Osimertinib beyond disease progression in T790M EGFR-positive NSCLC patients: a multicenter study of clinicians' attitudes.

BACKGROUND: In most cases, T790M EGFR-positive NSCLC patients receiving osimertinib developed "non-drugable" progression, as the patients with common EGFR-sensitizing mutations were treated with first-line osimertinib. In both settings, chemotherapy represents the standard treatment and local ablative treatments (LATs) are potential useful options in the case of oligo-progression. METHODS: We conducted a study on "post-progression" (pp) outcomes of T790M EGFR-positive NSCLC patients treated with osimertinib, according to the therapeutic strategy applied: osimertinib beyond progression (± LATs), "switched therapies" or best supportive care only (BSC). RESULTS: 144 consecutive patients were evaluated: 53 (36.8%) did not received post-progression treatments (BSC), while 91 (63.2%) patients received at least 1 subsequent treatment; 50 patients (54.9%) received osimertinib beyond disease progression [19 (20.9%) of them with adjunctive LATs] and 41 (45.1%) a switched therapy. Median ppPFS (progression-free survival) and median ppOS (overall survival) of patients who received osimertinib beyond progression vs. switched therapies were 6.4 months vs. 4.7 months, respectively [HR 0.57 (95% CI 0.35-0.92), p = 0.0239] and 11.3 months vs 7.8 months, respectively [HR 0.57 (95% CI 0.33-0.98), p = 0.0446]. Among patients who received osimertinib beyond progression with and without LATs median ppPFS was 6.4 months and 5.7 months, respectively [HR 0.90 (95% CI 0.68-1.18), p = 0.4560], while median ppOS was 20.2 months and 9.9 months, respectively [HR 0.73 (95% CI 0.52-1.03), p = 0.0748]. At the univariate analysis, the only factor significantly related to the ppPFS was the therapeutic strategy in favor of osimertinib beyond progression (± LATs). Moreover, the only variable which was significantly related to ppOS at the multivariate analysis was osimertinib beyond progression (± LATs). CONCLUSION: Our study confirmed that in clinical practice, in case of "non-druggable" disease progression, maintaining osimertinib beyond progression (with adjunctive LATs) is an effective option.

Clinical and prognostic role of matrix metalloproteinase-2, -9 and their inhibitors in breast cancer and liver diseases: A review.

Matrix metalloproteinases are a family of zinc endopeptidases with proteolytic activity against the extracellular matrix components. In particular, two members of this family named Gelatinase A and B, as amply documented in the literature, play a key role in the process of tumor growth/metastasis in breast and hepatocellular carcinoma. Their activity is regulated by Tissue Inhibitor of metalloproteinases-1 and -2, which are the physiological inhibitor of Gelatinases A and B respectively. The aim of this review is to determine the current understanding of the clinical and prognostic role of Metalloproteinases-2 and -9 and their inhibitors in the course of breast cancer and liver diseases. Forty-one articles were selected from PubMed by entering the following keywords: liver diseases, breast cancer, MMP-2, TIMP-2; all articles were read and notes were made regarding the number of enrolled patients, pathology, measures, results and these data were used to write this review. Over-expression of both gelatinases is associated with the relapse of disease, metastasis, shorter overall survival in breast cancer and hepatocellular carcinoma and invasion and progression to tumors in chronic liver diseases, and MMPs/TIMPs ratio could be useful in the follow-up of these patients.

miRNA profiling in serum and tissue samples to assess noninvasive biomarkers for NSCLC clinical outcome.

In NSCLC, the altered expression of some miRNAs in primary tumor tissues has been correlated with diagnosis and prognosis, while the role of circulating miRNAs as cancer biomarkers is currently emerging. MiRNA expression profile through miRNA Affymetrix array was evaluated on a training set formed by the tumor component (n = 30 NSCLC serum, n = 11/30 tumor tissues) and the control component (n = 10 healthy serum and n = 11/30 noncancerous counterparts). Statistical analyses highlighted the following: a = 55 miRNAs deregulated in tumor serum, b = 27 miRNAs deregulated in tumor tissues, and c = 2 miRNAs deregulated both in tumor serum and in tumor tissues. MiRwalk tool and enrichment pathway analyses selected some miRNAs whose target genes are correlated with the main pathways involved in NSCLC tumorigenesis. The altered expression of the selected miR-486-5p (a), miR-29c* (b), and miR-133a (c) was confirmed in the validation set (n = 40). MiR-486-5p had a higher expression in tumor serum than in tumor tissues (P = 0.004), and miR-29c* showed a lower expression in tumor tissues than in tumor serum (P < 0.001). MiR-133a had a not different expression in both tumor serum and tumor tissues (P = 0.07). The low level of miR-486-5p expression in the serum of affected patients was associated with a worse time to progression of disease (P = 0.010), and serum level of miR-486-5p was a significant prognostic indicator of NSCLC (adjusted hazard ratio = 0.179, P = 0.019). These data suggest the possibility to monitor affected patients through serum and/or tissue samples, analyzing the altered expression of specific miRNAs, in order to detect prognostic biomarkers in the NSCLC.

VEGF concentration from plasma-activated platelets rich correlates with microvascular density and grading in canine mast cell tumour spontaneous model.

Canine cutaneous mast cell tumour (CMCT) is a common cutaneous tumour in dog, with a higher incidence than in human. CMCT is classified in three subgroups, well and intermediately differentiated (G1 and G2), corresponding to a benign disease, and poorly differentiated (G3), corresponding to a malignant disease, which metastasize to lymph nodes, liver, spleen and bone marrow. In this study, we have evaluated serum (S), platelet-poor plasma (P-PP), plasma-activated platelet rich (P-APR) and cytosol vascular endothelial growth factor (VEGF) concentrations, microvascular density (MVD) and mast cell density (MCD) in a series of 86 CMCTs and we have correlated these parameters with each other, by means of ELISA detection of VEGF and immunohistochemistry. Results show that VEGF level from cytosol P-APR and MVD were significantly higher in G3 CMCTs as compared to G1 or G2 subgroups. Moreover, a significantly strong correlation among VEGF levels from P-PAR and cytosol, MVD and MCD was found in G3 subgroup. Because VEGF levels from P-APR well correlated with MVD and malignancy grade in CMCT, we suggest that VEGF might be secreted from MCs and it may be a suitable surrogate inter-species angiogenetic markers of tumour progression in CMCT. Finally, CMCT seems to be a useful model to study the role of MCs in tumour angiogenesis and inhibition of MCs degranulation or activation might be a new anti-angiogenic strategy worthy to further investigations.

Stop-flow perfusion with mitomycin-C as locoregional approach in the treatment of large-unresectable liver metastases.

BACKGROUND: New treatments are being investigated in patients with multiple or unresectable liver metastases, usually characterized by poor prognosis. Based on the predominant arterial blood supply of hepatic neoplasms, liver transarterial chemoembolization administers cytotoxic drugs in combination with the ischemic effect due to vascular occlusion. Mitomycin-C (MMC) is characterized by a high liver extraction rate and is potentiated by a hypoxic environment. PATIENTS AND METHODS: This technique is performed by inducing a stop-flow of the hepatic artery, obtained by the placement of a balloon-catheter and followed by the infusion of MMC; in addition, in order to prevent iatrogenic lesions of the vascular wall, caused by the inflation of the balloon-catheter, a vascular stent is placed at the beginning of the procedure. RESULTS: Thirty-one patients with liver metastases from various solid tumors were treated, while 47 sessions of treatment were performed. Toxicity was moderate; three cases of iatrogenic obstruction of the hepatic artery were observed, thus precluding further treatment. CONCLUSION: The feasibility and the good tolerability of this procedure make it an interesting option in the therapeutical strategy for patients with advanced metastatic liver disease, as well as in combination with systemic chemotherapy, ablative and cytoreductive treatments and/or free-flow liver perfusions with anticancer drugs.

Serum vascular endothelial growth factor concentrations in hepatocellular cancer patients undergoing percutaneously radiofrequency thermal ablation.

Vascular endothelial growth factor (VEGF) is known to play a central role in tumour angiogenesis. However, no data have been published with regard to the clinical-biological significance of serum (S)-VEGF in hepatocellular cancer (HCC) patients undergoing to percutaneously radiofrequency thermal ablation (PRFA). The aim of this study was to assess the modifications of S-VEGF levels in a series of 28 HCC patients in hepatitis C virus-positive cirrhosis before and after PRFA, respectively. Samples of S were taken before, 2 and 5 days after PRFA respectively and VEGF levels were assessed by ELISA. No significant difference was found between pre- and post-VEGF levels (p= n.s.; by Wilcoxon test). We suggest that S-VEGF level is not useful as early predictive marker of response to PRFA.

Radiofrequency thermal ablation of 69 lung neoplasms.

Radiofrequency thermal ablation (RFA) is a new, minimally invasive technique offered in the treatment of various neoplasms. RFA produces ionic agitation within the area to be treated, resulting in the heating of neoplastic tissue using a radiofrequency generator. Well defined areas of coagulative necrosis are formed, thereby destroying the tumor. Percutaneous CT-guided RFA was performed in 34 patients with 69 lung neoplasms. Six patients were affected by primary Non-Small Cell Lung Cancer (NSCLC), and 28 patients presented with metastatic lung nodules originating in various solid tumors. Patients were considered ineligible for surgery for the following reasons: medical comorbidities; technical reasons; severe respiratory insufficiency; refusal of surgery. Adequacy of treatment was assessed by CT-Scan and Nuclear Magnetic Resonance (NMR) with gadolinium. A median follow-up of 9 months (3-25 months) resulted in 30 patients evaluable for response with a total of 63 nodules to be treated, 58 of which achieved complete necrotic response. Relapse occurred in 5/63 treated nodules. In 2 of these patients, relapse occurred exclusively in the treated nodules, whereas in the other 3 patients, relapse occurred in the treated nodules as well as at distant sites. 9 patients are alive and disease free. Pneumothorax requiring pleural drainage was the main complication, observed in 16% of the treatment sessions. Lung RFA has shown itself to be a safe and feasible option in the treatment of lung neoplasms in patients otherwise ineligible for surgery. The high rate of complete responses obtained in our study (92%) suggests that further investigation of lung RFA, combined with chemotherapy and/or radiation therapy is warranted with the objective of improving local disease control and survival rates.

Phase I/II study of gemcitabine plus mitoxantrone as salvage chemotherapy in metastatic breast cancer.

The purpose of this study was to determine the maximum-tolerated dose of gemcitabine plus mitoxantrone in women with metastatic breast cancer (MBC) and to evaluate activity and toxicity of this combination in a phase II trial. Sixty-three patients with MBC, previously treated with chemotherapy including anthracycline and/or taxanes, were treated with mitoxantrone 10 or 12 mg m(-2) intravenously on day 1 plus gemcitabine in escalating doses from 600 to 1200 mg m(-2) intravenously on days 1 and 8, every 3 weeks. In phase I, on 23 patients entered on study, dose-limiting toxicity occurred at the dosage of 1200 mg m(-2) gemcitabine and 10 mg m(-2) mitoxantrone, with three out of five patients developing grade 4 neutropenia. In phase II, with gemcitabine administered at 1000 mg m(-2) and mitoxantrone at 10 mg m(-2), 12 (30%) out of 40 assessable patients responded, even if no complete response was obtained. Moreover, stable disease was observed in eight (20%) patients. The median time to treatment failure was 22 weeks (range, 2-33), and median survival was 42 weeks (range, 2-92). Grade 3 and 4 neutropenia were observed in 12 (30%) and one (2.5%) cases respectively; grade 3 thrombocytopenia was observed in two patients (5%), grade 2 mucositis in two patients (5%), grade 3 anaemia in two patients (5%), grade 3 alopecia in one patient (2.5%) and asymptomatic cardiotoxicity in three patients (8%), respectively. In conclusion, the doses of 10 mg m(-2) (day 1) for mitoxantrone and 1000 mg m(-2) for gemcitabine (days 1-8) every 3 weeks resulted active and safe in MBC. Further investigations in less heavily pretreated patients are warranted.

Hypoxic stop-flow perfusion with mitomycin-C in the treatment of multifocal liver metastases. Usefulness of a vascular arterial stent to prevent iatrogenic lesions of the hepatic arterial wall.

13 patients affected by multifocal and/or large liver metastases from various solid tumors have been treated with stop-flow liver perfusion, to evaluate the safety and feasibility of hypoxic loco-regional infusion with Mitomycin C. The treatment was based on the hypoxic effect due to stop-flow, potentiating the cytotoxic activity of Mitomycin C, combined with the ischemic damage caused by the embolization of the vascular supply to the tumor. The schedule consisted in blocking arterial flow by an angiographic occlusion balloon catheter inflated in the hepatic artery, with previous placement of a vascular stent in order to prevent iatrogenic arterial lesions, and followed by the intraarterial administration of Mitomycin C; finally, arterial hepatic embolization was performed by a gelatine sponge. The study is ongoing with a median follow up of 8 months (range 2-12). Partial response was observed in 1/13 patients (8%), stable disease in 8/13 patients (61%), while progressive disease occurred in 4/13 patients (31%). Nine patients are still alive, and four patients died for hepatic progressive disease, three of them heavily pre-treated with multiple lines of chemotherapy for advanced disease. Toxicity was mild; main side effects were anaemia and thrombocytopenia(Grade 3 both in 1/15 treatments), while fever, nausea and vomiting and upper abdominal pain were short-lasting and easily manageable. No iatrogenic lesion of the hepatic arterial wall occurred. These preliminary data, although the small number of patients and the short follow up, show that the procedure is safe and feasible, with a interesting percentage of clinical responses. In addition, the placement of an arterial stent have demonstrated to protect vascular wall ensuring a regular blood flow, so allowing to perform repeated treatments in responsive patients. The good tolerability of this therapeutic modality suggests further investigation in order to determine its efficacy even in combination with systemic chemotherapy and other locoregional treatments such as termoablative procedures and/or intraarterial antiblastic perfusions in patients affected by metastatic liver disease.

Epithelial ovarian cancer: second and third line chemotherapy (review).

Standard therapy for patients affected with advanced epithelial ovarian cancer is cytoreductive surgery followed by combination chemotherapy. With this treatment, most patients obtain clinical complete or partial response, nevertheless, relapse is common and salvage chemotherapy is often needed. The probability of response to second line chemotherapy following platinum-based treatments is usually related to the platinum-free interval, even if recent studies have reported some other clinical features as having prognostic value, such as tumour burden and histology. Salvage monochemotherapy is generally used, but when the platinum-free interval is longer than 24 months, re-treatment with platinum compounds and/or taxanes is indicated. Moreover, a number of new agents with demonstrated activity in ovarian cancer are currently available. Sequentially used in recurrent disease, these agents may improve survival and/or quality of life. Among these new drugs, the most promising are: topotecan, doxil, gemcitabine and platinum analogues such as oxaliplatin, nedaplatin, satraplatin, BBR3464 and ZD0473. However, the real aim of salvage chemotherapy in relapsed ovarian cancer still remains palliative care, because complete responses are very rarely reported and long lasting responses are very seldom observed.

Paclitaxel, cisplatin and lonidamine in advanced ovarian cancer. A phase II study.

A potential way to improve the results obtained with the standard carboplatin/cisplatin (CDDP)-paclitaxel treatment regimen in advanced ovarian cancer is to incorporate a modulating agent such as lonidamine (LND). In fact, LND has been shown to revert the resistance to cisplatin and to potentiate cisplatin activity experimental models and in clinical studies. 35 consecutive patients with advanced ovarian cancer, not previously treated with chemotherapy were treated with paclitaxel at a dose of 135 mg/m(2) intravenously (i.v.) on day 1 (in a 3 h infusion) and cisplatin at a dose of 75 mg/m(2) iv on day 2 plus LND orally (p.o.) at a dose of 450 mg/die for 6 consecutive days starting two days before chemotherapy, every 3 weeks for six cycles. Complete plus partial responses were observed in 8 (80%) out of the 10 women with measurable disease. In the 25 patients with evaluable disease, only four clinical progressions were observed (16%). Median progression-free survival (PFS) and overall survival (OS) were 28.5 (95% confidence interval (CI) 22.2-34.8) and 46.5 (95% CI 32.4-60.00) months respectively. Grade 3-4 neutropenia was observed in 9 (26%) patients. Alopecia, nausea and vomiting (Grade 3) were observed in 33 (94%) and 5 (14%) patients, respectively. In conclusion, the combination of CDDP/paclitaxel plus LND is active and tolerable in the treatment of advanced ovarian cancer.

High efficacy of paclitaxel and doxorubicin as first-line therapy in advanced breast cancer: a phase I-II study.

The aim of this study was to define the maximum tolerated dose (MTD) of paclitaxel (TAX) in combination with doxorubicin (ADM). To evaluate the efficacy and tolerability of this combination, TAX was administered in escalating doses of 30 mg/m2, starting from 120 mg/m2, by 1 hour continuous infusion, per group of three patients; ADM was administered at a fixed dose of 50 mg/m2, 24 hours before administering TAX (phase 1). The combination was recycled every 3 weeks. In phase II, TAX was administered at the MTD defined in phase I. Thirty-six women were enrolled. The MTD of TAX was 220 mg/m2. Objective responses were observed in 28/34 (82%) assessable patients. The median progression-free survival was 11.8 months and overall survival 27.8 months. The main clinical toxicity was neutropenia (grade III-IV) of short duration (94%). Two patients developed cardiac toxicity. The combination TAX+ADM is very effective in advanced breast cancer.

Mitoxantrone, L-leucovorin and 5-fluorouracil: an effective and well tolerated first-line treatment for advanced breast cancer.

AIMS AND BACKGROUND: The combination of mitoxantrone plus leucovorin/fluorouracil in heavily pretreated patients with advanced breast cancer has shown significant activity and extremely good tolerability. The aim of this study was to evaluate the activity of this combination in patients not previously submitted to chemotherapy. METHODS: From May 1993 to December 1995 we treated 80 patients with advanced breast cancer with a combination of mitoxantrone, l-leucovorin and 5-fluorouracil. All patients had histologically or cytologically proven breast cancer, WHO performance status 0-3, normal hematological parameters and normal serum bilirubin. Prior chemotherapy for metastatic disease was not allowed, whereas adjuvant CMF (cyclophosphamide, methotrexate and 5-fluorouracil) or adjuvant anthracycline (doxorubicin or epirubicin) therapy was allowed; a single prior hormone treatment was permitted. Chemotherapy consisted of mitoxantrone 12 mg/m2 i.v. day 1, l-leucovorin 150 mg/m2 i.v. days 1, 2 and 3 and 5-fluorouracil 350 mg/m2 i.v. days 1, 2 and 3. The courses were repeated every 3 weeks. RESULTS: Objective response (CR + PR) was observed in 46/80 (57%) patients (95% CI, 46%-68%). Complete response (CR) was observed in 21/80 cases (26%). Response was observed in 14/24 (58%) patients with soft tissues as the dominant site of disease, in 22/34 (65%) patients with visceral involvement and in 10/22 (45%) of those with bone as the dominant site of disease. The median duration of response and survival was 9 months (range, 3-16) and 22 months (range, 2-48+), respectively. Toxicity was very manageable, with grade 4 leukopenia and thrombocytopenia in 6/80 (7.5%) and 1/80 (1.25%) patients, respectively, and negligible non-hematological toxicity. CONCLUSIONS: The combination of mitoxantrone, 5-fluorouracil and high-dose l-leucovorin is a safe and effective regimen for first-line treatment of advanced breast cancer.

Neoadjuvant chemotherapy with accelerated CNF plus G-CSF in patients with breast cancer tumors larger than three centimeters: a pilot study.

From February 1992 to November 1993, forty patients with operable breast cancer tumors larger than three centimeters were enrolled in this study of accelerated neo-adjuvant chemotherapy. Thirty-seven patients are evaluable: one patient was excluded from the protocol and two refused to continue treatment after the first cycle. Chemotherapy consisted of three presurgical cycles of CNF [cyclophosphamide at 600 mg/m2, mitoxantrone (Novantrone) at 10 mg/m2 and 5-fluorouracil at 600 mg/m2] administered every 2 weeks, plus G-CSF (5 microg/kg s.c./day on days 7-12). Twenty-six of 37 patients (70%) achieved objective tumor response and were submitted to quadrantectomy. Toxicity was easily manageable. After a median 55-month follow-up (range 48-70), no locoregional recurrences were observed. Distant metastases occurred in 12/37 (32%) patients. The five-year disease-free (DFS) and overall (OS) survival were 58% and 80%, respectively. Accelerated CNF plus G-CSF proved to be a safe and tolerable regimen yielding a good clinical response thereby increasing the possibility of breast conservation surgery for patients otherwise candidates for mastectomy.

Combined carboplatin plus ifosfamide and cisplatin in patients with advanced ovarian carcinoma. A phase I-II study. GOCS (Gynecological Oncology Cooperative Study).

Because of the relative lack of overlapping toxicity, carboplatin (PPL) and cisplatin (CDDP) can be easily combined for treatment of ovarian cancer to increase total platinum dose intensity. Ifosfamide (IFO), one of the most effective single agents in ovarian cancer, has a low hematological toxicity when administered in continuous infusion. From January 1991 to December 1993, 34 patients with advanced ovarian cancer, previously untreated with chemo- or radiotherapy, were enrolled in a phase I-II study with the aim of determining the maximum tolerated dose (MTD) of CDDP (on day 8 of a 28-day cycle) in combination with PPL (300 mg/m2 on day 1) and IFO (4,000 mg/m2/24 h by continuous infusion on day 1). The initial dose level of CDDP was 40 mg/m2, which was continuously increased by 10 mg/m2 up to the MTD defined as one dose level below that inducing dose-limiting toxicity (DLT) in at least two-thirds of treated patients; no dose escalation was allowed in the same patient. Grade 3-4 leukopenia and thrombocytopenia were observed in 54 and 49% of patients, respectively. The DLT was reached at 70 mg/m2 and therefore the dose recommended for the phase II study was 60 mg/m2. Complete (CR) plus partial response was observed in 88% of patients with a 21% pathological CR. With a minimum follow-up of 32 months (median 40 months), median progression-free survival and overall survival were 21 and 39 months, respectively. In conclusion, the combination of CDDP, PPL, and IFO provides an effective regimen for ovarian cancer with an acceptable toxicity profile.

Revertant and potentiating activity of lonidamine in patients with ovarian cancer previously treated with platinum.

PURPOSE: Lonidamine (LND) is an energolytic derivative of indazol-carboxylic acid that has been shown to enhance cisplatin (CDDP) activity in both sensitive (A2780) and resistant (A2780/Cp8) ovarian cancer cell lines. The aim of this study was to confirm the potentiating or reverting activity of LND on CDDP activity obtained in experimental models in a phase II study of advanced ovarian cancer patients previously treated with platinum-based regimens. PATIENTS AND METHODS: Twenty-seven consecutive women with histologically proven and measurable ovarian cancer previously treated with platinum compounds were treated with CDDP plus LND. CDDP was administered at 1 mg/kg intravenously (IV) once weekly for 6 weeks and every 3 weeks thereafter until disease progression or toxicity. LND was administered at 450 mg daily (1 tablet every 8 hours) for the entire period of therapy starting 3 days before the first CDDP administration. In addition, a higher LND dosage was provided on the day of CDDP administration in an attempt to maximize the synergy of this drug with CDDP. RESULTS: Ten patients achieved a complete response (CR) or partial response (PR) for an overall response rate of 37% (95% confidence interval [CI], 19% to 55%). In particular, responses were observed in five of 18 (28%) refractory or early relapsed patients (one CR and four PRs) and in five of nine patients (55%) in the late-relapsed group (two CRs and three PRs). Grade 3 or 4 anemia, leukopenia, and thrombocytopenia were observed in 19%, 15%, and 11% of patients, respectively, whereas seven of 27 patients (26%) showed LND-related myalgia. Grade 3 renal toxicity was observed in two patients (8%). Neurotoxicity, often concealed by LND-related myalgia, was recorded as grade 1 or 2 in six patients (22%) and as grade 3 in one (4%). CONCLUSION: The 37% response rate observed in this study (28% in refractory or early-relapsed patients), suggests that the synergism between CDDP and LND observed in vitro against ovarian cancer cell lines can be clinically confirmed. However, larger series and randomized studies are needed to assess definitely the revertant activity of LND on CDDP-refractory patients.

Accelerated neoadjuvant chemotherapy of non-small cell lung cancer (NSCLC).

Thirty patients with marginally resectable stage IIIA or stage IIIB NSCLC were treated with cisplatin (80 mg/ m(2)/i.v./dl), ifosfamide (4,000 mg/m(2)/i.v./dl) and vinorelbine (30 mg/m(2)/i.v./dl) plus G-CSF 300 mu g/s.c. on days 7-12 every 14 days for three cycles before surgery. In 26 evaluable patients, the radiographically assessed response rate to chemotherapy was 77% (8% complete). Three septic deaths (10%) occurred in spite of G-CSF and 1 patient refused to continue after the first cycle. Thoracothomy was performed in 23 patients including 19 complete resections. At 15 months median follow-up (range 10-22+), 11/19 (57%) completely resected patients relapsed. The overall median time to treatment failure was 11 months (range 0-17). Actuarial survival probability at 12, 18 and 24 months are 56%, 43% and 36%, respectively. In conclusion, the combination of cisplatin, ifosfamide and vinorelbine in full doses at a 14 day interval (accelerated chemotherapy) was very effective in neoadjuvant NSCLC setting. Nevertheless, relevant toxicity was demonstrated with a 10% death rate probably due to the overlapping toxicity of chemotherapy cycles, suggesting the need for a more intense supportive care or longer interval between cycles.

Ovarian fibroma. A report of three cases.

The authors report three cases of ovarian fibroma in women in advanced menopause (mean age: 70 years). The neoplasm was bilateral in one patient. Early symptoms were pelvic pain, and, in one patient, menorrhagia without histologic alterations of the atrophic endometrium. The histology was typical of ovarian fibromas, except for one case which was characterized by a dense pseudofibrosarcomatous pattern and by the presence of numerous sex cord elements.

Results of a clinical multicentric randomized phase-ii study of nonsmall cell lung-cancer treated with vinorelbine Cisplatin versus vinorelbine alone.

From July 1992 to December 1993, 62 patients with non-small cell lung cancer (NSCLC) were admitted to a multicentric randomized study. The patients were treated with vinorelbine (V) alone at a dose of 25 mg/m(2)/i.v. weekly or with V at a dose of 25 mg/m(2)/i.v. on day 1 and 8 plus cisplatin at a dose of 80 mg/m(2)/i.v. on day 1 every 3-4 weeks (VP). An objective response was observed in 42% of patients treated with VP versus 12.5% of those treated with vinorelbine alone (p=0.038). There was no significant difference in the median survival duration between the two groups (38 versus 30 weeks for VP and V, respectively). Toxicity was tolerable but more severe in the VP regimen. These data suggest that V is an active agent in NSCLC and that the VP regimen may yield results comparable to other cisplatin combinations for treatment of these tumors.

Mitoxantrone in the treatment of recurrent ascites of pretreated ovarian carcinoma.

In this study we treated 19 patients with relapsed ovarian cancer with malignant peritoneal effusion. All patients were previously treated with cisplatin-containing regimens. Intraperitoneal mitoxantrone was administered at a dosage of 20-30 mg/mq repeated every 28 days if ascites was still present. No patient was treated with systemic chemotherapy during the study. In 15 of 19 patients progressive ascites reduction was obtained. Moreover, in 4 of 15 responsive patients, a progressive reduction of the quantity of ascites was observed even though the abdominal masses demonstrated an increase in volume. Serum concentrations of Mitoxantrone (MXN) were determined, in ten patients, by high performance liquid chromatography with spectrophotometric detection, and low serum levels (1-30 ng/ml) with a maximum at the first or second hour were revealed. In conclusion, in patients with ovarian carcinoma and recurrent neoplastic ascites, palliative treatment with mitoxantrone was effective and well tolerated. The reduction of ascites and frequency of paracentesis represents a marked advantage for these patients and improves their quality of life.