Efficacy and safety of ramucirumab plus carboplatin and paclitaxel in untreated metastatic thymic carcinoma: RELEVENT phase II trial (NCT03921671).

BACKGROUND: Thymic carcinoma (TC) is a rare tumor with aggressive behavior. Chemotherapy with carboplatin plus paclitaxel represents the treatment of choice for advanced disease. Antiangiogenic drugs, including ramucirumab, have shown activity in previously treated patients. RELEVENT trial was designed to evaluate the activity and safety of ramucirumab plus chemotherapy as first-line treatment in advanced TC. PATIENTS AND METHODS: This phase II trial was conducted within the Italian TYME network. Eligible patients had treatment naive advanced TC. They received ramucirumab, carboplatin and paclitaxel for 6 cycles, followed by ramucirumab maintenance until disease progression or intolerable toxicity. Primary endpoint was ORR according to RECIST v1.1 as assessed by the investigator. Secondary endpoints were PFS, OS and safety. Centralized radiologic review was performed. RESULTS: From 11/2018 to 06/2023, 52 patients were screened, 35 were enrolled. Median age was 60.8 years, 71.4% of patients were male and 85.7% had Masaoka-Koga stage IVB. ECOG PS was 0 in 68.5%, 1 in 31.4% patients. At the present analysis carried out some months later the interim analysis (earlier than expected) on 35 patients, ORR was 80.0% [95%CI 63.1-91.6]. At the centralized radiological review of 33/35 evaluable patients, ORR was 57.6% [95%CI 39.2-74.5]. After a median follow-up of 31.6 months, median PFS was 18.1 [95%CI 10.8-52.3] and median OS 43.8 [95%CI 31.9-NR] months. Thirty-two out of 35 patients (91.4%) experienced at least one treatment-related adverse event (AE), of which 48.6% were AE≥G3. CONCLUSIONS: In previously untreated advanced TC, the addition of ramucirumab to carboplatin and paclitaxel showed the highest activity compared to historical controls, with a manageable safety profile. Despite the small number of patients, given the rarity of the disease, the trial results support the consideration of this combination as first-line treatment in TC.

Lurbinectedin as second- or third-line palliative therapy in malignant pleural mesothelioma: an international, multi-centre, single-arm, phase II trial (SAKK 17/16).

BACKGROUND: Systemic second- and third-line therapies for malignant pleural mesothelioma (MPM) result in a median progression-free survival (mPFS) of <2 months and median overall survival (mOS) of 6-9 months. Lurbinectedin binds to the DNA of the regulatory region while inhibiting tumour-associated macrophage transcription. In early trials, encouraging outcomes occurred in patients (pts) with MPM treated with lurbinectedin. We aimed to generate lurbinectedin efficacy and safety data among pts with progressive MPM. PATIENTS AND METHODS: Pts with progressing MPM treated with first-line platinum-pemetrexed chemotherapy with or without immunotherapy received lurbinectedin monotherapy. Treatment was given intravenously at 3.2 mg/m2 dose every 3 weeks until progression or unacceptable toxicity. Using Simon's two-stage design, the primary endpoint, progression-free survival (PFS) at 12 weeks (PFS12wks), was met if achieved by ≥21 pts (p0 ≤35% versus p1 ≥55%). RESULTS: Forty-two pts from nine centres across Switzerland and Italy were recruited. Histology was epithelioid in 33 cases, sarcomatoid in 5, and biphasic in 4. Overall 10/42 (23.8%) underwent prior immunotherapy and 14/42 (33.3%) had progressed ≤6 months after first-line chemotherapy. At data cut-off PFS12wks was met by 22/42 pts (52.4%; 90% confidence interval (CI): 38.7% to 63.5%; P = 0.015) with an mPFS of 4.1 months and mOS of 11.1 months. The best response was complete and partial remission observed in one patient each and stable disease in 20 pts. The duration of disease control was 6.6 months (95% CI: 5.2-7.4). No significant difference in PFS12wks, mPFS, and mOS was recorded in epithelioid versus non-epithelioid cases and pts with prior immunotherapy versus those without. Similar mPFS but shorter mOS were observed among pts who progressed within ≤6 months after first-line chemotherapy. Lurbinectedin-related grade 3-4 toxicity was seen in 21 pts, mostly being neutropenia (23.8%) and fatigue (16.7%). CONCLUSIONS: The primary efficacy endpoint was reached with acceptable toxicity. Lurbinectedin showed promising activity regardless of histology, prior immunotherapy, or outcome on prior treatment. CLINICALTRIALS. GOV IDENTIFIER: NCT03213301.

Role of proton-coupled folate transporter in pemetrexed resistance of mesothelioma: clinical evidence and new pharmacological tools.

BACKGROUND: Thymidylate synthase (TS) has a predictive role in pemetrexed treatment of mesothelioma; however, additional chemoresistance mechanisms are poorly understood. Here, we explored the role of the reduced-folate carrier (RFC/SLC19A1) and proton-coupled folate transporter (PCFT/SLC46A1) in antifolate resistance in mesothelioma. PATIENTS AND METHODS: PCFT, RFC and TS RNA and PCFT protein levels were determined by quantitative RT-PCR of frozen tissues and immunohistochemistry of tissue-microarrays, respectively, in two cohorts of pemetrexed-treated patients. Data were analyzed by t-test, Fisher's/log-rank test and Cox proportional models. The contribution of PCFT expression and PCFT-promoter methylation to pemetrexed activity were evaluated in mesothelioma cells and spheroids, through 5-aza-2'-deoxycytidine-mediated demethylation and siRNA-knockdown. RESULTS: Pemetrexed-treated patients with low PCFT had significantly lower rates of disease control, and shorter overall survival (OS), in both the test (N = 73, 11.3 versus 20.1 months, P = 0.01) and validation (N = 51, 12.6 versus 30.3 months, P = 0.02) cohorts. Multivariate analysis confirmed PCFT-independent prognostic role. Low-PCFT protein levels were also associated with shorter OS. Patients with both low-PCFT and high-TS levels had the worst prognosis (OS, 5.5 months), whereas associations were neither found for RFC nor in pemetrexed-untreated patients. PCFT silencing reduced pemetrexed sensitivity, whereas 5-aza-2'-deoxycytidine overcame resistance. CONCLUSIONS: These findings identify for the first time PCFT as a novel mesothelioma prognostic biomarker, prompting prospective trials for its validation. Moreover, preclinical data suggest that targeting PCFT-promoter methylation might eradicate pemetrexed-resistant cells characterized by low-PCFT expression.

Thyroid volume and serum calcitonin changes during pregnancy.

BACKGROUND: Pregnancy has a profound impact on thyroid homeostasis which results in change of thyroid function and thyroid volume (TV). Moreover, calcitonin (CT), and its gene-related peptide have been demonstrated to play an important role in the implantation process. PURPOSE: To evaluate changes in TV and serum CT levels during pregnancy. METHODS: One hundred and fifty-five pregnant women were consecutively enrolled at the first trimester of gestation and underwent clinical, biochemical and sonographic assessment at enrollment, at the second and third trimesters and at 6 months after delivery. RESULTS: Throughout gestation serum TSH exceeded the upper specific first trimester cut-off in 5% of patients. TV significantly increased at the third trimester of gestation and returned to baseline levels at 6 months after delivery, while serum CT levels did not show significant changes. TV directly correlated with BMI or gestational weight gain at each trimester of pregnancy, while no significant association between serum CT levels and either weight or TV were found. Finally, in none of the patients with nodular goiter an increase in the volume of the nodules was noted. The appearance of a nodule was recorded during the second trimester in one patient. CONCLUSION: This study confirms a prevalence of thyroid autoimmunity/hypertropinemia in 3-5% of pregnant women and shows that serum CT does not change in relation to the transient increase in TV occurring during gestation. An adequate daily iodine supplementation might be particularly useful during pregnancy to limit the TSH increase and the resulting thyroid gland and nodule enlargement.

Phase I and pharmacodynamic study of high-dose NGR-hTNF in patients with refractory solid tumours.

BACKGROUND: NGR-hTNF exploits the peptide asparagine-glycine-arginine (NGR) for selectively targeting tumour necrosis factor (TNF) to CD13-overexpressing tumour vessels. Maximum-tolerated dose (MTD) of NGR-hTNF was previously established at 45 µg m(-2) as 1-h infusion, with dose-limiting toxicity being grade 3 infusion-related reactions. We explored further dose escalation by slowing infusion rate (2-h) and using premedication (paracetamol). METHODS: Four patients entered each of 12 dose levels (n=48; 60-325 µg m(-2)). Pharmacokinetics, soluble TNF receptors (sTNF-R1/sTNF-R2), and volume transfer constant (K(trans)) by dynamic imaging (dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)) were assessed pre- and post-treatment. RESULTS: Common related toxicity included grade 1/2 chills (58%). Maximum-tolerated dose was not reached. Both C(max) (P<0.0001) and area under the plasma concentration-time curve (P=0.0001) increased proportionally with dose. Post-treatment levels of sTNF-R2 peaked significantly higher than sTNF-R1 (P<0.0001). Changes in sTNF-Rs, however, did not differ across dose levels, suggesting a plateau effect in shedding kinetics. As best response, 12/41 evaluable patients (29%) had stable disease. By DCE-MRI, 28/37 assessed patients (76%) had reduced post-treatment K(trans) values (P<0.0001), which inversely correlated with NGR-hTNF C(max) (P=0.03) and baseline K(trans) values (P<0.0001). Lower sTNF-R2 levels and greater K(trans) decreases after first cycle were associated with improved survival. CONCLUSION: asparagine-glycine-arginine-hTNF can be safely escalated at doses higher than MTD and induces low receptors shedding and early antivascular effects.

Final results of DIADEM, a phase II study to investigate the efficacy and safety of durvalumab in advanced pretreated malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a cancer with a high mortality rate and few therapeutic options. After platinum-pemetrexed combination, no further promising drug seems to be effective. Immune checkpoint inhibitors may have some activity in pretreated patients and no data are available in this population about durvalumab. MATERIALS AND METHODS: DIADEM was a multicenter, open-label, single-arm, phase II trial aimed at evaluating the efficacy and safety of durvalumab. Patients with locally advanced/metastatic MPM who progressed after platinum-pemetrexed chemotherapy were enrolled to receive durvalumab (1500 mg, intravenously Q4W) for 12 months or until evidence of disease progression or unacceptable toxicity. The primary endpoint was the proportion of patients alive and free from progression at 16 weeks (PFS16wks) calculated from treatment initiation. Secondary endpoints were progression-free survival, overall survival, overall response rate, and safety. RESULTS: Sixty-nine patients with a median age of 69 years (range 44-82 years) were enrolled; 62 patients (89.9%) had epithelioid histotype. As first-line treatment, all patients received platinum derivatives-pemetrexed combination (60.9% with carboplatin and 39.1% with cisplatin). As of March 2021, the median follow-up was 9.2 months (interquartile range 5.2-11.1 months). Six patients (8.7%) completed the 12-month treatment; 60 patients discontinued, of whom 42 for progressive disease, and 4 died. Seventeen patients (28.3%; 95% confidence interval 17.5% to 41.4%) were alive or free from progression at 16 weeks. Eleven patients (18.6%) had a grade 3 or 4 treatment-related adverse event (AE), and one (1.4%) had a grade ≥3 immune-related, treatment-related AE. There was one drug-related death. CONCLUSION: Durvalumab alone in pretreated non-selected MPM did not reach a meaningful clinical activity, showing any new major safety issue signals.

Alveolar soft part sarcoma metastatic to the mandible: A report and review of literature.

Alveolar soft part sarcoma (ASPS) is a rare neoplasm constituting less than 1% of all soft tissue sarcomas. It tends to occur in the deep soft tissues of the lower extremities, however approximately 5-12% of cases are primary to the head and neck region. ASPS metastatic to the oral cavity is rare, with only four documented cases in the literature. Here, we present the case of a 29-year-old woman with ASPS metastatic to the mandible. To the best of our knowledge, this represents only the 5th documented case of ASPS metastatic to the oral cavity, and more specifically, the 3rd documented case of mandibular metastasis.

Early and late residual renal function and surgical complications in living donors: a 15-year experience at a single institution.

Living donation in the field of renal transplantation has increased over time as well as the use of laparoscopic nephrectomy. We present a 15-year experience on 162 living donors (105 women, 57 men; mean age, 46.7 years; range, 31-74 years) who underwent nephrectomy using different surgical approaches as open lombotomic nephrectomy (OLN), open transperitoneal nephrectomy (OTN), and laparoscopic hand-assisted nephrectomy (LHAN). We collected data on residual donor and recipient renal function, as well as early versus late medical and surgical complications. With a mean follow-up of about 8 years, we observed normal residual renal function in all donors and similar results of early and late graft function independent of the surgical procedure. Long-term incidence of hypertension and noninsulin-dependent diabetes in living donors was similar to the general population. OLN and OTN donors showed higher incidences of early and late complications, readmissions, and reoperations than LHAN donors. Our results confirmed that living donor nephrectomy is a safe procedure without serious side effects in terms of renal function and long-term quality of life. LHAN should be the preferred technique because of a lower incidence of early and late complications.

Synergistic effect of pendant hydroxypropyl and pyrrolidine moieties randomly distributed along polymethacrylamide backbones on in vitro DNA-transfection.

In this work, the cationic monomer N-ethyl pyrrolidine methacrylamide (EPA) was copolymerized with the neutral monomer N-hydroxypropyl methacrylamide (HPMA) at different molar ratios obtaining linear random copolymers that were characterized and evaluated in vitro as non-viral gene carriers using murine Swiss 3T3 fibroblasts. The copolymers with excess or equimolar amount of EPA were able to complex DNA forming stable polyplexes with an average size between 50 and 200 nm, while the copolymers with an excess of HPMA do not. Cell viability was shown to depend on the EPA/HPMA molar ratio, exhibiting the equimolar copolymer poly (EPA-co-HPMA) 50:50 (EPA50) a full cytocompatibility, similar to the HPMA-rich systems. This copolymer EPA50 has also shown significantly higher transfection levels than the systems with other compositions and the positive controls poly L-lysine (PLL) and poly EPA (pEPA). This statistical equimolar copolymer EPA50 has unique properties related to its composition and microstructure, which allows it to complex DNA, showing an excellent biocompatibility and high transfection efficiency.

Comparison of open versus thoracoscopic lung biopsy for diffuse infiltrative pulmonary disease.

BACKGROUND: Patients with diffuse pulmonary infiltrates often require biopsy for a diagnosis. Standard operative therapy, open wedge resection via thoracotomy, is associated with known morbidity. We hypothesized that closed thoracoscopic wedge resection may result in reduced morbidity and decreased duration of hospital stay. This retrospective study compares open resection with thoracoscopic wedge resection in patients with diffuse pulmonary infiltrates. METHODS: Seventy-five patients with diffuse pulmonary infiltrates underwent diagnostic lung biopsy. Patients requiring mechanical ventilation and high levels of pressure support before biopsy were excluded from the study. Between March 1987 and September 1991, a total of 28 patients underwent open wedge resection via lateral thoracotomy. Since April 1991, a total of 47 patients underwent thoracoscopic resection. RESULTS: There was no difference between the groups in age, sex, presence of immunosuppression, or final pathologic diagnosis. Adequate tissue was obtained for pathologic diagnosis in all patients of both groups. All surgeons believed that thoracoscopic biopsy provided better visualization of the entire lung than did a limited thoracotomy. Mean operative time was 69 minutes for open biopsies and 93 minutes for thoracoscopic biopsies [p = 0.038]. Mean duration of chest tube drainage was not significantly different between the two groups. Duration of hospital stay was significantly less for thoracoscopic biopsy (4.9 days) than for open biopsy (12.2 days) (p = 0.018). Fourteen of 28 open biopsies resulted in complications compared with 9 of 47 closed biopsies (p = 0.009). There were 6 deaths among patients having open biopsies and 3 deaths among those having closed biopsies (p = not significant). CONCLUSION: A significant decrease in hospital stay was noted with thoracoscopic biopsy when compared with lung biopsy via the standard open approaches. Thoracoscopy provided excellent visualization and allowed for wedge resection that provided adequate tissue for diagnosis in patients with diffuse pulmonary interstitial disease.

Postoperative pain-related morbidity: video-assisted thoracic surgery versus thoracotomy.

One hundred thirty-eight consecutive, nonrandomized patients, with equivalent demographic and preoperative physiologic parameters, underwent either a video-assisted thoracic surgical (VATS) approach (n = 81) or a limited lateral thoracotomy (LLT) approach (n = 57) to accomplish pulmonary resection for peripheral lung lesions (< or = 3 cm in diameter). Wedge resection was done in 74 VATS patients and 19 LLT patients. Seven patients underwent VATS lobectomy and 38 patients had lobectomy performed through an LLT. Pain was quantitated by postoperative narcotic requirements, the need for intercostal/epidural analgesia, and patient perception of pain index scoring. Shoulder and pulmonary function (forced expiratory volume in 1 second) were measured preoperatively, 3 days postoperatively, and at 3 weeks of follow-up. Patients undergoing VATS experienced significantly less postoperative pain. No patients undergoing VATS required intercostal block/epidural analgesia; 31 LLT patients (54%) required this treatment for breakthrough pain (p = 0.001). Narcotic requirements were less (p = 0.05) among VATS patients, which correlated with lower perception of pain index after operation for VATS patients. Shoulder girdle strength was equally impaired at day 3, but function was more improved in VATS patients at 3 weeks (p = 0.01). Patients undergoing wedge resection alone by LLT had greater impairment in early (day 3) pulmonary function (forced expiratory volume in 1 second) (p = 0.002); this difference from VATS was not sustained at 3 weeks. Video-assisted thoracic surgery is associated with reduced pain, shoulder dysfunction, and early pulmonary impairment compared with LLT for select patients requiring pulmonary resection.

Performance evaluation of cascade filtration with high flow rate recirculating plasma on the secondary filter.

Cascade filtration (CF) has been performed in 67 on-line procedures in 9 normolipidemic patients with paraproteinemic disorders. A modified dead-end technique has been employed, with high flow rate recirculating plasma on the plasma fractionation filter (QD recycled CF), and an albumin-rich, globulin-poor filtrate was reinfused into the patient. Postprocedure recoveries were 81 +/- 15% for albumin, 55 +/- 23% for IgM and 48% for cryocrit, with an increase in A/G ratio from 1.8 to 2.1. An improvement was observed also in antiatherogenic/atherogenic lipoproteins ratio, suggesting a possible use of this technique in the treatment of familial hypercholesterolemia. Plasma primary separation was obtained by centrifugation or by filtration, and no significant differences were observed on subsequent protein fractionation process. An albumin priming of the plasmafractionation circuit accounted for an additional 13% saving in postprocedure level. Different surface area secondary filters have been employed: with larger surfaces, larger volumes were processed without any increase in the waste volume and with reduced need for washouts, but with an additional loss of small molecules possibly due to entrapping onto the membrane.

Efficacy of a combined treatment with plasma exchange and cytostatics in macroglobulinemia.

Monthly plasma exchange (PE) sessions have been carried out in 3 patients with advanced Waldenström macroglobulinemia, in order to reduce electrophoretic M band under 2g/100 ml. When PE was combined to low doses of cytostatics (n = 18), 3 procedures per session were required to obtain a mean 57.4 +/- 12.3% IgM reduction, from 4.2 +/- 1.2 to 1.7 +/- 0.5 g/100 ml. A mean 61.5 +/- 13.1% IgM reduction, from 5.5 +/- 1.3 to 2.1 +/- 1 g/100 ml, was obtained in 64 procedures carried out as the only therapy in 12 sessions, with 5.3 procedures requirement per monthly session. IgM percent reduction 24 hours after PE was greater with combined treatment (45 +/- 9.7 vs. 28.9 +/- 15.4%; p = 0.001). The advantage of a combined treatment is therefore either a lowered PE requirement or a tapered maintenance cytostatic dosage.

Different cascade filtration operating modalities in clinical use.

Cascade filtration (CF) can be performed in either the single-pass or dead-end configuration. The distinction, as predicted by experimental models, is that solute removal is lower but constant in the former, and higher but variable with the quantity of filtrate in the latter. Moreover, unpredictable plugging reduces permeability during operation. It is therefore unclear which configuration is preferable in clinical use. In four cryo- and three macroglobulinemic patients, the data of 10 dead-end CF (QP) and 11 modified single-pass CF with high flow rate recycling plasma (QD) were compared. Both groups had similar starting values. Centrifugal primary plasma separation was performed. No exogenous reinfusions were used. Either 0.8 and 1.2 sq.m. surface secondary filters were employed. The ratio of plasma processed to patients' plasma volume was 1.1 +/- 0.3 in QP, and 0.94 +/- 0.09 in QD. The mean percentage removals of albumin, IgG and IgM respectively were 25.8 +/- 9, 32 +/- 17 and 47.5 +/- 26% in QP, 30.5 +/- 12, 40.5 +/- 19 and 48 +/- 17.5% in QD: albumin vs IgM p less than 0.025 in QP and p less than 0.02 in QD. A/G ratio increased from 1.6 +/- 0.5 to 2.06 +/- 0.6 in QP, and from 1.5 +/- 0.3 to 1.7 +/- 0.3 in QD. Plugging occurred in both groups, requiring 2.3 +/- 1.8 washouts/run in QP vs 1.5 +/- 1.2 in QD. IgM removal was comparable. Removal of albumin and IgG was slightly higher in QD. Similar performances can be obtained with either technique in clinical use, provided an adequate fractionation surface is available.

Renal abnormalities reverted by plasma exchange in thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is usually accompanied by renal disfunction presumable due to diffuse thrombotic occlusions in the microcirculation. Two patients with TTP and slight renal failure with proteinuria and microscopic hematuria, were treated by repeated plasma exchanges with fresh frozen plasma, associated with prednisone and cyclophosphamide in one case, and prednisone alone in the other one. Platelet count, hematocrit and lactic dehydrogenase reverted to normal values within the fourth exchange; circulating immune complexes were never detected. Plasma factor stimulating prostacyclin activity lacked in only one patient and returned to normal levels after plasma exchange without being affected during a hematologic relapse. Renal function and urinary abnormalities reverted to normal by the end of plasma exchange and nine and six months renal and hematologic follow-up is still negative. Renal abnormalities in TTP seem to take advantage of early treatment by plasma exchange, which further to replacement of missing plasma factors, can account for the removal of toxic substances to be further investigated on.

Plasma exchange in acute renal failure by cortinarius speciosissimus.

Mushroom poisoning by Cortinarius speciosissimus (C. spec.) leading to irreversible renal failure has been described; in a recent report, an expected bad prognosis has probably been overcome as a result of the very early use of hemoperfusion. In Sep. '81, a healthy couple of wife and husband, both aged 38, had gastrointestinal symptoms 2 days after ingestion of C. spec. On day 8 an acute renal failure developed and the same day, before dialysis, plasma exchange (PE) was undertaken. Renal biopsies disclosed a common pattern of tubular necrosis, scattered infiltrates and interstitial edema. Diuresis and partial recovery started in the man on day 10, while failure persisted over six months in the woman. Further to individual sensitivity to C. spec. toxins, renal damage, once established, may be irreversible, irrespectively of early treatment. Limited usefulness of PE in C. spec. poisoning is probably related to the long latency between ingestion and occurrence of the first renal symptoms.

Vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma.

BACKGROUND: Pemetrexed-platinum chemotherapy is the standard first-line treatment of unresectable malignant pleural mesothelioma (MPM). At progression, patients are generally selected to experimental trials, when available, or, in every-day clinical practice, they are offered second-line chemotherapy. The optimal treatment has not yet been defined. The aim of this retrospective, single-center study was to evaluate the activity and toxicity of vinorelbine administered to a consecutive series of pemetrexed-pretreated MPM patients. METHODS: Vinorelbine 25 mg/m(2) was administered intravenously as a single agent on days 1, 8 every three weeks, either as second-line (2L) or further-line (>2L) therapy. Treatment was repeated for a maximum of 6 cycles, until progression, or unacceptable toxicity. RESULTS: Fifty-nine patients were included in this analysis. Vinorelbine was given to 34 patients as 2L, and to 25 as > 2L treatment. The median age was 69 years (range 45-80). Forty-two patients (71.2%) had a good EORTC prognostic score. Partial response was observed in 9 (15.2%) cases, stable disease in 20 (33.9%). The overall disease control rate (DCR) was 49.1%. Median progression-free survival (PFS) and overall survival (OS) were 2.3 and 6.2 months, respectively. ECOG performance status (PS) (HR(0 vs. 1-2) 0.50; 95%CI: 0.3-0.8; p = 0.014) and PFS ≥ 6 months following first-line (FL) chemotherapy (HR(FL-PFS>6 ms vs. <6 ms) 0.50; 95%CI: 0.3-0.9; p = 0.031) were significantly associated to OS in multivariate analysis. No difference was observed in terms of DCR, PFS, and OS in relation to age, histology, sex, line of vinorelbine therapy, or response to FL treatment. Hematological toxicity was acceptable, with grade 3/4 neutropenia occurring in 5 (8.4%) patients, and there were no cases of febrile neutropenia. The main non-hematological toxicities were grade 2 fatigue in 17 (28.8%) and constipation in 7 (11.8%) patients. CONCLUSIONS: Vinorelbine was moderately active in pemetrexed-pretreated MPM patients, with an acceptable toxicity profile, particularly in patients with ECOG-PS0 and FL-PFS ≥ 6 months.

Second-line chemotherapy in malignant pleural mesothelioma: results of a retrospective multicenter survey.

The pemetrexed-cisplatin chemotherapy is standard of care in first-line (FL) treatment of malignant pleural mesothelioma (MPM). The second-line (SL) chemotherapy is considered, but the optimal treatment has not been defined yet. The aim of this study was to evaluate the clinical outcomes of SL-therapy in a series of MPM-patients included in a retrospective multicenter database. Clinical records of MPM-patients who received SL-treatment from 1996 to 2008 were reviewed. Study endpoints were response, overall-survival (OS), and progression-free-survival (PFS) for SL, stratified for patient characteristics, FL-outcomes, and type of SL. Out of 423 patients, 181 with full clinical data were identified. Patients' characteristics: median-age 64 years (range: 36-85); male gender 115 (63.5%); good EORTC-score 109 (60.2%); epithelial histology 135 (74.6%). After FL, 147 (81.2%) patients achieved disease-control (DC) and 45 had a time-to-progression≥12 months (TTP≥12). After SL, 95 patients (52.6%) achieved DC (21 response; 74 stable-disease); median PFS and OS were 4.3 and 8.7 months, respectively. According to multivariate analysis, DC after SL-therapy was significantly related to pemetrexed-based treatment (OR: 2.46; p=0.017) and FL-TTP≥12 (OR: 3.50; p=0.006). PFS was related to younger age (<65 years) (HR: 0.70; p=0.045), ECOG-PS0 (HR: 0.67; p=0.022), and FL-TTP≥12 (HR: 0.45; p<0.001). OS was significantly related to ECOG-PS0 (HR: 0.43; p<0.001) and to FL-TTP≥12 (HR: 0.54; p=0.005). In pemetrexed pre-treated patients, re-treatment with a pemetrexed/platinum combination significantly reduced the risk-of-death than pemetrexed alone (HR: 0.11; p<0.001). In conclusion, SL-chemotherapy seems to be active in MPM-patients, particularly in younger patients with ECOG-PS0 and prolonged TTP after FL-pemetrexed-based chemotherapy. In selected patients, re-challenge with pemetrexed-based regimens, preferentially associated with platinum-compound, appears to be an option for SL-setting. Considering the important limitations of this study, due to retrospective nature and the possible selection bias, prospective clinical trials are warranted to clarify these issues.