Benefit of pazopanib in advanced gastrointestinal stromal tumours: results from a phase II trial (SSG XXI, PAGIST).

BACKGROUND: Patients with advanced gastrointestinal stromal tumours (GISTs) resistant to the tyrosine kinase inhibitors imatinib and sunitinib may be treated with regorafenib, which resulted in a median progression-free survival (PFS) of 4.8 months in the GRID trial. Also, pazopanib, another tyrosine kinase inhibitor, has been studied in a randomized, placebo-controlled trial (PAZOGIST) in the third line, which showed a PFS of 45.2% 4 months after study entry, but patients intolerant to sunitinib were also included. We designed another trial evaluating pazopanib, enrolling only patients with progression on both imatinib and sunitinib. PATIENTS AND METHODS: Since all eligible patients had progressive disease, we preferred a non-randomized, phase II multicentre trial so that all patients could receive a potentially active drug. Patients had a progressive metastatic or locally advanced GIST and were ≥18 years of age, with a performance status of 0-2, and sufficient organ functions. The primary endpoint was disease control rate (defined as complete remission + partial remission + stable disease) at 12 weeks on pazopanib. A Simon's two-stage analysis was used with an interim analysis 12 weeks after enrollment of the first 22 patients, and if passed, there was a full enrolment of 72 patients. GIST mutational analysis was done, and most patients had pazopanib plasma concentration measured after 12 weeks. RESULTS: Seventy-two patients were enrolled. The disease control rate after 12 weeks was 44%, and the median PFS was 19.6 weeks (95% confidence interval 12.6-23.4 weeks). Pazopanib-related toxicity was moderate and manageable. No statistically significant differences were found related to mutations. Plasma concentrations of pazopanib had a formal but weak correlation with outcome. CONCLUSION: Pazopanib given in the third line to patients with GIST progressing on both imatinib and sunitinib was beneficial for about half of the patients. The PAGIST trial confirms the results from the PAZOGIST trial, and the median PFS achieved seems comparable to the PFS achieved with regorafenib in the third-line setting.

Guidelines for time-to-event end point definitions in sarcomas and gastrointestinal stromal tumors (GIST) trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)†.

BACKGROUND: The use of potential surrogate end points for overall survival, such as disease-free survival (DFS) or time-to-treatment failure (TTF) is increasingly common in randomized controlled trials (RCTs) in cancer. However, the definition of time-to-event (TTE) end points is rarely precise and lacks uniformity across trials. End point definition can impact trial results by affecting estimation of treatment effect and statistical power. The DATECAN initiative (Definition for the Assessment of Time-to-event End points in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for RCT in sarcomas and gastrointestinal stromal tumors (GIST). METHODS: We first carried out a literature review to identify TTE end points (primary or secondary) reported in publications of RCT. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points. Recommendations were developed through a validated consensus method formalizing the degree of agreement among experts. RESULTS: Recommended guidelines for the definition of TTE end points commonly used in RCT for sarcomas and GIST are provided for adjuvant and metastatic settings, including DFS, TTF, time to progression and others. CONCLUSION: Use of standardized definitions should facilitate comparison of trials' results, and improve the quality of trial design and reporting. These guidelines could be of particular interest to research scientists involved in the design, conduct, reporting or assessment of RCT such as investigators, statisticians, reviewers, editors or regulatory authorities.

Neuronal involvement in cisplatin neuropathy: prospective clinical and neurophysiological studies.

Although it is well known that cisplatin causes a sensory neuropathy, the primary site of involvement is not established. The clinical symptoms localized in a stocking-glove distribution may be explained by a length dependent neuronopathy or by a distal axonopathy. To study whether the whole neuron or the distal axon was primarily affected, we have carried out serial clinical and electrophysiological studies in 16 males with testicular cancer before or early and late during and after treatment with cisplatin, etoposide and bleomycin at limited (<400 mg/m2 cisplatin), conventional (approximately 400 mg/m2 cisplatin) or high (>400 mg/m2 cisplatin) doses. At cumulative doses of cisplatin higher than 300 mg/m2 the patients lost distal tendon and H-reflexes and displayed reduced vibration sense in the feet and the fingers. The amplitudes of sensory nerve action potentials (SNAP) from the fingers innervated by the median nerve and the dorsolateral side of the foot innervated by the sural nerve were 50-60% reduced, whereas no definite changes occurred at lower doses. The SNAP conduction velocities were reduced by 10-15% at cumulative doses of 400-700 mg/m2 consistent with loss of large myelinated fibres. SNAPs from primarily Pacinian corpuscles in digit 3 and the dorsolateral side of the foot evoked by a tactile probe showed similar changes to those observed in SNAPs evoked by electrical stimulation. At these doses, somatosensory evoked potentials (SEPs) from the tibial nerve had increased latencies of peripheral, spinal and central responses suggesting loss of central processes of large dorsal root ganglion cells. Motor conduction studies, autonomic function and warm and cold temperature sensation remained unchanged at all doses of cisplatin treatment. The results of these studies are consistent with degeneration of large sensory neurons whereas there was no evidence of distal axonal degeneration even at the lowest toxic doses of cisplatin.

Quantitation of regional cerebral blood flow corrected for partial volume effect using O-15 water and PET: I. Theory, error analysis, and stereologic comparison.

Limited spatial resolution of positron emission tomography (PET) can cause significant underestimation in the observed regional radioactivity concentration (so-called partial volume effect or PVE) resulting in systematic errors in estimating quantitative physiologic parameters. The authors have formulated four mathematical models that describe the dynamic behavior of a freely diffusible tracer (H215O) in a region of interest (ROI) incorporating estimates of regional tissue flow that are independent of PVE. The current study was intended to evaluate the feasibility of these models and to establish a methodology to accurately quantify regional cerebral blood flow (CBF) corrected for PVE in cortical gray matter regions. Five monkeys were studied with PET after IV H2(15)O two times (n = 3) or three times (n = 2) in a row. Two ROIs were drawn on structural magnetic resonance imaging (MRI) scans and projected onto the PET images in which regional CBF values and the water perfusable tissue fraction for the cortical gray matter tissue (hence the volume of gray matter) were estimated. After the PET study, the animals were killed and stereologic analysis was performed to assess the gray matter mass in the corresponding ROIs. Reproducibility of the estimated parameters and sensitivity to various error sources were also evaluated. All models tested in the current study yielded PVE-corrected regional CBF values (approximately 0.8 mL x min(-1) x g(-1) for models with a term for gray matter tissue and 0.5 mL x min(-1) x g(-1) for models with a term for a mixture of gray matter and white matter tissues). These values were greater than those obtained from ROIs tracing the gray matter cortex using conventional H2(15)O autoradiography (approximately 0.40 mL x min(-1) x g(-1)). Among the four models, configurations that included two parallel tissue compartments demonstrated better results with regards to the agreement of tissue time-activity curve and the Akaike's Information Criteria. Error sensitivity analysis suggested the model that fits three parameters of the gray matter CBF, the gray matter fraction, and the white matter fraction with fixed white matter CBF as the most reliable and suitable for estimating the gray matter CBF. Reproducibility with this model was 11% for estimating the gray matter CBF. The volume of gray matter tissue can also be estimated using this model and was significantly correlated with the results from the stereologic analysis. However, values were significantly smaller compared with those measured by stereologic analysis by 40%, which can not be explained by the methodologic errors. In conclusion, the partial volume correction was essential in quantitation of regional CBF. The method presented in this article provided the PVE-corrected regional CBF in the cortical gray matter tissue. This study also suggests that further studies are required before using MRI derived anatomic information for PVE correction in PET.

Ifosfamide in malignant mesothelioma: a phase II study.

Malignant mesothelioma is a rare malignancy with a median survival, ranging from 4 to 18 months in untreated patients. In a phase II study of patients with mesothelioma, the efficacy and toxicity of ifosfamide and mesna was evaluated. Twenty-nine previously untreated patients, with histologically proven and unresectable mesothelioma, entered the study. Three patients were later excluded from the study due to revision of the diagnoses. The patients had to have bidimensionally measurable disease by CT scans and a WHO performance status < or = 3. Eligible patients received ifosfamide 3000 mg/m2 per day for 3 days as a 1-h infusion and mesna 1800 mg/m2 per day for 3 days every third week. Dose modifications were made according to the degree of hematologic, neurologic and renal toxicity. Response to treatment was evaluated in accordance with WHO criteria. The median age of patients was 59 years (range 39-68), 18 patients (69%) had a history of asbestos exposure and the median of treatment cycles was four (range 1-10). No complete responses were observed. One patient obtained a partial response after five cycles with a duration of response of 25 months. Nine patients (35%) had stable disease, while 13 (54%) progressed. The median survival for all patients was 10 months. The toxicity of the treatment was considerable. Thirteen patients (50%) had grade 4 leucopenia, ten patients (38%) had grade 3 or 4 reversible neurotoxicity and ten patients (38%) had grade 3 or 4 nausea and vomiting. Eleven patients (42%) went off the study due to the toxicity of the treatment. In conclusion, ifosfamide did not show any substantial activity of relevance in malignant mesothelioma at the dose level investigated, in spite of considerable toxicity.

Histology and platinum content of sensory ganglia and sural nerves in patients treated with cisplatin and carboplatin: an autopsy study.

Cisplatin is a valuable antineoplastic drug which as a dose-limiting side-effect causes sensory neuropathy, and which therefore is often combined with less neurotoxic carboplatin. It has not been possible to reproduce cisplatin neuropathy in experimental animals, and the neurotoxic mechanism in man is disputed. We investigated post-mortem material from 12 patients and 15 control subjects. Half of the fibres with diameters of > or = 9 microns, or more than 15% of all fibres (P < 0.02), had disappeared in the sural nerves of patients. Signs of axonal regeneration were lacking. The dorsal root ganglia D12 and L2 of some but not of all patients contained necrotic neurons and nodules of Nageotte. The mean volume of the somata was reduced by 18% (P < 0.03). A relation between cumulated doses, treatment free interval and changes in nerve or ganglia was not found. The platinum content was high in all tissues except in the spinal cord when the patient had died shortly after treatment, and it decreased with increasing interval, least so in liver, sensory ganglia and sural nerves. The results support the hypothesis that cisplatin neuropathy is a neuroneopathy rather than a dying-back axonopathy.

[Patients and attitudes to a palliative unit in H:S--a questionnaire study]. / Patientunderlag og holdninger til en palliativ enhed i H:S--en spørgeskemaundersøgelse.

A questionnaire was mailed to 42 representative in-patient departments of hospitals in the City of Copenhagen asking the medical staff to state what number of their patients could possibly be referred to a future hospital--associated palliative care unit. All-together 215 answers were returned from two questionnaire dates two weeks apart, comprising more than 1750 patients each day. Furthermore, 42 of 60 general practitioners answered another questionnaire on the same topic. From the hospital questionnaire it was concluded that approximately 8% of all patients were admitted for palliative care reasons, 75% suffering from incurable cancer. More than 50% of patients admitted for palliative care reasons were assessed to be suitable candidates for a palliative care unit. The general practitioners recognised at least 50 patients treated only for palliative reasons. In the same month the general practitioners referred more than 20 patients to hospital wards, but two-thirds of the practitioners would have preferred that these patients could have had the option of staying at home for terminal care. In general, more than 50% of the medical staff opted for establishing a palliative care unit.

Early clinical investigation of sulofenur with a daily schedule in advanced solid tumours.

Sulofenur, a sulfonylurea, has demonstrated antitumour effect in preclinical studies. A phase I trial was initiated to study the clinical aspects. Sulofenur was given p.o. daily for a period of 28 days in 5-week courses. The initial dosage was 250 mg/m2 escalating to 700 mg/m2 daily with no dose modification for the individual patient at any given dose level; 38 patients with advanced solid malignant tumours were enrolled. Haemolytic anaemia was the main side effect. The toxicity was marked at dose levels of 600 and 700 mg/m2. Moderate methaemoglobinaemia also occurred. One case of reversible toxic hepatitis was observed. Generally was ALAT, and more moderately basic phosphatases, and LDH elevated. Tumour regression was not observed but one patient had stable disease throughout nine courses. The maximal detected plasma concentration of Sulofenur in this study was 348 x 10(-6) g/ml. In the present study the maximum tolerated dose (MTD) of Sulofenur was defined to 600 mg/m2. One conclusion from this study is that even at doses above that recommended for future studies-5-600 mg/m2-with this schedule, the suggested effective plasma level from preclinical studies could not be reached. The overall conclusion is that this schedule should not be recommended at all for future studies and the recommendation should be to try to find a schedule in which higher plasma levels can be achieved at a clinically tolerated dose.

Determination of platinum by neutron activation analysis in nerve tissue from rats treated with cisplatin.

The analytical method used for the determination of traces of platinum and gold in different tissues of Wistar rats is based on neutron activation analysis with radiochemical separation of gold. This separation is performed by electrolytic deposition of gold on a niobium cathode, which ensures the highest radiochemical purity without any spectral interference from calcium or other major elements. Corrections for the nuclear interference from double neutron capture, caused by the gold content of the samples, were found to be insignificant at the levels reported. The following neural tissues were analyzed for their content of platinum: the dorsal root ganglions as well as the dorsal and ventral part of the spinal cord. The highest level of platinum was found in dorsal root ganglions.

Examination of distal involvement in cisplatin-induced neuropathy in man. An electrophysiological and histological study with particular reference to touch receptor function.

Cisplatin is a widely used anti-neoplastic agent with dose-dependent sensory neuropathy as a major side-effect. The mechanism for the neuropathy is poorly understood; it may be caused by a lesion of the dorsal root ganglion cells or by a distal axonopathy. This distinction is important since regeneration in a neuronopathy is impossible, whereas recovery may occur if the axon is affected only distally. The most distal part of the sensory nerve fibre is, however, not accessible for conventional electrophysiological examination. To ascertain whether the distal receptor-associated part of the fibre is involved, we have used a method previously untested in patients with neuropathy. In 26 males treated with cisplatin for testicular cancer 3-6.5 years previously, and in 22 normal males, the compound sensory action potentials evoked by a tactile probe were recorded through needle electrodes placed close to the sural and median nerves. The responses were compared with action potentials evoked by electrical stimulation of the same nerves. Biopsies from the distal sural nerve at the dorsolateral aspect of the foot were obtained in three patients and in four subjects not treated with cisplatin. Sixteen patients had received a conventional dose (307-435 mg/m2) of cisplatin and 10 patients had received a high dose (553-1197 mg/m2). Two-thirds of the conventional dose patients and all the high dose patients had mild to severe sensory loss and reduced or absent tendon reflexes. The amplitude of the electrically evoked sensory action potential decreased with increasing dose of cisplatin and was correlated with the reduction of vibration sense. Tactile responses, probably originating mainly from Pacinian corpuscles, were, with the exception of two high dose patients, recorded from all sural and median nerves. The two high dose patients without a tactile response had a severely reduced or no electrically evoked response at the sural nerve. The sural nerve biopsies from high dose patients showed loss of large fibres; Pacinian corpuscles were obtained in two of these patients and contained normal axons. Our findings do not suggest that cisplatin causes a primarily distal lesion with sparing of more proximal parts of the peripheral nerve. We interpret the results as being consistent with a neuronopathy affecting primarily large sensory neurons. Brainstem and somatosensory evoked potentials and H-reflexes suggested that the spinal cord and brainstem were affected as well.

Prednisolone in the treatment of severe malignant hypercalcaemia in metastatic breast cancer: a randomized study.

To determine the effect of prednisolone on severe hypercalcaemia in women with metastatic breast cancer, 30 patients with serum ionized calcium above 1.60 mmol l-1 (reference range 1.15-1.35 mmol l-1) entered a randomized trial. Performance status before entry to the trial and survival time after hypercalcaemia were also noted. All patients received 4 l of isotonic saline daily and 80 mg intravenous furosemide three times daily for 2 d; thereafter they received 3 l of isotonic saline daily and 80 mg furosemide twice daily for 6 d. Fifteen patients were randomized to receive prednisolone, 25 mg orally, three times daily for 8 d. Serum ionized calcium decreased significantly in both groups, but most markedly in the prednisolone group. The median difference was 0.28 mmol l-1 (95% confidence interval (CI), 0.09-0.52) on day 4 and 0.21 mmol l-1 (95% CI, 0.12-0.44) on day 8. In seven prednisolone-treated patients serum ionized calcium normalized, compared to none in the control group (Fisher's exact test; P = 0.028). No severe adverse effects were observed. Prior to detection of hypercalcaemia all patients were severely immobilized, primarily due to bone pain. Only 10 patients were still living after 3 months. Prednisolone, furosemide and rehydration is superior to furosemide and rehydration alone in severely hypercalcaemic patients with metastatic breast cancer in whom immobilization appears to be an early warning sign of life-threatening hypercalcaemia. The short survival time was not influenced by prednisolone.

Chemotherapy in malignant mesothelioma: a review.

This review of malignant mesothelioma focuses on the activity of single-agent and combination chemotherapy, a field in which research has thus far been rather unsystematic and sparse. Available results neither accede to any substantial drug activity nor justify the use of standard therapy. Furthermore, even when pooled most findings do not fulfil the basic criteria for a phase II trial. Prospective (multicenter) phase II trials are recommended for the identification of new agents that show antineoplastic activity in malignant mesothelioma. The use of computed tomography scans can assist in the prediction of the extent of disease both before and during treatment. Tumor-biological systems using mice xenografts or cell lines of human mesothelioma should be further developed so as to improve the screening of new agents exhibiting potential antineoplastic activity that is especially directed against mesothelioma.

Phase I study of 4-demethoxydaunorubicin by oral route in patients with advanced cancer.

In a phase I trial 4-demethoxydaunorubicin (4-dm DNR) was administered as oral capsules once a week to 51 adults with advanced mainly gastrointestinal solid tumors. No fatal toxicity was observed at doses up to 25.0 mg/m2. Dose-limiting granulocytopenia and non-hematologic toxicity developed at dosages greater than or equal to 22.5 mg/m2. No response to the therapy was observed. The plasma concentrations of 4-dm DNR were measured in 4 of the patients.

Pharmacokinetics of doxorubicin in man with induced acid or alkaline urine.

The common side effects of doxorubicin (DOX) treatment, i.e. vomiting and diarrhoea, would be expected to alter the pharmacokinetics of DOX in man, the efficacy of treatment, and further aggravate the side effects through acid/base disturbances. The pharmacokinetics were therefore investigated in 4 anthracycline naive females with advanced mammary carcinoma in 2 series of DOX monotherapy 70 mg/m2 administered with an interval of 4 weeks between the treatments. Sequential loading either with acid or base was instituted 2 days before and continued for 2 days after DOX infusion. Median urine pH was 5.0 or 8.0, and median arterial blood pH 7.30 or 7.43 respectively. Plasma and urine samples were analyzed by high performance liquid chromatography (HPLC). No difference was seen between the acid and alkaline condition for DOX or doxorubicinol with regard to clearance from blood plasma, area under the curve, renal clearance, renal drug clearance/renal creatinine clearance. Thus moderate acid/base metabolic disturbances did not alter the pharmacokinetics of DOX up to 48 h after DOX infusion.