A systematic literature review and network meta-analysis of effectiveness and safety outcomes in advanced melanoma.

BACKGROUND: Although a myriad of novel treatments entered the treatment paradigm for advanced melanoma, there is lack of head-to-head evidence. We conducted a network meta-analysis (NMA) to estimate each treatment's relative effectiveness and safety. METHODS: A systematic literature review (SLR) was conducted in Embase, MEDLINE and Cochrane to identify all phase III randomised controlled trials (RCTs) with a time frame from January 1, 2010 to March 11, 2019. We retrieved evidence on treatment-related grade III/IV adverse events, progression-free survival (PFS) and overall survival (OS). Evidence was synthesised using a Bayesian fixed-effect NMA. Reference treatment was dacarbazine. In accordance with RCTs, dacarbazine was pooled with temozolomide, paclitaxel and paclitaxel plus carboplatin. To increase homogeneity of the study populations, RCTs were only included if patients were not previously treated with novel treatments. RESULTS: The SLR identified 28 phase III RCTs involving 14,376 patients. Nineteen and seventeen treatments were included in the effectiveness and safety NMA, respectively. For PFS, dabrafenib plus trametinib (hazard ratio [HR] PFS: 0.21) and vemurafenib plus cobimetinib (HR PFS: 0.22) were identified as most favourable treatments. Both had, however, less favourable safety profiles. Five other treatments closely followed (dabrafenib [HR PFS: 0.30], nivolumab plus ipilimumab [HR PFS: 0.34], vemurafenib [HR PFS: 0.38], nivolumab [HR PFS: 0.42] and pembrolizumab [HR PFS: 0.46]). In contrast, for OS, nivolumab plus ipilimumab (HR OS: 0.39), nivolumab (HR OS: 0.46) and pembrolizumab (HR OS: 0.50) were more favourable than dabrafenib plus trametinib (HR OS: 0.55) and vemurafenib plus cobimetinib (HR OS: 0.57). CONCLUSIONS: Our NMA identified the most effective treatment options for advanced melanoma and provided valuable insights into each novel treatment's relative effectiveness and safety. This information may facilitate evidence-based decision-making and may support the optimisation of treatment and outcomes in everyday clinical practice.

Comparison of Nutrition-Related Adverse Events and Clinical Outcomes Between ICE (Ifosfamide, Carboplatin, and Etoposide) and MCEC (Ranimustine, Carboplatin, Etoposide, and Cyclophosphamide) Therapies as Pretreatment for Autologous Peripheral Blood Stem Cell Transplantation in Patients with Malignant Lymphoma.

BACKGROUND The aim of this study was to compare nutrition-related adverse events and clinical outcomes of ifosfamide, carboplatin, and etoposide regimen (ICE therapy) and ranimustine, carboplatin, etoposide, and cyclophosphamide regimen (MCEC therapy) instituted as pretreatment for autologous peripheral blood stem cell transplantation. MATERIAL AND METHODS We enrolled patients who underwent autologous peripheral blood stem cell transplantation between 2007 and 2012. Outcomes were compared between ICE therapy (n=14) and MCEC therapy (n=14) in relation to nutrient balance, engraftment day, and length of hospital stay. In both groups, we compared the timing of nutrition-related adverse events with oral caloric intake, analyzed the correlation between length of hospital stay and duration of parenteral nutrition, and investigated the association between oral caloric intake and the proportion of parenteral nutrition energy in total calorie supply. Five-year survival was compared between the groups. RESULTS Compared with the MCEC group, the ICE group showed significant improvement in oral caloric intake, length of hospital stay, and timing of nutrition-related adverse events and oral calorie intake, but a delay in engraftment. Both groups showed a correlation between duration of parenteral nutrition and length of hospital stay (P=0.0001) and between oral caloric intake (P=0.0017) and parenteral nutrition energy sufficiency rate (r=-0.73, P=0.003; r=-0.76, P=0.002). Five-year survival was not significantly different between the groups (P=0.1355). CONCLUSIONS Our findings suggest that compared with MCEC therapy, ICE therapy improves nutrition-related adverse events and reduces hospital stay, conserving medical resources, with no significant improvement in long-term survival. The nutritional pathway may serve as a tool for objective evaluation of pretreatment for autologous peripheral blood stem cell transplantation.

Good clinical activity and favorable toxicity profile of once weekly bortezomib, fotemustine, and dexamethasone (B-MuD) for the treatment of relapsed multiple myeloma.

Since multiple myeloma (MM) is still not-curable, the management of relapse remains challenging. Given the known efficacy of alkylating agents in MM, we conducted a phase I/II study to test a new three drug combination in which Fotemustine (Muphoran), an alkylating agent of nitrosurea family, was added to bortezomib + dexamethasone backbone (B-MuD) for the treatment of MM relapsed patients. Fotemustine was administered at two dose levels (80-100 mg/m² i.v.) on day 1. The original 21-day schedule was early amended for extra-hematological toxicity and a 35-day schedule was adopted (Bortezomib 1.3 mg/m² i.v. on days 1, 8, 15, and 22, Dexamethasone 20 mg i.v. on days 1, 8, 15, and 22) for a total of six courses. Twenty-four patients were enrolled. The maximum tolerated dose of Fotemustine was 100 mg/m². The overall response rate was of 62% (CR 8%, VGPR 33%, and PR 21%). The median OS was 28.5 months, the median progression-free survival (PFS) was 19.1 months. B-MuD resulted effective in patients previous exposed to bortezomib without difference of response (P = 0.25) and PFS (P = 0.87) when compared to bortezomib-naive patients. Thrombocytopenia was the most common AE overall. In conclusion, B-MuD is an effective and well tolerated combination in relapsed MM patients even in advanced disease phase.

Fotemustine chemoembolization of hepatic metastases from uveal melanoma: a retrospective single-center analysis.

OBJECTIVE: The purpose of the current study was to retrospectively evaluate response and survival in patients with hepatic metastasis from uveal melanoma treated by palliative transarterial chemoembolization (TACE) with fotemustine. MATERIALS AND METHODS: During the study period, 21 patients with hepatic metastases from uveal melanoma were treated by TACE. A series of TACE interventions (mean number per patient, 3.29 interventions; range, 1-6 interventions) was performed on each patient with an emulsion of fotemustine dissolved in 10 mL of saline mixed with 10 mL of an oily contrast agent. Tumor response based on the Response Evaluation Criteria in Solid Tumors was evaluated using contrast-enhanced CT scans obtained 6-10 weeks after embolization. RESULTS: CT showed partial regression after TACE in three patients (14%). Six patients (29%) presented with stable disease but no significant change in tumor size after TACE, and 12 patients (57%) presented with progressive disease after TACE treatment. The overall response rate was 43%. The mean survival after diagnosis of hepatic metastasis was 28.7 months. CONCLUSION: TACE of hepatic metastasis from uveal melanoma with fotemustine is well tolerated, and the survival rates in this study (mean, 28.7 months) are among the longest reported.

Preclinical studies of steroid-linked nitrosoureas in murine pancreatic adenocarcinoma PANO2.

PURPOSE: In earlier studies, this laboratory carried out research on the synthesis and anticancer evaluation of hybrid compounds, which combine two molecules in one such as homo-aza-steroidal esters (HASE) of carboxylic derivatives of N, N-bis (2-chloroethyl) aniline. In this combination, steroidal hormones are employed as carriers for transporting the alkylating agents to specific targeted tissues. Aiming to continue our research, we used alkylating agents, as nitrosoureas, instead of nitrogen mustards. In this work the N-[N- (2-chloroethyl)-N-nitroso-carbomoyl]-L-alanine (CNC-ala) has been used and was bound to 7 newly synthesized modified steroidal esters (carrier molecule) of nitrosourea and the hybrid molecules were tested for antitumor activity against PANO2 murine pancreatic adenocarcinoma. MATERIALS AND METHODS: PANO2 adenocarcinoma was used in this study. C57Bl mice were used for chemotherapy evaluation. The activity was assessed from the inhibition of tumor growth and the oncostatic parameter T/C %. RESULTS: The antitumor activity displayed by 7 hybrid steroidal esters of nitrosourea was quite interesting. It was able to discern 4 of 7 compounds that exhibited considerable antitumor activity, increasing the lifespan of the tumor-bearing mice by inhibiting the tumor growth. CONCLUSION: The comparative study of 7 newly synthesized hybrid steroidal esters of nitrosourea shows that the antitumor effects of compound 7, which has an enlarged (7 carbon atoms) A-lactamic ring and nitrosourea esterified at the position 17, which seems to be the most appropriate for the connection of a DNA cross-linking amino acid derivative is superior.

Complete remissions in chemotherapy of lung cancer models induced in mice by asbestos.

Chemotherapy trials were run with mice bearing transplants of carcinomas originally induced from fetal mouse lung cells by asbestos. After treatments with a nitrosourea (PCNU), mice bearing transplants of a large-cell carcinoma (ASB XIV) had complete remissions (CR) in 13 of 20 animals on a 15 mg/kg regimen, in 6 of 20 on an 8 mg/kg regimen, and in none of 10 on a 4 mg/kg regimen. With comparable total doses, treatment was most effective when PCNU was given in a few large doses. In groups where CRs occurred, continued PCNU treatment of animals without CRs prolonged survival but yielded no additional CRs. No CRs of ASB XIV occurred in 80 mice treated with eight other anticancer agents or in 50 controls injected with 0.9% NaCl solution. In mice bearing transplants of a squamous cell carcinoma (ASB XIII), treatments with PCNU were followed by CRs in 3 of 38 animals on 15 mg/kg regimens and in 3 of 28 animals on 8 mg/kg regimens. In groups of 6 mice fed a retinoid (Ro 10-9359) and treated with PCNU, CRs of ASB XIII occurred in 3 animals in each of two trials and in none in a third trial. Ro 10-9359 inhibited growth of transplants of squamous cell carcinoma LC 12 that had been induced from fetal mouse lung cells by a polycyclic hydrocarbon. In trials of four other anticancer agents vs. ASB XIII, CRs occurred only with cyclophosphamide (CPA). There were 7 CRs among 8 mice treated with CPA 100 mg/kg x 3, no CRs in 10 after 100 mg/kg x 2, one CR in 8 after 50 mg/kg x 3, and no CRs in 6 after 50 mg/kg x 4. With the 50 mg/kg x 4 regimen of CPA and 7.5 mg/kg PCNU on the same days, there were 5 CRs in 8 mice. As a single agent, aziridinylbenzoquinone (AZQ) increased life span but gave no CRs. There were CRs of ASB XIII in all of 8 mice after toxic combined therapy with PCNU and AZQ. There were no CRs in 66 control mice bearing ASB XIII.

Neurofibromatosis type 1-associated unusual pleomorphic astrocytoma displaying continual malignant progression.

Patients with neurofibromatosis type 1 (NF1) often have gliomas as a complication, most of which are benign pilocytic astrocytomas which have arisen in optic pathways. In the present case, a 17-year-old girl (at death) with stigmata of NF1, initially had a bulky tumor mass in the left thalamus, developing into the lateral ventricle, at 13 years of age. Partially resected tissue samples showed pleomorphic astrocytoma with abundant xanthoma cells and degenerative structures such as Rosenthal fibers (RF) and eosinophilic granular bodies. Fine eosinophilic granules identical to RF, both immunophenotypically and ultrastructurally, were also seen. The residual tumor was subtotally resected 6 months later, and the tumor histology was essentially similar as before, accompanying the regenerative structures; this was believed to be a good prognostic indicator. However, several anaplastic features such as mitosis, necrosis and vascular proliferation appeared even in areas rich in the regenerative structures. After a 2-year, disease-free interval, multiple tumor relapse occurred in June 1997. Partially resected tumor tissues were composed of monotonous small anaplastic cells with prominent proliferative activity. Surprisingly, the tumor cells had retained eosinophilic granules within the cell bodies. Postoperative chemotherapy with procarbazine, MCNU and vincristine (PCV) suppressed the residual tumor dramatically, but the regrowing tumor finally became uncontrollable, leading to the patient's death. TP53 mutation was not detected, while p27 immunopositivity was constantly high during malignant progression, suggesting acquisition of proliferative activity to overcome p53 and p27 inhibitory functions. A review of previously published reports failed to reveal any cases of this type.

Two glycine containing 2-chloroethylnitrosoureas--a comparative study on some physicochemical properties, in vivo antimelanomic effects and immunomodulatory properties.

Physicochemical properties such as alkylating and carbamoylating activity and in vivo antimelanomic effects against B16 melanoma of the spin labeled (nitroxyl free radical containing) glycine nitrosourea (SLCNUgly) and its nonlabeled analogue (ChCNUgly), synthesized in our laboratory are studied and compared to those of antitumour drug 3-cyclohexyl-1-(2-chloroethyl)-1-nitrosourea (CCNU). We have demonstrated that introducing of glycine moiety in the nitrosourea structure in practice does not affect either alkylating or carbamoylating activity. On the other hand replacement of cyclohexyl moiety in ChCNUgly structure with nitroxyl free radical leads to a decrease in carbamoylating activity and an increase in alkylating activity. Compound ChCNUgly showed in vivo a higher antimelanomic activity against B16 melanoma in comparison with CCNU and SLCNUgly. It completely inhibited B16 melanoma growth (TGI=100%) at a dose 64.0 mg/kg. Moreover, we established that joint i.p. application in normal mice of SLCNUgly plus a new immunostimulator (C3bgp) formerly isolated in our laboratory led to a 75% restoration in immune function with respect to antibody production measured by Jerne hemolytic plaque assay. In contrast, no immunostimulation was found after joint application of C3bgp plus ChCNUgly or CCNU at the same experimental conditions. Based on these preliminary results, a possibility for developing of new combination immunochemotherapy schemes for treatment of human cancers is discussed.

Planning of hyperthermic treatment for malignant glioma using computer simulation.

Interstitial hyperthermia was applied using a radiofrequency generator in the treatment of four malignant glioma patients who had especially deep seated brain tumours or were at high risk. Prior to heating tumours, treatment planning based on an accurate prediction of temperature distribution is essential. The present paper introduces a novel treatment planning method and discusses its clinical efficacy. The two-dimensional finite element method was used for simulation of temperature distribution, which was calculated using the bioheat transfer equation. This technique was applied to plan treatment. Temperature was measured at two points during heating and these values were compared with those estimated by the simulation. In addition, the area of the contrast enhanced (CE) rim on the pre-heating computed tomography (CT) image was compared with the low density area of the CE rim on the post-heating CT image, which was obtained within 2 months after heating. The optimal position and number of radiofrequency (RF) electrodes to include the outside of the CE rim in the simulated area above 42 degrees C contour could be easily determined using this planning system in all cases. The temperature estimated by the simulation was in good agreement with the actual values obtained (within 0.4 degrees C). The post-heating CT image revealed that the hyperthermic procedure described herein achieved more than an 80% low density area within the CE rim in all cases (mean 86.0%). These results demonstrate that this novel treatment planning method may prove to be a clinically valuable tool in the treatment of malignant glioma with RF electrodes.

Chemotherapy for progressive pilocytic astrocytomas in the chiasmo-hypothalamic regions.

Over the past 25 years, we have treated 17 patients with chiasmo-hypothalamic astrocytomas. Before 1988, the initial treatments consisted of surgery and/or radiotherapy, while since 1989, 4 children (1 male, 3 females, aged 3-8 years) were treated primarily with chemotherapy. None of them was associated with neurofibromatosis. After a biopsy of the tumor, the intravenous administration of ranimustine (MCNU; 30-86 mg/m2) and/or nimustine (ACNU; 30.3-64.1 mg/m2) was given without radiation therapy. Chemotherapy was usually given as an out-patient, with a total of 5-13 courses. The total doses of MCNU and ACNU administered ranged from 150 to 570 mg and from 64.8 mg to 100 mg, respectively. After chemotherapy 2 patients showed clinical improvement and tumor regression on neuro-imaging, while one patient showed clinical improvement and tumor size stabilization on neuro-imaging. The remaining one child, however, showed a clinical worsening and tumor progression on neuro-imaging studies. He was thus treated with a second chemotherapy regimen with carboplatin and etoposide, which brought about tumor regression. The acute and subacute toxicity of chemotherapy was mild. All patients are now leading almost normal lives with a median of 43 months after diagnosis. Although a longer and more careful clinical observation is required, the authors conclude that chemotherapy with MCNU and/or ACNU may benefit patients with unresectable pilocytic astrocytoma requiring treatment. The advantages of this therapy include its mild side effects and the lack of any hospitalization in most patients. It may also delay the need for radiation therapy, which can have a deleterious effect on the young developing brain.

Hyperthermia in the treatment of brain metastases from lung cancer. Experience on 17 cases.

Medium or long-term survival in metastatic "non oat cell" lung tumors is seldom possible only if surgery can eradicate the lesion. Out of 17 patients treated with hyperthermia plus nitrosoureas 16 (94%) responded, with clinical improvement, radiological regression or disease stabilization. The survival time of the improved patients was 12.7 months. Hyperthermia in combination with nitrosoureas seems to allow clinically and radiologically satisfactory responses in lung tumors metastatic to the brain.

New approaches to the chemotherapy of melanoma.

Several new investigational agents have shown some promise in the treatment of patients with disseminated melanoma. While earlier studies of combination chemotherapy led to increased toxicity without improved anti-tumor effect, more recent combination regimens have produced responses up to 50%. One of these is a dose-intensification regimen using high-dose cisplatin and the chemoprotective drug WR-2721. Other treatments under study include autologous bone marrow transplantation plus thiotepa, a combination regimen of chemotherapy and interferon, and newer agents such as taxol, tauromustine, and detrorubicin.

O6-methylguanine and temozolomide can reverse the resistance to chloroethylnitrosoureas of a mouse L1210 leukemia.

Using L1210 and a subline resistance to chloroethylnitrosoureas (L1210/BCNU), we found that the resistance to 1-(2-chloroethyl)-1-nitrosourea (CNU) or to diethyl-1-3-(2-chloroethyl)-3-nitrosoureido ethyl phosphonate (fotemustine) can be reversed by a pretreatment with O6-methyl Guanine (O6-mGua) or temozolomide. In L1210/BCNU but not in L1210 the pretreatment with O6mGua caused an increased peak level of CNU-induced DNA-interstrand crosslinks. We then evaluated whether the resistance to BCNU could be counteracted in vivo by i.p. O6mGua treatment of L1210/BCNU bearing mice. The results were negative due to the fact that O6mGua, which was not toxic when given alone, caused a high toxicity when associated with BCNU.

Evaluation of a new nitrosoureido water-soluble sugar, ecomustine or CY 233 (NSC 609224), on human xenografts.

Because of its wide spectrum of activity against murine models regardless of the route of administration, CY 233 (NSC 609624) was investigated in human tumours xenografted in nude mice, namely one amelanotic melanoma, MeXF 274, and three colon adenocarcinomas, i.e. CXF 233, CXF 243 and CXF 609. CY 233 was highly active against the MeXF 274 melanoma and produced a complete response on day 14 at 20 mg/kg given i.v. on days 0 and 7. After three intermittent i.v. injections of 10 mg/kg, it produced a partial response of long duration against the colon adenocarcinoma CXF 243. The interesting fact that resistant lines responded to CY 233 warrants further investigation of other schedules of treatment and of the sensitivity profile of CY 233 in a wider panel of tumour xenografts.

Biological activity of hydroxylated chloroethylnitrosoureas.

1-Nitroso-1-(2-hydroxyethyl)-3-(2-chloroethyl)urea (Compound I) and 1-nitroso-1-(2-hydroxypropyl)-3-(2-chloroethyl)urea (Compound II) display significantly reduced antitumor activity compared to the corresponding isomeric derivatives 1-nitroso-1-(2-chloroethyl)-3-(2-hydroxyethyl) urea (Compound III) and 1-nitroso-1-(2-chloroethyl)-3-(2-hydroxypropyl) urea (Compound IV). Their low therapeutic activity is paralleled by low toxicity while mutagenicity and carcinogenicity are high. A comparative investigation of the genotoxicity of Compounds I and III using primary cultures of fetal hamster lung cells revealed an about 14-fold higher rate of DNA single-strand breaks following exposure (100 microM, 1 h) to Compound I as compared to Compound III. The rate of DNA interstrand cross-links, on the other hand, was 11-fold higher following Compound III as compared to Compound I. The results underline that the therapeutic activity of chloroethylnitrosoureas is mainly attributable to their cross-linking potential while induction of DNA single-strand breaks plays a decisive role for mutagenicity and carcinogenicity but appears not to be relevant for antineoplastic effectiveness.

Nucleoside analogues: 7. Effect on colon, breast and lung tumours in mice of 5-fluorouracil/nitrosourea molecular combinations incorporating alkoxy and oxidized sulphur functions.

This study considers further changes in the carrier moiety of molecular combinations of the pyrimidine antimetabolite 5-fluorouracil (5-FU) and the alkylating group chloroethylnitrosourea (CNU). Detailed chemical syntheses are described of compounds incorporating (a) a simpler alkoxy group in the 'sugar' fragment, (b) attachment of the 5-FU residue to the C-X-C-C chain on the side of the heteroatom X distal from the CNU group, and (c) higher oxidation states of the sulphur atom in the prototypical compound B.3839. Anti-tumour activity of these analogues against a series of experimental murine colon, lung and mammary tumours is described. The pattern of activity reveals that the carrier moiety is important but further pharmacokinetics and metabolism studies are required to determine structure-activity relationships.

Effects of tauromustine, a water-soluble nitrosourea compound on NMU-1 murine lung tumor.

This study assessed the antitumor activity of 1-(2-chloroethyl)-3-/2-(dimethylaminosulfonyl)ethyl-1-nitrosourea (TCNU), a newly soluble nitrosourea, on NMU-1 lung tumor, a transplantable murine model poorly sensitive to BCNU. TCNU delivered orally was more effective after weekly than after biweekly treatments. When TCNU was given weekly intravenously, its therapeutic index was higher than after oral treatment. Compared with BCNU, TCNU showed superior antitumor effects on NMU-1 murine lung tumor. In this experimental model, TCNU activity was comparable to that of drugs active on human lung cancer.

CGP 6809--a new nitrosoureido-sugar derivative with activity in human tumor xenografts.

CGP 6809 [ethyl-6-deoxy-3,5-di-O-methyl-6-(3-methyl-3-nitrosoureido)-alpha-D- glucofuranoside] is a new methylnitrosoureido-sugar derivative that has been shown to be active against a broad spectrum of transplantable tumours in mice and rats. We investigated the anti-tumour effect of CGP 6809 in ten selected, human tumour xenograft lines growing s.c. in nude mice. The p.o. administration of 125 mg/kg per day for 10-15 days was less toxic (lethality 12% in tumour-bearing nude mice) than the i.p. injection of 62.5 mg/kg per day (lethality 22%). The anti-tumour effect was similar for both application routes; two large bowel cancers responded to treatment with CGP 6809, rectal cancer CXF 158 showed a remission, and the rapidly growing, undifferentiated colonic cancer CXF 280 exhibited a transient no-change. Furthermore, remissions were observed in the epidermoid lung cancer LXF 322 and in thyroid cancer 117. Tumour progression was found in another epidermoid lung cancer and in three stomach cancers, one melanoma, and one soft tissue sarcoma. CGP 6809 is a promising new agent for clinical trials, especially for large bowel and epidermoid lung cancer.