three cycles of induction chemotherapy (cisplatin, 25 mg/m2 per day from d1 to d5; 5-fluorouracil, 600 mg/m2 per day from d1 to d5 and vinorelbine, 25 mg/m2 per day at d1 and d5 with a 4-week interval) in 15 patients with locally advanced unresectable non-small cell lung cancer. All patients received the planned sequence. RESULTS: The dose-limiting toxicity was esophagitis (5 out of 15 grade 4). No toxic deaths were observed. The tumor response rate was high: six out of 15 complete responses and 14 out of 15 tumor regressions greater than 50%. The median survival was not reached after a mean follow-up of 14 months (range, 6-28 months). CONCLUSION: We are now planning a multicenter phase II study using the following combination: 20 mg/m2 of daily carboplatin over 10 min and a 60-Gy irradiation dose over 4 weeks.

Phase II trial of decapeptyl (D-TRP-6), a potent luteinizing hormone-releasing hormone analogue in untreated advanced breast cancer.

Decapeptyl (D-TRP-6), a potent luteinizing hormone-releasing hormone analogue, was administered to 27 premenopausal women with advanced breast cancer; patients were known to have hormone receptor-positive tumors. An overall response rate of 70% was achieved (complete response = 18%, partial response = 52%), with a median time to progression for the whole patient population of 12 months. Toxicity of the schedule was restricted to hot flushes, and the use of a 4-week initial covering period of tamoxifen prevented any flare-up of disease activity from occurring.

Interstrain variations in the cytomegalovirus (CMV) glycoprotein B gene sequence among CMV-infected children attending six day care centers.

Using the shell vial assay and sequence analysis of a variable region of the glycoprotein B (gB) gene, cytomegalovirus (CMV) excretion rates in urine and virus transmission were studied among 93 children from six day care centers (DCCs). During a 6-month period, excretion rates differed significantly between DCCs (P < .001). The 6 gB gene sequences, obtained from 24 CMV-infected children, were classified in four previously defined groups. In five DCCs, 2 or 3 strains cocirculated, and none was dominant. Infection could have been acquired outside the DCC for 2 children and inside it for 9. Two children from the same DCC had mixed infections. No differences in hygiene, child care practices, or experience and level of qualification of the staff could explain this wide variety of excretion rates between DCCs. The distribution of gB gene patterns observed does not suggest that 1 type was dominant or more efficiently transmitted.