Intra-arterial induction high-dose chemotherapy with cisplatin for oral and oropharyngeal cancer: long-term results

Intra-arterial (IA) chemotherapy for curative treatment of head and neck cancer experienced a revival in the last decade. Mainly, it was used in concurrent combination with radiation in organ-preserving settings. The modern method of transfemoral approach for catheterisation, superselective perfusion of the tumour-feeding vessel, and high-dose (150 mg m−2) administration of cisplatin with parallel systemic neutralisation with sodium thiosulphate (9 g m−2) made preoperative usage feasible. The present paper presents the results of a pilot study on a population of 52 patients with resectable stage 1–4 carcinomas of the oral cavity and the oropharynx, who were treated with one cycle of preoperative IA chemotherapy executed as mentioned above and radical surgery. There have been no interventional complications of IA chemotherapy, and acute side effects have been low. One tracheotomy had to be carried out due to swelling. The overall clinical local response has been 69%. There was no interference with surgery, which was carried out 3–4 weeks later. Pathological complete remission was assessed in 25%. The mean observation time was 3 years. A 3-year overall and disease-free survival was 82 and 69%, respectively, and at 5 years 77 and 59%, respectively. Survival results were compared to a treatment-dependent prognosis index for the same population. As a conclusion, it can be stated that IA high-dose chemotherapy with cisplatin and systemic neutralisation in a neoadjuvant setting should be considered a feasible, safe, and effective treatment modality for resectable oral and oropharyngeal cancer. The low toxicity of this local chemotherapy recommends usage especially in stage 1–2 patients. The potential of survival benefit as indicated by the comparison to the prognosis index should be controlled in a randomised study

A phase I trial of S-1 with concurrent radiotherapy for locally advanced pancreatic cancer

This study investigated the maximum tolerated dose of S-1 based on the frequency of its dose-limiting toxicities (DLT) with concurrent radiotherapy in patients with locally advanced pancreatic cancer. S-1 was administered orally at escalating doses from 50 to 80 mg m−2 b.i.d. on the day of irradiation during radiotherapy. Radiation therapy was delivered through four fields as a total dose of 50.4 Gy in 28 fractions over 5.5 weeks, and no prophylactic nodal irradiation was given. Twenty-one patients (50 three; 60 five; 70 six; 80 mg m−2 seven patients) were enrolled in this trial. At a dose of 70 mg m−2 S-1, two of six patients demonstrated DLT involving grade 3 nausea and vomiting and grade 3 haemorrhagic gastritis, whereas no patients at doses other than 70 mg m−2 demonstrated any sign of DLT. Among the 21 enrolled patients, four (19.0%) showed a partial response. The median progression-free survival time and median survival time for the patients overall were 8.9 and 11.0 months, respectively. The recommended dose of S-1 therapy with concurrent radiotherapy is 80 mg m−2 day−1. A multi-institutional phase II trial of this regimen in patients with locally advanced pancreatic cancer is now underway

Phase I trial of oral S-1 combined with gemcitabine in metastatic pancreatic cancer

The objective of this study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of S-1, an oral fluorouracil derivative, combined with gemcitabine, the current standard treatment for advanced pancreatic cancer (APC). The subjects were histopathologically proven APC patients with distant metastasis. S-1 was administered orally twice daily each day for 14 days and gemcitabine on days 8 and 15 of each cycle, and this was repeated every 21 days. Doses of each drug were planned as follows: level 1: 800/60, level 2a: 800/80, level 2b: 1000/60, level 3: 1000/80 (gemcitabine (mg m−2)/S-1 (mg m−2 day−1)). In all, 21 patients with APC were enrolled. The main grade 3–4 toxicities observed during first cycle were neutropenia (33%), anaemia (10%), thrombocytopenia (14%) and anorexia (10%). There were no DLT observed in level 1. Three of six patients in level 2a had DLT and this level was considered the MTD. In all, 12 patients in level 2b had no DLT and this level was selected as the recommended dose. Applicable responses were one complete response and nine partial responses (48%). As toxicities were well tolerated and antitumour activities seem to be promising, this combination can be recommended for further phase II studies with APC

Randomized scheduling feasibility study of S-1 for adjuvant chemotherapy in advanced head and neck cancer

The purpose of this study was to determine the feasible adjuvant therapy administration schedule of S-1 for locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). Patients receiving definitive treatments were randomly assigned to either arm A (51 cases) receiving oral S-1 of 2-week administration followed by 1-week rest for 6 months, or arm B receiving S-1 of 4-week administration followed by 2-week rest for 6 months. Planned treatment was given in 40% of patients in arm A and 29% in arm B. The cumulative rates of the relative total administration dose of S-1 at 100% were 54.9% (95% CI: 40.1–69.7%) in arm A and 34.3% (95% CI: 21.1–47.4%) in arm B, respectively (P=0.054). Adverse events were recorded in 41 patients (82.0%) in arm A and 48 patients (94.1%) in arm B (P=0.060). The incidences of diarrhoea (10 vs 28%; P<0.05) and skin toxicities (18 vs 37%; P<0.05) were significantly higher in arm B. One-year disease-free survival was similar in both arms: arm A 81.2% (95% CI: 70.0–92.4%); arm B 77.0% (95% CI: 65.0–89.0%). The schedule of 2-week administration followed by 1-week rest seems to be more feasible for oral 6-month administration of S-1 in adjuvant chemotherapy of locoregionally advanced SCCHN

EORTC Early Clinical Studies Group early phase II trial of S-1 in patients with advanced or metastatic colorectal cancer

Cancer of the colon and rectum is one of the most frequent malignancies both in the US and Europe. Standard palliative therapy is based on 5-fluorouracil/folinic acid combinations, with or without oxaliplatin or irinotecan, given intravenously. Oral medication has the advantage of greater patient convenience and acceptance and potential cost savings. S-1 is a new oral fluorinated pyrimidine derivative. In a nonrandomized phase II study, patients with advanced/metastatic colorectal cancer were treated with S-1 at 40 mg m-2 b.i.d. for 28 consecutive days, repeated every 5 weeks, but by amendment the dose was reduced to 35 mg m-2 during the study because of a higher than expected number of severe adverse drug reactions. In total 47 patients with colorectal cancer were included. In the 37 evaluable patients there were nine partial responses (24%), 17 stable diseases (46%) and 11 patients had progressive disease (30%). Diarrhoea occurred frequently and was often severe: in the 40 and 35 mg m-2 group, respectively, 38 and 35% of the patients experienced grade 3-4 diarrhoea. The other toxicities were limited and manageable. S-1 is active in advanced colorectal cancer, but in order to establish a safer dose the drug should be subject to further investigations

Hyaluronic acid hydrogels incorporating platelet lysate enhance human pulp cell proliferation and differentiation

The restoration of dentine-pulp complex remains a challenge for dentists; nonetheless, it has been poorly addressed. An ideal system should modulate the host response, as well as enable the recruitment, proliferation and differentiation of relevant progenitor cells. Herein was proposed a photocrosslinkable hydrogel system based on hyaluronic acid (HA) and platelet lysate (PL). PL is a cocktail of growth factors (GFs) and cytokines involved in wound healing orchestration, obtained by the cryogenic processing of platelet concentrates, and was expected to provide the HA hydrogels specific biochemical cues to enhance pulp cellsâ recruitment, proliferation and differentiation. Stable HA hydrogels incorporating PL (HAPL) were prepared after photocrosslinking of methacrylated HA (Met-HA) previously dissolved in PL, triggered by the Ultra Violet activated photoinitiator Irgacure 2959. Both the HAPL and plain HA hydrogels were shown to be able to recruit cells from a cell monolayer of human dental pulp stem cells (hDPSCs) isolated from permanent teeth. The hDPCs were also seeded directly over the hydrogels (5 Ã 104 cells/hydrogel) and cultured in osteogenic conditions. Cell metabolism and DNA quantification were higher, in all time-points, for PL supplemented hydrogels (p < 0,05). Alkaline phosphatase (ALPL) activity and calcium quantification peaks were observed for the HAPL group at 21 days (p < 0,05). The gene expression for ALPL and COLIA1 was up-regulated at 21 days to HAPL, compared with HA group (p < 0,05). Within the same time point, the gene expression for RUNX2 did not differ between the groups. Overall, data demonstrated that the HA hydrogels incorporating PL increased the cellular metabolism and stimulate the mineralized matrix deposition by hDPSCs, providing clear evidence of the potential of the proposed system for the repair of damaged pulp/dentin tissue and endodontics regeneration.LFDA acknowledges Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) for the grant 2014/12017-8. Portuguese Foundation for Science and Technology (FCT) for PSB PhD grant SFRH/BD/73403/2010, MTR post-doctoral grant (SFRH/BPD/111729/2015), MEG grant (IF/00685/2012), and RECOGNIZE project (UTAP-ICDT/CTM-BIO/0023/2014), RL3-TECT - NORTE-07-0124-FEDER-000020 project co-financed by ON.2 (NSRF) through ERD. This study also received financial support from FCT/Ministério da Ciência, Tecnologia, e Ensino Superior (FCT/MCTES) and Fundo Social Europeu through Programa Operacional do Capital Humano (FSE/POCH) PD/59/2013 for the LA ICVS-3Bs (UID/Multi/50026/2013). The authors would like to thank Maurizio Gulino, for its support in the in vitro experiments and Maló Clinic, Porto, Dra Ana Ferro and Dr Bruno Queridinha for the donation of permanent teethinfo:eu-repo/semantics/publishedVersio