MART-1 TCR gene-modified peripheral blood T cells for the treatment of metastatic melanoma: a phase I/IIa clinical trial.

Background: Adoptive cell therapy with peripheral blood T cells expressing transgenic T-cell receptors (TCRs) is an innovative therapeutic approach for solid malignancies. We investigated the safety and feasibility of adoptive transfer of autologous T cells expressing melanoma antigen recognized by T cells 1 (MART-1)-specific TCR, cultured to have less differentiated phenotypes, in patients with metastatic melanoma. Materials and methods: In this phase I/IIa trial, peripheral blood T cells from HLA-A2∗02:01-positive patients with unresectable stage IIIC/IV melanoma expressing MART-1 were selected and stimulated with anti-CD3/CD28 beads, transduced with a modified MART-1(26-35)-specific 1D3 TCR (1D3HMCys) and expanded in interleukin (IL)-7 and IL-15. Patients received a single infusion of transgenic T cells in a dose-escalating manner. Feasibility, safety and objective response rate were assessed. Results: Twelve pretreated metastatic cutaneous (n = 7) and uveal (n = 5) melanoma patients were included. Patient 1 received 4.6 × 109 1D3HMCys T cells and experienced grade 5 toxicity after 9 days. Subsequent patients received 5.0 × 107 [n = 3; cohort (c) 2], 2.5 × 108 (n = 2; c3) and 1.0 × 108 (n = 6; c4) 1D3HMCys T cells. The study was prematurely terminated because of dose-dependent toxicity, concerning skin (10/12), eyes (3/12), ears (4/12) and cytokine release syndrome (5/12), with 7 patients experiencing grade 3-5 toxicity. Partial responses were seen in 2/11 (18%) assessable patients and persistence of 1D3HMCys T cells corresponded to infused cell dose. Conclusions: Production of TCR-modified cells as described leads to highly potent T cells. Partial responses were seen in 18% of patients with dose-dependent 'on-target, off-tumor' toxicity and a maximum tolerated dose of 1.0 × 108 cells.

A phase Ib study of pertuzumab, a recombinant humanised antibody to HER2, and docetaxel in patients with advanced solid tumours.

Pertuzumab represents the first in a new class of targeted therapeutics known as HER dimerisation inhibitors. We conducted a phase Ib study to determine the maximum-tolerated dose, the dose limiting toxicities (DLT), and pharmacokinetic (PK) interaction of docetaxel when administered in combination with pertuzumab. Initially, two dose levels of docetaxel (60 and 75 mg m(-2)) were explored in combination with a fixed dose of 1050 mg of pertuzumab; then two dose levels of docetaxel (75 and 100 mg m(-2)) were explored in combination following a fixed dose of 420 mg of pertuzumab with a loading dose of 840 mg. Both drugs were administered intravenously every 3 weeks. The latter dose of pertuzumab was allowed after an amendment to the original protocol when phase II data suggesting no difference in toxicity or activity between the 2 doses became available. Two patients out of two treated at docetaxel 75 mg m(-2) in combination with pertuzumab 1050 mg suffered DLT (grade 3 diarrhoea and grade 4 febrile neutropaenia). Two out of five patients treated at docetaxel 100 mg m(-2) in combination with pertuzumab 420 mg with a loading dose of 840 mg suffered DLT (grade 3 fatigue and grade 4 febrile neutropaenia). Stable disease was observed at four cycles in more than half of the patients treated and a confirmed radiological partial response with a >50% decline in PSA in a patient with hormone refractory prostate cancer were observed. There were no pharmacokinetic drug-drug interactions. The recommended phase II dose of this combination was docetaxel 75 mg m(-2) and 420 mg pertuzumab following a loading dose of 840 mg.

The phospholipid composition and cholesterol content of platelet-derived microparticles: a comparison with platelet membrane fractions.

BACKGROUND: The processes that govern the distribution of molecules between platelets and the microparticles (MP) they release are unknown. Certain proteins are sorted selectively into MP, but lipid sorting has not been studied. OBJECTIVES: To compare the phospholipid composition and cholesterol content of platelet-derived MP obtained with various stimuli with that of isolated platelet membrane fractions. METHODS: Washed platelets from venous blood of healthy individuals (n = 6) were stimulated with collagen, thrombin, collagen plus thrombin, or A23187. Platelet activation, MP release and antigen exposure were assessed by flow cytometry. MPs were isolated by differential centrifugation. Platelet plasma-, granule- and intracellular membranes were isolated from platelet concentrates (n = 3; 10 donors each) by pressure homogenization and Percoll density gradient fractionation. The phospholipid composition and cholesterol content of MPs and membrane fractions were analyzed by high performance thin layer chromatography. RESULTS: The phospholipid composition of MPs was intermediate compared with that of platelet plasma- and granule membranes, and differed significantly from that of intracellular membranes. There were small but significant differences in phospholipid composition between the MPs produced by the various agonists, which paralleled differences in P-selectin exposure in case of the physiological agonists collagen, thrombin, or collagen plus thrombin. The cholesterol content of MPs tended to be higher than that of the three-platelet membrane fractions. CONCLUSIONS: Regarding its phospholipid content, the MP membrane is a composite of the platelet plasma- and granule membranes, showing subtle differences depending on the platelet agonist. The higher cholesterol content of MPs suggests their enrichment in lipid rafts.

Phase I/II trial of irinotecan plus high-dose 5-fluorouracil (TTD regimen) as first-line chemotherapy in advanced colorectal cancer.

BACKGROUND: We conducted a phase I/II study of weekly irinotecan [30 min intravenous (i.v.) infusion] combined with 5-fluorouracil (5-FU 3 g/m(2) weekly 48 h i.v. infusion, TTD regimen) as first-line chemotherapy for patients with advanced colorectal cancer (CRC). PATIENTS AND METHODS: The maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) in the treatment of gastrointestinal solid tumors (in phase I), and the antitumor activity and toxicity of the recommended phase I dose (in phase II) were determined. RESULTS: Diarrhea was the DLT, and irinotecan 80 mg/m(2) plus 5-FU 3 g/m(2) was the recommended phase I dose. In phase II, the confirmed response rate was 44% [95% confidence interval (CI) 29% to 59%] and the median overall survival was 23.8 months. However, grade 3/4 diarrhea affected 59% of patients and led to withdrawal of three patients. A second cohort of patients studied using the same schedule but with a reduced 5-FU starting dose of 2.25 g/m(2) showed improved tolerance (the incidence of grade 4 diarrhea decreased from 28% to 11% and overall grade 3/4 diarrhea to 56%, with no patient withdrawals) but the confirmed response rate was 28% (95% CI 14% to 45%) and median overall survival was 17.2 months. CONCLUSIONS: We found weekly irinotecan 80 mg/m(2) plus TTD regimen (5-FU 2.25 g/m(2) given as 48-h i.v. infusion) to be a feasible and active combined chemotherapy for the first-line treatment of advanced colorectal cancer.

Intervening sequences in rrl genes and fragmentation of 23S rRNA in genera of the family Enterobacteriaceae.

Intervening sequences (IVSs) in the rrl genes for 23S rRNA are transcribed but later removed by RNase III without religation during RNA processing, leading to fragmented rRNA. We examined about 240 strains of the family Enterobacteriaceae for presence of IVSs using PCR. No IVSs were detected in strains belonging to Escherichia, Shigella, Enterobacter, Erwinia, Ewingella, Hafnia, Kluyvera, Morganella, Pantoea, or Serratia. Previously unreported IVSs were detected in Klebsiella oxytoca, Citrobacter amalonaticus, and Providencia stuartii; previously reported IVSs are in species of Salmonella, Proteus, Providencia, and Yersinia. The sporadic distribution of IVSs indicates lateral genetic transfer of IVSs.

Pharmacokinetics of ifosfamide are changed by combination with docetaxel: results of a phase I pharmacologic study.

The pharmacokinetics of the combination of docetaxel and ifosfamide were studied in a phase I study. Docetaxel was given to cancer patients as a 1-hour infusion followed by a 24-hour infusion of ifosfamide (schedule A). After the dose-limiting toxicity of the combination was reached, ifosfamide was administered as a 24-hour infusion followed after 24 hours by a 1-hour infusion of docetaxel (schedule B). Cycle duration was 21 days. Docetaxel was determined by high-performance liquid chromatography, and ifosfamide and its metabolites, by gas chromatography-mass spectrometry. Twenty-seven patients were treated according to schedule A, and 6 according to schedule B. Combining the two drugs did not change their respective plasma half-lives. The sequence of drug administration did not affect the clearance and the area under the curve (AUC) of docetaxel. There was a decrease in the AUC of ifosfamide in schedule A compared with schedule B, resulting from an increase in the clearance of ifosfamide. The pharmacokinetics of docetaxel are not influenced by combination with ifosfamide, regardless of the drug sequence, but ifosfamide pharmacokinetics are changed by docetaxel, depending on the sequence of administration. The increase of clearance in schedule A may be due to the pretreatment with corticosteroids.

A phase I and pharmacokinetic study of the combination of capecitabine and docetaxel in patients with advanced solid tumours.

Capecitabine and docetaxel are both active against a variety of solid tumours, while their toxicity profiles only partly overlap. This phase I study was performed to determine the maximum tolerated dose (MTD) and side-effects of the combination, and to establish whether there is any pharmacokinetic interaction between the two compounds. Thirty-three patients were treated with capecitabine administered orally twice daily on days 1-14, and docetaxel given as a 1 h intravenous infusion on day 1. Treatment was repeated every 3 weeks. The dose of capecitabine ranged from 825 to 1250 mg m(-2) twice a day and of docetaxel from 75 to 100 mg m(-2). The dose-limiting toxicity (DLT) was asthenia grade 2-3 at a dose of 1000 mg m(-2) bid of capecitabine combined with docetaxel 100 mg m(-2). Neutropenia grade 3-4 was common (68% of courses), but complicated by fever in only 2.4% of courses. Other non-haematological toxicities were mild to moderate. There was no pharmacokinetic interaction between the two drugs. Tumour responses included two complete responses and three partial responses. Capecitabine 825 mg m(-2) twice a day plus docetaxel 100 mg m(-2) was tolerable, as was capecitabine 1250 mg m(-2) twice a day plus docetaxel 75 mg m(-2).

Docetaxel in 253 previously treated patients with progressive locally advanced or metastatic breast cancer: results of a compassionate use program in The Netherlands.

The aims of this study were to evaluate the efficacy and safety of docetaxel (Taxotere) in patients with progressive locally advanced or metastatic breast cancer, previously treated with at least one chemotherapy regimen, and the effect of the number of previous chemotherapy lines on response rate, progression-free survival and overall survival. Two-hundred and fifty-three patients from 10 hospitals in The Netherlands received docetaxel as part of a compassionate use program. The majority had received prior anthracycline-containing chemotherapy (84.2%). The recommended starting dose was 100 mg/m2 i.v. every 3 weeks. All patients received corticosteroid premedication. Two-hundred and thirty patients were evaluable for response. The overall response rates (ORR) to docetaxel when used as second-, third- or fourth-line treatment were, respectively, 40.2, 26.0 and 34.6% (p value 0.30). The median progression-free survival for this population was 4.9 months and the median overall survival of the whole group was 8.5 months, and both were not related to the number of previous chemotherapy regimens (p value, respectively, 0.71 and 0.16). The toxicity of docetaxel was manageable and neutropenia was the most frequently noted toxicity. This study confirms that docetaxel is an active cytotoxic agent in pretreated patients with progressive locally advanced or metastatic breast cancer and is still active when used as third- or fourth-line treatment.

Phase II study of weekly dose-intensified cisplatin chemotherapy with oral etoposide in recurrent glioma.

BACKGROUND: In most patients with recurrent glioma chemotherapy is the only remaining treatment option. In general results of chemotherapy in these patients are poor, and trials on new regimens are indicated. Because relatively good results have been achieved with combinations of platin compounds and etoposide, we investigated a dose-intensified cisplatin regimen with oral etoposide. METHODS: Eligible patients, with recurrent glioma after surgery and radiation therapy were treated with two four week-cycles with cisplatin 70 mg/m2 on days 1, 8 and 15, combined with oral etoposide 50 mg daily on days 1-15. In responding or stabilized patients, treatment was continued with six four week-cycles of oral etoposide 50 mg/m2 on days 1-21. Toxicity was assessed using the NCI Common Toxicity Criteria, a 50% decrease in contrast enhancing area on MRI scan was considered a partial response. Time to progression was measured from the start of chemotherapy. RESULTS: Sixteen patients were included, 11 were progressive during or immediately after the induction cycles. Two patients achieved a partial response with a time to progression of 42 and 58 weeks. Three patients were stable for 11, 14 and 15 weeks respectively. Toxicity was modest. DISCUSSION: This dose-intensified cisplatin regimen did not result in a significant number of objective responses and even the number of 'stable disease' was small. Given the low response rate of this intensive treatment, we consider this intensive regimen inappropriate for these patients.

Phase I and pharmacologic study of the arotinoid Ro 40-8757 in combination with cisplatin and etoposide in patients with non-small cell lung cancer.

This phase I study was performed to assess the feasibility of combining cisplatin/etoposide (VP-16) with the arotinoid Ro 40-8757 and to determine the dose-limiting toxicity (DLT) of Ro 40-8757 in this combination. Patients with non-small cell lung cancer were eligible. Treatment consisted of Ro 40-8757 p.o. day 1-21, cisplatin 100 mg/m2 i.v. on day 2 and VP-16 100 mg/m2 i.v. on day 2-4, repeated every 3 weeks. Eighteen patients were evaluable for toxicity and response. The doses of Ro 40-8757 ranged from 84 mg/m2 once daily to 42 mg/m2 thrice daily (tid). DLT consisting of delayed nausea/vomiting was reached at 42 mg/m2 tid. Consequently, the maximum tolerated dose was set at one dose level below the DLT, i.e. 28 mg/m2 tid. Skin toxicity occurred but was well manageable. Pharmacological analyses showed a small increase in the volume of distribution of cisplatin and VP-16 between the first and third course. However, no relationship with side effects was found. A response was achieved in 50% of patients. The combination of cisplatin/VP-16 with Ro 40-8757 appears to be feasible at a dose schedule of 28 mg/m2 tid. The response rate was at the upper rate of what can be expected with cisplatin and VP-16.

The venotonic drug hydroxyethylrutosiden does not prevent or reduce docetaxel-induced fluid retention: results of a comparative study.

PURPOSE: Fluid retention, which includes peripheral edema, ascites, pleural or pericardial effusion, or a combination of these that is sometimes associated with significant weight gain, is one of the most troublesome cumulative side effects of docetaxel. A suggestive observation from the data base available at the manufacturer (Rhone-Poulenc Rorer) was that patients who received venotonic drugs appeared to tolerate more courses of docetaxel. This prompted a comparative study to investigate whether the venotonic drug hydroxyethylrutosiden could reduce or delay docetaxel-related fluid retention. METHODS: A total of 85 patients with metastatic breast cancer who were treated with docetaxel at a dose of 100 mg/m2 with corticoid comedication were allocated to receive either 300 mg hydroxyethylrutosiden given orally four times daily (group A) or no hydroxyethylrutosiden (group B). The end point for analysis was the development of fluid retention of > or = grade 2. RESULTS: Fluid retention of > or = grade 2 was reported in 14 of 42 patients (33%) in group A and in 15 of 43 patients (35%) in group B and occurred after a median of 4 cycles of docetaxel in both groups. Weight gain was similar in groups A and B. CONCLUSION: We conclude that hydroxyethylrutosiden does not reduce or delay the incidence and severity of docetaxel-related fluid retention.

Corticosteroid co-medication does not reduce the incidence and severity of neurotoxicity induced by docetaxel.

Docetaxel is a new antimicrotubule agent that induces a predominantly sensory neuropathy that is mild in most patients. This prospective study was performed to determine if corticosteroid co-medication reduces the incidence and severity of docetaxel-induced neuropathy. Two groups of patients treated with docetaxel in subsequent cohorts were prospectively analyzed for neurotoxicity. Group A consisted of 38 patients with a variety of solid tumors, who were treated in studies before corticosteroid co-medication was recommended, while 49 female patients in group B with metastatic breast cancer were treated after co-medication with corticosteroids was introduced as a routine. Neuropathy was evaluated by a clinical sum-score for symptoms and signs, and by measurement of the vibration perception threshold (VPT). The severity of neuropathy was graded according to NCI Common Toxicity Criteria. In 42% of patients of group A and in 65% of patients of group B a mainly mild neuropathy was documented. There was no statistically significant difference in neurotoxicity between group A and B. The cumulative dose of docetaxel showed a significant correlation with post-treatment scores of VPT, sensory sum-score, grade of paresthesias, and grade of neurosensory and neuromotor toxicity. Corticosteroid co-medication does not reduce the development of docetaxel-related neuropathy.

Response rate and prognostic factors of recurrent oligodendroglioma treated with procarbazine, CCNU, and vincristine chemotherapy. Dutch Neuro-oncology Group.

OBJECTIVES: To determine the response rate and factors correlated with response of oligodendroglial tumors to procarbazine, lomustine (CCNU), and vincristine (PCV) chemotherapy. DESIGN: Retrospective, observational multicenter study. METHODS: Patients treated with PCV or intensified PCV chemotherapy for a recurrent oligodendroglial tumor after surgery and radiation therapy with measurable disease were retrospectively evaluated for response. A 50% reduction in cross-sectional enhancing tumor area was considered a partial response. Stabilized or responding patients received six cycles of PCV unless unacceptable toxicity occurred. RESULTS: Fifty-two patients were included; median time to progression (MTP) for the entire group was 10 months. In 17% of patients a complete response (MTP, 25 months) was obtained, and in 46% a partial response (MTP, 12 months) was obtained. Median overall survival was 20 months. Although treatment was discontinued for toxicity in seven patients, it was generally well tolerated. The intensified PCV regimen was more toxic. Patients initially presenting with seizures and patients with tumor necrosis in histologic specimens had a better response rate in contrast to patients who had their first relapse within 1 year of first treatment (surgery and radiation therapy). CONCLUSIONS: Oligodendroglial tumors are chemosensitive, but most patients will have relapsed after 12 to 16 months. New studies must aim at improving initial treatment and second-line chemotherapy.

Docetaxel and ifosfamide in patients with advanced solid tumors: results of a phase I study.

Docetaxel is a new antimicrotubule agent that has been shown to be active against a variety of solid tumors. Ifosfamide is an alkylating drug that has demonstrated activity against non-small cell lung cancer, testicular cancer, breast cancer, and soft tissue sarcoma. This phase I study of the combination of these drugs was performed to assess the feasibility of using the two agents together, to determine the maximum tolerated dose and the side effects, and to propose a safe schedule for further phase II studies. Thirty-four patients with histologically confirmed solid tumors who had not been treated previously with taxanes or ifosfamide and who had received no more than one line of chemotherapy for advanced disease were entered into the study. Treatment consisted of docetaxel given as a 1-hour infusion followed by ifosfamide as a 24-hour infusion (schedule A), or ifosfamide followed by docetaxel (schedule B) every 3 weeks. Docetaxel doses ranged from 60 to 85 mg/m2 and ifosfamide doses from 2.5 to 5.0 g/m2. Grades 3 and 4 granulocytopenia were observed in 89% of courses and appeared to be of short duration and related to the ifosfamide dose. Febrile neutropenia and sepsis occurred in 17% and 2% of courses, respectively. Severe anemia and thrombocytopenia were uncommon. Nonhematologic toxicities were mild to moderate, and included alopecia, nausea, vomiting, mucositis, diarrhea, sensory neuropathy, skin and nail toxicity, hypersensitivity reactions, and edema. Schedule B appeared to induce more gastrointestinal toxicity than schedule A. One complete response in soft tissue sarcoma and two partial responses, one in cancer of unknown primary and the other in non-small cell lung cancer, were documented. The dose-limiting toxicity for schedule A was neutropenic fever at a dose of 85 mg/m2 docetaxel and 5 g/m2 ifosfamide. The dose-limiting toxicity for schedule B was neutropenic fever at a dose of 75 mg/m2 docetaxel and 4 g/m2 ifosfamide. A dose of 75 mg/m2 docetaxel combined with 5 g/m2 ifosfamide according to schedule A can be recommended for further studies.

Phase I study on docetaxel and ifosfamide in patients with advanced solid tumours.

Docetaxel and ifosfamide have shown significant activity against a variety of solid tumours. This prompted a phase I trial on the combination of these drugs. This phase I study was performed to assess the feasibility of the combination, to determine the maximum tolerated dose (MTD) and the side effects, and to propose a safe schedule for further phase II studies. A total of 34 patients with a histologically confirmed solid tumour, who were not pretreated with taxanes or ifosfamide and who had received no more than one line of chemotherapy for advanced disease were entered into the study. Treatment consisted of docetaxel given as a 1-h infusion followed by ifosfamide as a 24-h infusion (schedule A), or ifosfamide followed by docetaxel (schedule B) every 3 weeks. Docetaxel doses ranged from 60 to 85 mg m(-2) and ifosfamide doses from 2.5 to 5.0 g m(-2). Granulocytopenia grade 3 and 4 were common (89%), short lasting and ifosfamide dose dependent. Febrile neutropenia and sepsis occurred in 17% and 2% of courses respectively. Non-haematological toxicities were mild to moderate and included alopecia, nausea, vomiting, mucositis, diarrhoea, sensory neuropathy, skin and nail toxicity and oedema. There did not appear to be any pharmacokinetic interaction between docetaxel and ifosfamide. One complete response (CR) (soft tissue sarcoma) and two partial responses (PRs) were documented. A dose of 75 mg m(-2) of docetaxel combined with 5.0 g m(-2) ifosfamide appeared to be manageable. Schedule A was advocated for further treatment.

Phase I and pharmacologic study of docetaxel and cisplatin in patients with advanced solid tumors.

PURPOSE: This phase I study was performed to assess the feasibility of the combination of docetaxel and cisplatin and to determine the maximum-tolerated dose (MTD) and the side effects with an emphasis on sequence-dependent side effects. MATERIALS AND METHODS: Patients who were not pretreated with taxanes or cisplatin derivatives and who had received no more than one prior combination chemotherapy regimen or two single-agent regimens were entered. Treatment consisted of docetaxel given as a 1-hour infusion followed by cisplatin as a 3-hour infusion (schedule A), or cisplatin followed by docetaxel (schedule B). Docetaxel doses ranged from 55 to 100 mg/m2 and cisplatin doses from 50 to 100 mg/m2. RESULTS: Leukocytopenia and granulocytopenia were common (overall, 90%; grade 3 or 4, 87%), short-lasting, and docetaxel dose-dependent. Infections and neutropenic fever occurred in 10% and 4.5% of courses, respectively. Nonhematologic toxicities were mild to moderate and included alopecia, nausea, vomiting, diarrhea, mucositis, neurotoxicity, fluid retention, and skin and nail toxicity. There were no significant differences in pharmacokinetic parameters between schedules A and B. Tumor responses included one complete response (CR) and nine partial responses (PRs). CONCLUSION: The dose levels docetaxel 100 mg/m2 plus cisplatin 75 mg/m2 and docetaxel 85 mg/m2 plus cisplatin 100 mg/m2 appeared to be manageable. At these dose levels, the median relative dose-intensity was high and 81% and 88% of all cycles, respectively, could be given at full dose. Schedule A is advocated for further treatment.

The correlation of CA15.3 and TPS with tumor course in patients with metastatic breast cancer.

PURPOSE: This study was performed to determine the correlation of CA15.3 and TPS with disease course in patients with metastatic breast cancer. METHODS: Levels of CA15.3 and tissue polypeptide antigen using the M3 monoclonal antibody (TPS) were determined in the serum of 60 patients with metastatic breast cancer. CA15.3 and TPS were measured at two assay times. RESULTS: A change of more than 25% in the serum level of CA15.3 or TPS was highly correlated with tumor response. The association between response and change in marker levels was stronger for CA15.3 (P = 0.0001) than for TPS (P = 0.0005). Distinct mismatches between marker changes and the tumor response were observed for both CA15.3 and TPS. CONCLUSION: CA15.3 and TPS are useful in the determination of response to treatment. Because of observed disagreement, marker changes can only be regarded as indicative of disease course.

Peripheral neuropathy induced by combination chemotherapy of docetaxel and cisplatin.

Docetaxel, a new semisynthetic taxoid that has demonstrated promising activity as an antineoplastic agent, was administered in combination with cisplatin to 63 patients in a dose-escalating study. As both drugs were known to be potentially neurotoxic, peripheral neurotoxicity was prospectively assessed in detail. Neuropathy was evaluated by clinical sum-score for signs and symptoms and by measurement of the vibration perception threshold (VPT). The severity of neuropathy was graded according to the National Cancer Institute's 'Common Toxicity Criteria'. The docetaxel-cisplatin combination chemotherapy induced a predominantly sensory neuropathy in 29 (53%) out of 55 evaluable patients. At cumulative doses of both cisplatin and docetaxel above 200 mg m(-2), 26 (74%) out of 35 patients developed a neuropathy which was mild in 15, moderate in ten and severe in one patient. Significant correlations were present between both the cumulative dose of docetaxel and cisplatin and the post-treatment sum-score of neuropathy (P < 0.01) as well as the post-treatment VPT (P < 0.01). The neurotoxic effects of this combination were more severe than either cisplatin or docetaxel as single agent at similar doses.

Recombinant human interleukin 6 in metastatic renal cell cancer: a phase II trial.

A phase II trial investigating the anti-tumour effects of recombinant human interleukin 6 (rhIL-6) in patients with metastatic renal cell cancer was carried out. RhIL-6 (150 microgram) was administered as a daily subcutaneous injection for 42 consecutive days on an outpatient basis. Forty-nine patients were studied, 12 with and 37 without previous immunotherapy. Forty patients were evaluable for response. A partial remission was noted in two patients, stable disease in 17 and progressive disease in 21. Toxicity was moderate and reversible and consisted mainly of fever, flu-like symptoms, nausea, weight loss and hepatotoxicity. Anaemia, leucocytosis and thrombocytosis and induction of acute phase protein synthesis were noted in most patients. In 15% of the patients anti-IL-6 antibodies developed, and were neutralising in only one patient. Baseline plasma IL-6 concentrations did not correlate with tumour behaviour before or after rhIL-6 treatment. In conclusion, rhIL-6 can be safely administered on an outpatient basis for prolonged period of time and has moderate, reversible toxicity. Its administration induces IL-6-antibody production in only a minority of patients. Antitmour effects of rhIL-6 in metastatic renal cancer are limited.

Emerging drug treatments for solid tumours.

A number of novel anticancer agents have emerged during the past few decades, which show high activity in preclinical tumour models and promising activity in early trials in patients with solid tumours. Most of the agents have novel and unique mechanisms of action, and show activity against a variety of malignancies, including tumours which are notoriously resistant to systemic treatment. Recently, our understanding of the molecular basis of cancer has increased considerably. This is reflected in the development of agents that are directed at well defined molecular targets, such as the mitotic tubulin/microtubuli system (taxoids), nuclear enzymes (topoisomerase I inhibitors) and cell signal transduction pathways (protein kinase C inhibitors). In addition, significant advances have been made in our understanding of mechanisms of toxicity, especially of cisplatin. This has resulted in the development of agents modulating cisplatin toxicity, among which amifostine (WR-2721) is one of the most promising. The outlined emerging drug therapies with novel anticancer agents and treatment modalities will, it is hoped, result in increased response rates of advanced tumours, longer disease-free and total survival and better palliative care.