Trabectedin Followed by Irinotecan Can Stabilize Disease in Advanced Translocation-Positive Sarcomas with Acceptable Toxicity.

Background. Preclinical data indicate that trabectedin followed by irinotecan has strong synergistic effects on Ewing sarcoma. This is presumably due to hypersensitization of the tumor cells to the camptothecin as an effect of trabectedin in addition to synergistic suppression of EWS-FLI1 downstream targets. A strong effect was also reported in a human rhabdomyosarcoma xenograft. Procedure. Twelve patients with end-stage refractory translocation-positive sarcomas were treated with trabectedin followed by irinotecan within a compassionate use program. Eight patients had Ewing sarcoma and four patients had other translocation-positive sarcomas. Results. Three-month survival rate was 0.75 after the start of this therapy. One patient achieved a partial response according to RECIST criteria, five had stable disease, and the remaining six progressed through therapy. The majority of patients experienced significant hematological toxicity (grades 3 and 4). Reversible liver toxicity and diarrhea also occurred. Conclusions. Our experience with the combination of trabectedin followed with irinotecan in patients with advanced sarcomas showed promising results in controlling refractory solid tumors. While the hematological toxicity was significant, it was reversible. Quality of life during therapy was maintained. These observations encourage a larger clinical trial.

The benefits of humanized yeast models to study Parkinson's disease.

Over the past decade, the baker's yeast Saccharomyces cerevisiae has proven to be a useful model system to investigate fundamental questions concerning the pathogenic role of human proteins in neurodegenerative diseases such as Parkinson's disease (PD). These so-called humanized yeast models for PD initially focused on α -synuclein, which plays a key role in the etiology of PD. Upon expression of this human protein in the baker's yeast Saccharomyces cerevisiae, the events leading to aggregation and the molecular mechanisms that result in cellular toxicity are faithfully reproduced. More recently, a similar model to study the presumed pathobiology of the α -synuclein interaction partner synphilin-1 has been established. In this review we will discuss recent advances using these humanized yeast models, pointing to new roles for cell wall integrity signaling, Ca(2+) homeostasis, mitophagy, and the cytoskeleton.

Phase I dose-escalation study of vinflunine hard capsules administered twice a day for 2 consecutive days every week in patients with advanced/metastatic solid tumors.

BACKGROUND: Vinflunine is a new microtubule inhibitor of the vinca-alkaloid family. It is marketed in transitional cell carcinoma of urothelial tract as a 20 min infusion given every 3 weeks in Europe. METHODS: In this phase I study, vinflunine was administered to patients with advanced malignancies as hard capsules given twice a day on days 1-2 every week, with 3 weeks cycles. Serial blood samples were collected during the first cycle for pharmacokinetic investigations. RESULTS: Thirty-six patients (pts) were treated at 6 dose levels 150 (3 pts), 190 (3 pts), 230 (8 pts), 300 mg/day (6 pts) and then 250 (3 pts) and 270 mg/day (13 pts). The Maximal Tolerated Dose (MTD) was reached at 300 mg/day where 2 patients out of 6 experienced a dose limiting toxicity (febrile neutropenia with diarrhea). The lower dose level of 270 mg/day was the recommended dose (RD), the toxicity profile being mainly anaemia, neutropenia, fatigue and constipation. The pharmacokinetic analysis demonstrated the adequacy of the flat-fixed dosing regimen, as no correlation between clearance of vinflunine and body surface area was evidenced. Blood concentrations and exposure increased with dose, and a pharmacokinetic accumulation was observed, which is consistent with the terminal half-life of the compounds. The inter-individual exposure variability at the RD was 35%. CONCLUSION: Repeated weekly administration of oral vinflunine is feasible and exhibits a moderate inter-individual PK variability. The MTD was achieved at 300 mg/day given for 2 consecutive days. According to the protocol rules, the RD was established at 270 mg/day.

Diarrhea and the rationale to use Sandostatin.

This paper reviews the research that has been conducted into the use of Sandostatin to control the debilitating symptoms of diarrhea in a number of different etiologies. These are cancer-related diarrheas, including diarrhea related to chemotherapy, radiotherapy, neuroendocrine tumor carcinoid syndrome, vasoactive intestinal peptide-secreting tumors and also non-cancer related diarrhea, including short bowel syndrome, ileo- and jejunostomy, dumping syndrome, graft versus host disease and AIDS-related diarrhea. There is an increasing recognition of the need to balance the cost of care with patient outcome. It is becoming clear that although the cost of a therapeutic regimen with Sandostatin is substantially greater than the current non-specific therapy, the overall cost is potentially greater without the use of Sandostatin for patients with refractory diarrhea due to the inevitable need for further treatment and/or hospitalization with intravenous fluid supplementation. Initial trials and reports from preclinical testing and clinical practice have shown promising results and, although in the majority of cases they strengthen the view taken in the published consensus guidelines for the use of Sandostatin for refractory diarrhea, further, larger scale, comparative clinical trials are required for any evidence-based definition of dosage and efficacy as a treatment or prophylactic agent to combat and control diarrhea.

Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer. EORTC study 40015.

BACKGROUND: The study aimed to demonstrate the noninferiority of capecitabine to 5-fluorouracil (5-FU)/folinic acid (FA), in relation to progression-free survival (PFS) after first-line treatment of metastatic colorectal cancer and the benefit of adding celecoxib (C) to irinotecan/fluoropyrimidine regimens compared with placebo (P). PATIENTS AND METHODS: Patients were randomly assigned to receive FOLFIRI: irinotecan (180 mg/m(2) i.v. on days 1, 15 and 22); FA (200 mg/m(2) i.v. on days 1, 2, 15, 16, 29 and 30); 5-FU (400 mg/m(2) i.v. bolus, then 22-h, 600 mg/m(2) infusion) or CAPIRI: irinotecan (250 mg/m(2) i.v. infusion on days 1 and 22); capecitabine p.o. (1000 mg/m(2) b.i.d. on days 1-15 and 22-36). Patients were additionally randomly assigned to receive either placebo or celecoxib (800 mg: 2 x 200 mg b.i.d.). RESULTS: The trial was closed following eight deaths unrelated to disease progression in the 85 enrolled (629 planned) patients. Response rates were 22% for CAPIRI + C, 48% for CAPIRI + P, 32% for FOLFIRI + C and 46% for FOLFIRI + P. Median PFS and overall survival (OS) times were shorter for CAPIRI versus FOLFIRI (PFS 5.9 versus 9.6 months and OS 14.8 versus 19.9 months) and celecoxib versus placebo (PFS 6.9 versus 7.8 months and OS 18.3 versus 19.9 months). CONCLUSION: Due to the small sample size following early termination, no definitive conclusions can be drawn in relation to the noninferiority of CAPIRI compared with FOLFIRI.

Phase II feasibility study of concurrent radiotherapy and gemcitabine in chemonaive patients with squamous cell carcinoma of the head and neck: long-term follow up data.

BACKGROUND: Radiotherapy (RT) with concurrent chemotherapy is the current standard of care for patients with unresectable locally advanced squamous cell carcinoma of the head and neck (SCCHN). Gemcitabine (GEM) is a potent radiosensitizer and in addition has activity as an anticancer agent in SCCHN. PATIENTS AND METHODS: Twenty-six patients with locally far advanced SCCHN were enrolled in a chemoradiation feasibility study between November 1998 and September 2003. Use was made of conventionally fractionated RT and GEM 100 mg/m(2), which was given within 2 h prior to radiotherapy on a weekly basis starting on day 1 of RT. Response was assessed according to WHO criteria, toxicity according to NCI-CTC version 2. RESULTS: The patients received a median of 7 (2-8) weekly cycles of gemcitabine and a median cumulative RT dose of 70 Gy (66-84.75). Hematologic toxicity was mild, but non-hematologic toxicity was severe: grade 3-4 stomatitis occurred in 85% of patients, dermatitis in 69%, pharyngitis/esophagitis in 81% and 80% of the patients needed a feeding tube during treatment. All 22 evaluable patients responded (50% complete, 50% partial). Median follow up of the surviving patients is 46 months. Median disease-free and overall survival is 13 months and 19 months, respectively; 27% of the patients are alive without evidence of recurrence beyond 3 years. CONCLUSIONS: Conventionally fractionated RT in combination with GEM 100 mg/m(2) weekly is feasible and highly active in the treatment of locally advanced SCCHN. In particular, long-term local control rate is promising. Acute mucosal toxicities are significant but manageable. Long-term toxicity interferes with normal food intake.

A phase I study of bendamustine hydrochloride administered day 1+2 every 3 weeks in patients with solid tumours.

The aim of the study was to determine the maximum tolerated dose (MTD), the dose limiting toxicity (DLT), and the pharmacokinetic profile (Pk) of bendamustine (BM) on a day 1 and 2 every 3 weeks schedule and to recommend a safe phase II dose for further testing. Patients with solid tumours beyond standard therapy were eligible. A 30-min intravenous infusion of BM was administered d1+d2 q 3 weeks. The starting dose was 120 mg m(-2) per day and dose increments of 20 mg m(-2) were used. Plasma and urine samples were analysed using validated high-performance liquid chromatography/fluorescence assays. Fifteen patients were enrolled. They received a median of two cycles (range 1-8). The MTD was reached at the fourth dose level. Thrombocytopaenia (grade 4) was dose limiting in two of three patients at 180 mg m(-2). One patient also experienced febrile neutropaenia. Lymphocytopaenia (grade 4) was present in every patient. Nonhaematologic toxicity including cardiac toxicity was not dose limiting with this schedule. Mean plasma Pk values of BM were tmax 35 min, t(1/2) 49.1 min, Vd 18.3 l m(-2), and clearance 265 ml min(-1) m(-2). The mean total amount of BM and its metabolites recovered in the first micturition was 8.3% (range 2.7-26%). The MTD of BM in the present dose schedule was 180 mg m(-2) on day 1+2. Thrombocytopaenia was dose limiting. The recommended dose for future phase II trials with this schedule is 160 mg m(-2) per day.

Merkel cell carcinoma and multiple basal cell carcinoma in an African albino woman with HIV infection.

A 25-year-old HIV-infected African albino woman developed an aggressive Merkel cell carcinoma on her face and at least 10 basal cell carcinomas, mainly on sun-exposed parts of her body. HIV infection, immune deficiency and sun exposure are known risk factors for the development of Merkel cell carcinoma. Chemotherapy and radiotherapy were only temporarily successful. She died shortly after surgery was performed to remove the tumour.

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.

Pneumonectomy for lung metastases: report of ten cases.

Today, pulmonary resection for lung metastases is a widely accepted treatment if complete resection can be achieved. However, 5-year survival is only 40 %. Many patients develop recurrences, but some reports have demonstrated that salvage operations can result in a long-term survival. A resection of a complete lung or a resection of more than a lung is still controversial since procedure-related morbidity or mortality does not outweigh the survival benefit. We report on a series of 10 consecutive patients who underwent a primary pneumonectomy or an operation on the residual lung after pneumonectomy with curative intent for pulmonary metastases. 5 year survival rates for the 10 patients after pneumonectomy alone or with additional resection was 45 %, which was not significantly different from those who underwent a more minor resection with a 5-year survival of 39 % (p = 0.40). Since there is currently no alternative proven therapy for patients with isolated pulmonary metastases, a primary or completion pneumonectomy may be offered to selected patients as long as sufficient pulmonary reserve is present, and a complete resection can be achieved.

Methotrexate-associated liver toxicity in a patient with breast cancer: case report and literature review.

A patient with breast cancer developed severe asthenia, accompanied with progressively increasing transaminases, during adjuvant chemotherapy with CMF (cyclophosphamide, methotrexate and 5-fluorouracil). Additional blood tests and imaging were negative. A liver biopsy revealed a grade II toxic hepatitis. Because methotrexate was suspected to be the cause of the hepatotoxicity, the administration of this drug was stopped and mitoxantrone was given instead. A recovery of clinical symptoms and normalisation of the liver function tests was observed afterwards. In that sense, mitoxantrone appears to be a valuable alternative to methotrexate in cases of hepatotoxicity in patients with breast cancer. An overview of the literature regarding methotrexate hepatotoxicity is presented.

Clinical phase II study and pharmacological evaluation of rubitecan in non-pretreated patients with metastatic colorectal cancer-significant effect of food intake on the bioavailability of the oral camptothecin analogue.

A randomised, open label phase II study was performed in patients with advanced colorectal cancer to evaluate the safety, toxicity and antineoplastic activity of the topoisomerase I-inhibitor rubitecan. A cross-over design was chosen to determine the intrapatient variation of the bioavailability and pharmacokinetics of the anticancer agent depending on the timing of food intake in relation to the oral drug administration. Patients with previously untreated metastatic disease received two single oral doses of rubitecan 1.5 mg/m2 for assessment of the pharmacokinetics. They were randomised to have the first administration either after an overnight fasting period or immediately after a high calorie breakfast, and crossed over to the alternative schedule after a one-week washout period. After completion of the pharmacokinetic sampling, treatment continued with rubitecan given orally at a dose of 1.5 mg/m2/day, to be increased up to 2.0 mg/m2/day, under fasting conditions for 5 consecutive days per week until disease progression. 19 patients entered the trial after informed consent was obtained. A total number of 35 treatment cycles (median 2, range 1-4) were administered. All patients were evaluable for safety. The toxicity profile of rubitecan was generally mild to moderate, with sporadic cases of grade 4 toxicities (Common Toxicity Criteria (CTC) version 2.0) diarrhoea, leucopenia and neutropenia. None of 15 evaluable patients achieved an objective response. The majority had early disease progression. 14 patients were evaluable for pharmacokinetic analysis. The bioavailability of rubitecan was found to be strongly dependent on the timing of food intake with a fasted-to-fed ratio for C(max) of 1.98 (two-tailed P<0.001; ANOVA), T(max) 0.49 (P<0.001), AUC(0-8 h) 2.52 (P<0.001) and AUC(0-24 h) 1.64 (P=0.003). Rubitecan is well tolerated, but clinically inactive in colorectal cancer at the currently recommended dose and schedule. The bioavailability is strongly dependent on the timing of food intake in relation to the oral administration of the drug. The topoisomerase I-inhibitor should be administered under fasting conditions to achieve adequate drug exposure in future prospective trials in other tumour types.

Pharmacologic study of paclitaxel administered with or without the cytoprotective agent amifostine, and given as a single agent or in combination with epirubicin and cisplatin in patients with advanced solid tumors.

The main purpose of this study was to investigate whether the coadministration of amifostine alters the pharmacokinetic behavior of paclitaxel. Eight patients were included in the study: six received paclitaxel in combination with epirubicin and cisplatin, and two received paclitaxel as a single agent. Doses of paclitaxel in these protocols were 135, 150, 175, and 200 mg/m(2) and two patients were treated at each dose level. Pharmacokinetic sampling for paclitaxel analysis was performed in each patient during two consecutive cycles, one with and one without amifostine (750 mg/m(2) as a 15-minute intravenous infusion 30 minutes before paclitaxel administration). At each dose level, the pharmacokinetic data of paclitaxel were compared per patient for a cycle without amifostine versus a cycle with amifostine. Amifostine did not seem to interact pharmacokinetically with paclitaxel, given either alone or in combination chemotherapy. This is in line with the clinical findings that amifostine has no negative effects on the antitumor activity of various antineoplastic agents. Also, amifostine may reduce toxic effects of combination chemotherapy regimens that include paclitaxel.

Thoracic wall prosthesis prevents deep invasion by non-small-cell lung cancer.

Chest wall invasion is found in 5% of patients with non-small-cell lung cancer. Treatment for localized non-small-cell lung cancer consists of surgical resection and/or radiotherapy. We report a patient with lung cancer who had a local relapse after a reconstruction of the thoracic wall with a soft-tissue patch. Chemotherapy was given before reresection of the local relapse. Postoperative radiation therapy was performed. Twenty-one months after treatment for recurrent disease, the patient remains in complete remission. The history of this patient shows that a soft-tissue patch may prevent local tumor invasion. A review of the literature is given.

Methylene blue in the treatment and prevention of ifosfamide-induced encephalopathy: report of 12 cases and a review of the literature.

Ifosfamide is an alkylating agent used in the treatment of a variety of solid tumours. Ten to 15% of patients treated with ifosfamide develop an encephalopathy. Methylene blue (MB) may be used in the treatment of this encephalopathy. The purpose of this study was to evaluate the neuroprotective effect of MB in these patients and to review the literature. Between 1993 and 1997, 52 patients (age 16-77 years) with solid tumours were treated with ifosfamide in dosages ranging from 3 to 5 g m(-2) q3w when given in combination schedules and up to 12 g m(-2) q4w when given as a single agent. Twelve patients developed central nervous system (CNS) depression, defined as National Cancer Institute Common Toxicity Criteria (NCI-CTC) neurocortical toxicity grade 2 or higher. Eight were treated with MB at a dose of 6 x 50 mg day(-1) intravenously (i.v.). Four recovered fully within 24 h, two recovered partially after 24 h and completely after 48 h while two recovered only after 72 h. Four patients did not receive MB and all recovered only after 48 h. Three patients received prophylaxis with MB at a dose of 4 x 50 mg day(-1) i.v. for the subsequent chemotherapy cycles. Two developed milder encephalopathy; one had no CNS depression at all. We conclude that MB is an effective treatment for ifosfamide-induced encephalopathy. Our findings suggest that it may also be used as a prophylactic agent.

A personal view on the early history of the insulin-like growth factors.

Salmon and Daughaday, when trying to set up an in vitro assay for Growth Hormone (GH), failed to obtain a direct effect on sulphate uptake in cartilage of hypophysectomized (hypox) rats. They recognised that this was not the consequence of poor methodology or materials, but an encrypted message from the examined system. They decided to turn around and to try and decipher it. Treatment with GH appeared to render hypox rat serum active in stimulating sulphation in hypox rat cartilage. They proposed that GH induced an intermediary substance, responsible for this biological effect: sulphation factor (SF), later renamed to Somatomedin(s) (SM). This hypothesis met with great criticism and very few took on to study this hypothetical substance. Besides disbelief, slow progress was also due to initial lack of a practical assay and to the failure to find a tissue with enriched concentration from which to extract the activity. From experimental evidence, the concept gradually evolved that SF/SM was insulin-like and might be identical to NSILA (non-suppressible insulin-like activity). This again generated controversy. This characteristic was too far away from the known effects of GH to be readily acceptable as a physiological phenomenon. The subsequent recognition of the distinct characteristics of the receptors for SM/NSILA and insulin, the discovery of the SM/NSILA binding proteins and, much later, a beginning understanding of their interactions, modifications and breakdown, have gradually resolved this apparent contradiction. When the sequence of two NSILA molecules became known, they were named IGF-I and -II. Structural similarity with proinsulin and identity of IGF-I with SM-C and -A were established and it was found that Multiplication Stimulating Activity (MSA), a growth factor isolated from fetal calf serum and subsequently from conditioned media of a rat liver cell line, was the rat equivalent of IGF-II. Structure-function relations could be studied, a quest which is not yet brought to an end. Meanwhile, the endocrine profile of SF/SM had gradually emerged by measuring plasma levels with bioassays. The main determinants were found to be age, body size, GH and the nutritional state. Later, radioimmunoassays were developed, enabling consolidation and detailing of these early observations, and allowing explorations at the tissue level. As another aspect of the endocrine paradigm, in vivo effects of IGFs were studied. The initial demonstration of an effect of crude preparations on longitudinal growth in experimental animals raised heavy scepticism, since the effect might have been an artefact caused by contaminants. It took confirmation with highly purified preparations and biosynthetic IGF-I to ease this concern. Still, not until recent years it was demonstrated, by knocking out the genes, that a true physiological and not a pharmacological effect had been induced previously. When it was found that most tissues produce SMs and are sensitive to their actions, the concept emerged that IGFs may have para- and autocrine functions. Early experiments with combinations of growth factors in cell cultures had begun to define their specific roles in the cell cycle as competence or progression factors. SM-C fell in the latter category. Still, the awareness grew that, for obtaining physiologically meaningful results on the role of IGFs in complex, dynamic and tissue-specific environments, involving interactions of many hormones and growth factors, the intactness of tissue was a prerequisite. One result of this approach was the discovery of a direct interaction of GH with cartilage, leading, in concert with IGFs, to a clonal expansion of the cartilage cells of the growth plate. The isolation and sequencing of the IGF-I and -II genes, and later, of six IFG-BPs initiated the gradual elucidation of structure and function at the DNA and RNA level and the study of natural and synthetic IGF-variants. The generation of transgenic animals became feasible