Neurotoxic side effects of chemotherapy occur frequently and are often a reason to limit the dose of chemotherapy. Since bone marrow toxicity, as the major limiting factor in most chemotherapeutic regimens, can be overcome with growth factors or bone marrow transplantation, the use of higher doses of chemotherapy is possible, which increases the risk of neurotoxicity. Chemotherapy may cause both peripheral neurotoxicity, consisting mainly of a peripheral neuropathy, and central neurotoxicity, ranging from minor cognitive deficits to encephalopathy with dementia or even coma. In this article we describe the neurological adverse effects of the most commonly used chemotherapeutic agents. The vinca-alkaloids, cisplatin and the taxanes are amongst the most important drugs inducing peripheral neurotoxicity. These drugs are widely used for various malignancies such as ovarian and breast cancer, and haematological cancers. Chemotherapy-induced neuropathy is clearly related to cumulative dose or dose-intensities. Patients who already have neuropathic symptoms due to diabetes mellitus, hereditary neuropathies or earlier treatment with neurotoxic chemotherapy are thought to be more vulnerable for the development of chemotherapy-induced peripheral neuropathy. Methotrexate, cytarabine (cytosine arabinoside) and ifosfamide are primarily known for their central neurotoxic side effects. Central neurotoxicity ranges from acute toxicity such as aseptic meningitis, to delayed toxicities comprising cognitive deficits, hemiparesis, aphasia and progressive dementia. Risk factors are high doses, frequent administration and radiotherapy preceding methotrexate chemotherapy, which appears to be more neurotoxic than methotrexate as single modality. Data on management and neuroprotective agents are discussed. Management mainly consists of cumulative dose-reduction or lower dose-intensities, especially in patients who are at higher risk to develop neurotoxic side effects. None of the neuroprotective agents described in this article can be recommended for standard use in daily practise at this moment, and further studies are needed to confirm some of the beneficial effects described.

Neurotoxic complications of chemotherapy in patients with cancer: clinical signs and optimal management.

Purpose A multicenter phase II study evaluating efficacy, safety, and pharmacokinetics of ecteinascidin-743 (ET-743) in pretreated advanced soft tissue sarcoma patients. Patients and Methods Patients received ET-743 1,500 μg/m2 (24-hour intravenous infusion) every 3 weeks (group 1, 26 patients with one to two prior single agents or one previous combination chemotherapy; group 2, 28 patients with three or more prior single agents or two or more previous combination chemotherapies). Results Patients (30 women, 24 men) had a median age of 48 years (range, 22 to 71 years); 41% had leiomyosarcoma (eight of 22 of uterine origin), a median of two involved organs (range, one to four), and 93% had documented progressive disease at study entry. Patients received a median of three cycles (range, one to 20); 28% received six or more cycles. Fifty-two patients were assessable for response (WHO criteria): two partial responses, four minor responses, and nine with stable disease (≥ 6 months). Three patients were rendere...

https://ascopubs.org/doi/pdf/10.1200/JCO.2004.05.210

Phase II Study of Ecteinascidin-743 in Advanced Pretreated Soft Tissue Sarcoma Patients

Intrathecal methotrexate in children with leukemia is known to cause seizures, dementia, leukoencephalopathy, and cognitive dysfunction after long-term treatment. To investigate the cognitive dysfunction, male Wistar rats were given multiple intracerebroventricular injections of methotrexate. Its effect on behaviour was tested in the two-compartment conditioned avoidance task and dark-bright arena test. Levels of brain amines in the hippocampal region of the brain were estimated by HPLC. The qualitative and quantitative histopathological changes in the different regions of the hippocampus were studied by cresyl violet staining. Multiple injections (1 or 2 mg/kg) produced convulsions and learning and memory impairment but did not induce anxiolytic activity. They also reduced concentrations of all three brain amines (norepinephrine, dopamine, and serotonin) and the serotonin metabolite 5-hydroxyindoleacetic acid. The CA4 region of the hippocampus was severely affected by intraventricular methotrexate. Disruption of brain monoamines has been proposed as a cause of brain dysfunction from this chemotherapy, and that disruption may in turn involve cytotoxic effects of methotrexate on brain tissue. The outcomes of this study may have therapeutic implications in the management of cancer conditions, particularly in childhood lymphoblastic leukemia.

Hippocampal brain amines in methotrexate- induced learning and memory deficit

Background. Gemcitabine and docetaxel have a broad spectrum of clinical activity in patients with carcinoma. The Sarcoma Alliance for Research Through Collaboration conducted aphaseIItrialofgemcitabineincombinationwithdocetaxelin children and adults with recurrent Ewing sarcoma (EWS), osteosarcoma (OS), or unresectable or recurrent chondrosarcoma. The primaryobjectivewastodeterminetheobjectiveresponserateusing Response Evaluation Criteria in Solid Tumors (RECIST). Methods. Gemcitabine (675 mg/m 2 i.v. over 90 minutes on days 1 and 8) was administered in combination with docetaxel (75mg/m 2 i.v.over1houronday8)every21days.Allpatients received filgrastim or pegfilgrastim. A Bayesian formulation was used to determine the probability of achieving the target response rate for each subtype—0.35 for EWS and OS or 0.20 for chondrosarcoma. If the probability of achieving the target response rate was 0.05, the combination was considered inactive. Toxicity was graded according to Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Results. Fifty-three eligible patients were enrolled in the three subtype groups—OS (n 14), EWS (n 14), and chondrosarcoma (n 25). Toxicities included neutropenia, thrombocytopenia, fatigue, dyspnea, bronchospasm, edema, neuropathy, and liver function abnormalities. Dose modification for toxicity was required for eight patients during cycle 1 and 16 patients in subsequent cycles. Seven patients withdrew from therapy as a result of toxicity. No complete responses were observed. Partial responses were observed in OS (n1), EWS (n 2), and chondrosarcoma (n 2) patients. Conclusion. Gemcitabine in combination with docetaxel was associated with a probability of reaching the target 35% response rate of 5% in OS patients and 5.6% in EWS patients; the probability of reaching a 20% response rate in chondrosarcoma patients was 14%.

Phase II Study of Sequential Gemcitabine Followed by Docetaxel for Recurrent Ewing Sarcoma, Osteosarcoma, or Unresectable or Locally Recurrent Chondrosarcoma: Results of Sarcoma Alliance for Research Through Collaboration Study 003

The treatment of advanced soft-tissue sarcomas is often palliative, although a subset of patients may be cured or have a long disease-free interval. This paper reviews the historical data over 30 years of treatment that has led to the use of ifosfamide and doxorubicin as the mainstay in the treatment of metastatic disease. These treatments have a high toxicity, relative to other chemotherapeutic regimens, with median response durations on the order of months. Agents developed in the last few years, whose role in the treatment of sarcomas is still evolving, are discussed as well. Finally, we discuss the role of chemotherapy in combination with surgery and radiation in the adjuvant and neoadjuvant settings. The Oncologist 2002;7:348-359

https://theoncologist.onlinelibrary.wiley.com/doi/pdf/10.1634/theoncologist.7-4-348

The Use of Chemotherapy in Soft-Tissue Sarcomas

Because of the low number of active cytotoxic drugs and their limited activity, the evaluation of new anti-cancer agents for their activity in soft tissue sarcomas is a continuing need. The objectives of this prospective phase II trial of gemcitabine were to estimate the response rate and to define

Phase II trial of gemcitabine in patients with pretreated advanced soft tissue sarcomas.

An episode of subacute encephalopathy after the infusion of a moderate dose of methotrexate (1500 mg/m2) (MTX) is reported in a young adult with metastastic gastric cancer. Weakness of the right arm, focal seizures, lethargy and confusion appeared on day 10. High signal intensity in periventricular white matter was observed on T2-weighted magnetic resonance imaging. Symptoms resolved spontaneously and completely after 48 h. We believe that this represents an unusual case of moderate-dose MTX-induced neurotoxicity in a patient with gastric cancer, which has not previously been reported.

Subacute encephalopathy after combination chemotherapy including moderate-dose methotrexate in a patient with gastric cancer

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Phase II trial of gemcitabine in patients with pretreated advanced soft tissue sarcomas.

Subacute encephalopathy after combination chemotherapy including moderate-dose methotrexate in a patient with gastric cancer