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A 1-year complete remission could be achieved with high-dose systemic chemotherapy in a 33-year-old patient with relapsed germ cell tumor presenting with leptomeningeal carcinomatosis (LC). Although LC in general has a very poor prognosis for patients with chemosensitive malignancies, systemic chemotherapy should be considered.

Metastatic renal-cell carcinoma (mRCC) is highly resistant to cytotoxic agents or hormones and is currently mainly treated with cytokine-based therapy. Transient responses and moderate survival advantages have been achieved in a subset of patients with these aspecific biological response modifiers. Side-effects are considerable, especially with high-dose interleukin (IL)-2. Efforts made in the field of specific immunotherapy have focused on optimization of dendritic cell vaccination and on administration of monoclonal antibodies, either cold (unconjugated) or hot (radioactively labeled). Furthermore, allogeneic bone marrow transplantation is able to induce remissions but, regrettably, is related to substantial morbidity and mortality. Neutralization of the biological activity of some immunosuppressive cytokines produced by RCC (IL-6 and tumor necrosis factor-alpha) with monoclonal antibodies is currently under investigation. Insights gained into the processes and pathways underlying carcinogenesis have led to the development of new treatment strategies. These treatments can be used for clear cell RCC, since they focus on blocking gene products that are upregulated by mutations in the von Hippel-Lindau gene. Specific strategies include anti-vascular endothelial growth factor monoclonal antibody (bevacizumab) or inhibition of its receptor kinases (oral SU11248 or PTK787), or targeting the Raf kinase pathway (by BAY 43-9006) or the mammalian target of rapamycin (mTOR) pathway (by CCI-779). Early clinical results are promising, but their place in the treatment of RCC has to be determined.

Dendritic cells (DC) have been recognized as the most potent antigen presenting cells (APC) of the immune system. We performed a phase 1 study in twelve patients with metastatic renal cell carcinoma (RCC) using autologous immature DC loaded with autologous tumorlysate (TuLy) as a vaccine based on our earlier in vitro observations that such DC can activate tumor-specific cytotoxic T-lymphocytes. The treatment was combined with low-dose interleukin (IL)-2, as this has shown benefit in DC-based therapies. Patients received three intradermal vaccinations at two weekly intervals, and, after each vaccination, IL-2 was administered for 5 consecutive days. In six patients, keyhole-limpet hemocyanin (KLH) was added to the DC culture for immunologic monitoring purposes. In general, DC phenotype was CD14(low), CD86(high), CD40(high), CD80(low), and CD83(low). We noticed that the number of CD14+ cultured DC increased during treatment. Nevertheless, ovalbumin uptake remained high, underlining that these cells were still functional immature DC. The vaccine was able to elicit cellular anti-KLH responses, emphasizing the ability of the injected DC to mount an immunologic response. However, proliferative responses against TuLy were not detected, and humoral responses against TuLy or KLH were absent. Objective clinical responses were not observed, but extended stable disease was noted. The absence of cellular, humoral, or clinical antitumor responses suggests that the vaccination strategy with immature DC has little benefit for patients with advanced RCC. Nevertheless, this study shows the feasibility of a completely autologous DC and tissue culture methodology for the generation of TuLy pulsed DC.

Studies of combination therapy [with agents such as cisplatin, 5-fluorouracil (5-FU) and methotrexate] have shown some improvements in response rate; however, no obvious survival advantage over monotherapy in the treatment of patients with metastatic or advanced locoregional cancer of the head and neck have been observed. In the neoadjuvant setting, chemotherapy is helpful in preserving the larynx and hypopharynx but has no proven impact (positive or negative) on survival. New treatment options are needed to improve survival in head and neck cancer. Among the new options for chemotherapy in metastatic/recurrent disease is docetaxel. With monotherapy, response rates of 23-42% are seen, and, when used in combination with cisplatin and 5-FU, response rates of 52-100% have been reported in phase I/II trials. A phase III trial of the addition of docetaxel to standard neoadjuvant therapy with cisplatin and 5-FU is now underway.

The majority of patients with metastatic germ cell tumors can be cured with currently available poly-chemotherapy. Based on presenting criteria three prognostic groups can be discerned. In patients with a good prognosis (> 90% probability of 5-year survival) attempts have been made to diminish the dose of the active compounds in the BEP regimen. The omission of bleomycin cannot be recommended on presently available data; and a total dose of at least 240 mg seems appropriate. Platinum at a dose intensity below 75 mg/m2/3 weeks compromised efficacy and the recommended dose is 100 mg/m2. A true comparison between the two most frequently used etoposide doses has not been performed. Based on the available literature etoposide should be given in doses of at least 360 mg/m2/cycle when four courses are given and 500 mg/m2/cycle when three courses are given. For intermediate and high-risk patients alternating, accelerated and high-dose chemotherapy can be considered. None of the alternating and accelerated regimens has a proven advantage in randomized trials and they remain investigational. The addition of hematopoietic growth factors permits a higher dose intensity of BEP/EP and BOP/VIP; although to date there is no proven impact on outcome. The application of high-dose chemotherapy for one to four courses is feasible with the support of both hematopoietic growth factors and autologous bone marrow or peripheral stem cells. In true chemotherapy-resistant disease the value of this approach seems limited. Its role in patients with a first relapse should be further explored. The approach of high-dose chemotherapy in first line for patients with poor prognostic features should preferentially be investigated in a randomized fashion, but this will require extensive international collaboration in view of the low incidence and the expected advantage of the approach.

In recent years a new class of agents, the serotonin type 3 receptor antagonists, has been identified. This article reviews the preclinical, pharmacological and clinical data of ondansetron, granisetron and tropisetron, the first representatives of this group. Preclinical work showed that the drugs interfere with a variety of physiological processes, and hold promise for clinical utility in a wide range of areas. To date, these agents have proven, both in early clinical and comparative studies, to be potent antiemetic agents in patients receiving cisplatin and non-cisplatin chemotherapy as well as radiotherapy. In comparative studies the antiemetic efficacy mostly has been superior to conventional antiemetic drugs with regard to the acute chemotherapy-related symptoms; whereas their role in delayed emesis needs further investigation. This also applies for their role as an antiemetic in other types of nausea and vomiting (post-operative). Toxic effects have been modest, no extrapyramidal reactions have been reported. Potential clinical use in psychiatric disorders has been suggested, and the results of clinical trials are awaited.

Knowledge of the pharmacokinetics of propylene glycol (PG) is scarce, though it is used in a number of preparations for intravenous use. Although systemic toxicity appears to be uncommon, PG has been reported to cause lactic acidosis and other adverse effects. We describe a rapid gas chromatographic assay method for PG and the plasma pharmacokinetics after intravenous administration to six patients on nine occasions. The pharmacokinetics were nonlinear, based on a saturable clearance. The apparent first-order half-life was 2.3 +/- 0.7 h. There was no evidence of lactic acidosis, hemolysis, or increase in osmolality at 3-15 g/m2 PG infused over periods of 4 h.

The long-term analgesic effects and the complications of epidural narcotic analgesia (ENA) were investigated in 40 cancer patients in whom systemic narcotic therapy failed to relieve pain or caused unacceptable side effects. In 32 patients, an externally fixated polyamide epidural catheter was used ("external group"), and in 8 patients, a polyurethane epidural catheter was tunneled and connected to a subcutaneous access port ("internal group"). The average duration of catheter treatment was 80.9 days (range 9-533 days). Twenty-five patients were treated as outpatients, and 15 remained hospitalized. Initially, all patients had significant or complete pain relief from 10 mg morphine/day, but the daily epidural morphine requirement showed a threefold increase during the first 3 weeks. During ENA, other methods of pain relief (radiotherapy, chemotherapy, surgery, epidural administration of local anesthetics, and nerve blocks) were necessary in 14 patients. Pharmacological side effects were of minor importance, with transient pruritus being the main subjective complaint. In the "external" group, 31 catheter replacements were necessary, mostly due to backflow of injected morphine outside the catheter. In two patients of the internal group, neurological complications occurred, but these disappeared spontaneously after removal of the system. They were presumably due to epidural fibrosis with compression of the spinal cord. Further technical improvements are necessary for the easier use and higher safety of the catheter technique.

Induction combination chemotherapy with cisplatin, 100 mg/m2 i.v. day 1, and 5-fluorouracil, 1,000 mg/m2/24-h infusion days 1-4, was applied in 76 patients with locally far advanced squamous-cell cancer of the head and neck. The treatment program consisted of 3 cycles of chemotherapy, followed by local radiotherapy and/or surgery. Hematologic side effects were leukocytopenia (50%) and thrombocytopenia (35%). Other side effects included renal toxicity (23%), nausea and/or vomiting (86%), alopecia (18%), and phlebitis (45%). Thirteen patients (17%) achieved a complete remission and 37 patients (49%) a partial remission. Median progression-free and overall survival were 8 and 11 months, respectively. Only patients achieving a complete remission had a better prognosis. Although induction chemotherapy may facilitate further local treatment in about half of the patients, on the basis of presently available data, this procedure should not be routinely applied with the aim of better survival.