Reversible posterior leukoencephalopathy syndrome in cancer

Reversible posterior leukoencephalopathy syndrome (RPLS) is a subacute neurological syndrome typically manifesting with headache, cortical blindness, and seizures. The syndrome is associated with risk factors such as malignant hypertension, eclampsia, and renal failure. Numerous case reports depict its occurrence in cancer patients. The direct causal relationship for the mechanism of RPLS in cancer patients has not yet been defined. Cytotoxic chemotherapy may cause direct endothelium damage, which would impact the blood-brain barrier. Chemotherapies also cause elevations in blood pressure; this is significant because RPLS onset may be solely related to hypertension. An increased number of case reports involving new targeted agents suggests that RPLS incidence may increase in the future. Agents such as bevacizumab and sorafenib have been implicated in new cases of RPLS.     

Reversible Posterior Leukoencephalopathy Syndrome Associated with Concurrent Bevacizumab,Gemcitabine, and Oxaliplatin for Cholangiocarcinoma

Introduction  

Reversible posterior leukoencephalopathy syndrome (RPLS) is a rare disorder characterized by altered mental status, seizure, hypertension, and symmetrical white matter edema (leukoencephalopathy) typically in the posterior cerebral hemispheres on brain imaging. It is often linked to certain medication use, in particular, chemotherapeutic agents. Here, we present a case of chemotherapy-related RPLS and review the current literature on this topic.     

Gemcitabine and cisplatin chemotherapy induced reversible posterior leukoencephalopathy syndrome in a bladder cancer patient

Reversible posterior leukoencephalopathy syndrome (RPLS) is a rare clinical entity, the common clinical symptoms of which are headache, disturbance of consciousness, altered mental status, seizures, and visual disturbance. Recently, some cases have been reported in association with the increased use of cytotoxic and immunosuppressive agents in cancer patients, and relevant reports have increased with advances in radiological examinations. We describe here the case of a 50-year-old man with advanced bladder cancer who suddenly experienced diminished spontaneity and speech, and finally became semicomatose. Two months previously, he had received gemcitabine and cisplatin chemotherapy. Computed tomography and magnetic resonance imaging revealed symmetrical edema of the posterior occipital lobe and thalamus. Based on these findings, we made a diagnosis of RPLS and treated him with supportive measures. His mental status gradually improved in 2 weeks, although slight neurological symptoms persisted. When the level of consciousness of a cancer patient worsens rapidly, this syndrome should be included in the differential diagnosis and recognized at an early stage. Early supportive management and discontinuation of the causative medication may reverse the clinical and radiological manifestations of the syndrome.     

Vinorelbine in the treatment of non-small-cell lung cancer and breast cancer

Vinorelbine is a new semisynthetic vinca alkaloid with significantly less neurotoxicity than other vinca alkaloids. It was recently approved by the Ministry of Health and Welfare in Japan for the treatment of non-small-cell lung cancer. Vinorelbine is active in metastatic breast cancer with a first time response rate of 40% to 52%. High response rates were observed with combination chemotherapies of vinorelbine and other active agents for breast cancer. In non-small-cell lung cancer, four randomized phase III trials of vinorelbine demonstrated that vinorelbine alone, or combination chemotherapy of vinorelbine with cisplatin, improved survival more than best supportive care or cisplatin plus vindesine, respectively. There is a high level of evidence that vinorelbine is an effective agent for the treatment of non-small-cell lung cancer.     

Reversible posterior leukoencephalopathy induced by carboplatin and etoposide

Reversible posterior leukoencephalopathy syndrome (RPLS) is a rare neurologic condition characterised by specific clinical and radiologic findings. It usually manifests subacutely as insidious onset of headache, visual disturbance, altered consciousness and seizures in association with MRI findings of posterior white matter vasogenic oedema. RPLS has been reported in a wide variety of clinical settings. Hypertension, eclampsia, pre-eclampsia, renal impairment, autoimmune conditions and cytotoxic drugs are all cited as aetiologic variables. RPLS, albeit rare, is an important entity for physicians to be aware of as early recognition, and prompt intervention is critical to ensure resolution of the neurological deficit. We describe the case of a 69-year-old lady who collapsed with seizure activity after receiving carboplatin and etoposide chemotherapy for small cell lung cancer. In our opinion, the clinical and radiological courses are typical of RPLS. RPLS has rarely been reported secondary to this chemotherapy regimen, and the purpose of this report is to add to the literature and highlight the association between RPLS and cytotoxic chemotherapy.     

Efficacy and safety of palliative chemotherapy for patients with advanced breast cancer pretreated with anthracyclines and taxanes: a systematic review

No standard monotherapy or combination palliative chemotherapy currently exists for patients with advanced breast cancer pretreated with anthracyclines and taxanes. In this systematic review we assess the current knowledge on the efficacy and safety of palliative single-agent chemotherapy drugs--capecitabine, vinorelbine, gemcitabine, and liposomal doxorubicin--commonly used in daily clinical practice. We identified 22 studies, of which ten investigated capecitabine, nine investigated vinorelbine, three investigated gemcitabine, and one investigated liposomal doxorubicin. The greatest amount of information was available for capecitabine and vinorelbine. These two drugs showed good efficacy. The disease control rate differed significantly between the four drugs, which is relevant in terms of how well tumour symptoms can be improved and whether quality of life can be maintained or even improved. To obtain more evidence of the efficacy and safety of chemotherapeutic agents used in this pretreated population of advanced breast cancer patients, randomised comparisons of the various drugs, as monotherapy and in combination with targeted agents, are needed.     

Phase I study of Doxil and vinorelbine in metastatic breast cancer

Background: Vinorelbine and Doxil (liposomal doxorubicin) are active chemotherapeutic agents in metastatic breast cancer. A phase I study was designed to evaluate combination therapy.Patients and methods: Thirty women with metastatic breast cancer were enrolled. Dose-limiting toxicity was determined through a dose escalation scheme, and defined for the first treatment cycle, only. Pharmacokinetic studies were performed during the first cycle of treatment.Results: In the first cohort of Doxil 30 mg/m² day 1 and vinorelbine 25 mg/m² days 1 and 8, patients experienced severe neutropenia. Vinorelbine administration was changed thereafter to days 1 and 15 of each cycle. Dose limiting toxicity was observed at Doxil 50 mg/m² and vinorelbine 25 mg/m². Doxil 40 mg/m² and vinorelbine 30 mg/m² was defined as the maximally tolerated dose. Few toxicities (principally neutropenia) were seen at this dose level, with the notable absence of significant nausea, vomiting, or alopecia. Though 63% of patients had received prior anthracycline-based chemotherapy, only one patient developed grade 2 cardiac toxicity. Pharmacokinetic studies revealed prolonged exposure to high doxorubicin concentrations for several days following Doxil administration.Conclusions: Combination chemotherapy with Doxil and vinorelbine affords treatment with two active drugs in women with metastatic breast cancer, and appears to have a favorable toxicity profile. A schedule of Doxil 40 mg/m² day 1 and vinorelbine 30 mg/m² days 1 and 15 given every 28 days is recommended for phase II studies.     

Seizures and epilepsy in cancer: Etiologies,evaluation, and management

Seizure and epilepsy are common neurologic issues in cancer patients. Etiologies include structural abnormalities of the brain (eg, brain metastasis), cerebrovascular disease, reversible posterior leukoencephalopathy syndrome (RPLS), and radiation toxicity. Seizures associated with these etiologies often have focal features. Metabolic causes include hypoglycemia, electrolyte abnormalities, tumor lysis syndrome, thrombotic thrombocytopenic purpura (TTP), and medications used in cancer. A careful clinical evaluation can suggest the seizure etiology and guide subsequent work-up. Nonconvulsive status epilepticus should be suspected with persistent decreased level of consciousness following a seizure. Certain etiologies, such as RPLS and TTP, must be treated aggressively to minimize permanent neurologic injury. Routine prophylaxis with antiepileptic drugs (AEDs) is not recommended in patients with primary brain tumors or brain metastasis who have never had a seizure. Where indicated, the selection of AEDs should take into consideration side effects and interactions with chemotherapy. For this reason, non-enzyme-inducing AEDs are preferable in the cancer setting.     

A review of vinorelbine in the treatment of breast cancer

As combinations and sequences of anthracyclines and taxanes increasingly become standard adjuvant treatment for early breast cancer, a major need for new treatment options for metastatic breast cancer will arise. Vinorelbine is highly active in the treatment of metastatic breast cancer, both as a single agent and in combination regimens. Furthermore, it is well tolerated, with a low incidence of subjective toxicities. It is anticipated, therefore, that vinorelbine will become increasingly utilized for treating metastatic breast cancer due to its favorable safety profile, good tolerability, and promising results in combination with other chemotherapy agents. Combinations with trastuzumab and newer molecular targeting agents are being explored. Doublets or triplets of vinorelbine with drugs other than anthracyclines and taxanes could be considered in the next generation of adjuvant and neoadjuvant trials, where it is anticipated that anthracycline/taxane combinations are likely to replace anthracycline/cyclophosphamide combinations as the mainstay of adjuvant treatment.     

Bolus injection of vinorelbine reduces incidence of local venous toxicity in patients with non-small cell lung cancer and breast cancer

Vinorelbine is currently considered as one of the most active chemotherapeutic agents for non-small cell lung cancer and breast cancer. On the other hand, it is known as a vesicant drug frequently inducing venous irritation and phlebitis. Although the manufacturer's instructions recommend drip infusion for the drug administration in Japan, in 5 to 30% of patients venous toxicity has been reported that sometimes leads to treatment discontinuation even if it brings about a favorable response. In this report, we describe a retrospective study that compares drip infusion and bolus injection to prevent local venous toxicity. Seventy-one drip infusions and 196 bolus injections were administered to 18 and 40 non-small cell lung cancer patients, respectively. Also, 124 drip infusions and 335 bolus injections were administered to 13 and 38 breast cancer patients, respectively. We found that the bolus injection significantly reduced the incidence of vinorelbine- induced local venous toxicity in both diseases(22.2% versus 0% in non-small cell lung cancer patients, p<0.0006, and 46.2% versus 7.9% in breast cancer patients, p<0.0001). Our study demonstrates that bolus injection of vinorelbine is a suitable way for safe chemotherapy especially in an outpatient setting.     

Inhibition of tumor-associated fatty acid synthase activity enhances vinorelbine (Navelbine)-induced cytotoxicity and apoptotic cell death in human breast cancer cells

The lipogenic enzyme fatty acid synthase (FAS) is differentially overexpressed and hyperactivated in a biologically aggressive subset of breast carcinomas and minimally in most normal adult tissues, rendering it an interesting target for anti-neoplastic therapy development. Current trends in the treatment of human breast cancer are with drug combinations that result in improved responses as well as the ability to use less toxic concentrations of the drugs. Here, we envisioned that combinations of conventional chemotherapeutic agents with novel compounds directed against breast cancer-associated FAS hyperactivity may provide increased efficacy over existing therapy for human breast cancer. Specifically, we examined the ability of the mycotoxin cerulenin, a potent and non-competitive inhibitor of FAS activity, to enhance the cytotoxic effects of vinorelbine (Navelbine), a derivative of vinca alkaloid that interferes with tubulin assembly and exhibits activity against metastatic breast cancer. SK-Br3, MCF-7 and MDA-MB-231 human breast cancer cell lines were employed as models of high, moderate and low levels of FAS ('cerulenin-target'), respectively. Combinations of cerulenin with vinorelbine were tested for synergism, additivity or antagonism using the isobologram and the median-effect plot (Chou-Talalay) analyses. Breast cancer cells were either simultaneously exposed to cerulenin and vinorelbine for 24 h or sequentially to cerulenin for 24 h followed by vinorelbine for 24 h. Concurrent exposure to cerulenin and vinorelbine resulted in synergistic interactions in MCF-7 and MDA-MB-231 cell lines, while additivity was found in SK-Br3 cells. Sequencing cerulenin followed by vinorelbine resulted in synergism for SK-Br3 and MDA-MB-231 cells, whereas it showed additive effects in MCF-7 cells. FAS activity blockade was found to synergistically enhance apoptosis-inducing activity of vinorelbine, as determined by an enzyme-linked immunosorbent assay for histone-associated DNA fragments. To the best of our knowledge this is the first study demonstrating that breast cancer-associated FAS is playing an active role in human breast cancer chemosensitivity. We suggest that pharmacological inhibition of FAS activity is a novel molecular approach to enhance the cytotoxic effects of existing chemotherapeutic agents in human breast cancer.     

长春瑞滨联合希罗达治疗蒽环类和紫杉类耐药的晚期乳腺癌临床分析

  目的  观察长春瑞滨(NVB)联合希罗达(XEL)21天方案([NX]方案), 治疗蒽环类和紫杉类药物耐药的转移性乳腺癌(anthracycline-and taxanerefractory metastatic breast cance, ATRMBC)患者的疗效和不良反应  方法  NVB 25 mg/m 2d1, 8, 快速静滴; XEL2.0g/(m2·d), 早晚2次, 餐后30min口服, d1~14, 21天为1个疗程, 最多接受6个周期化疗或至疾病进展。  结果  48例患者共完成172个周期化疗, 中位化疗周期4个周期均可评价疗效和不良反应其中完全缓解(CR)0例, 部分缓解(PR)11例, 稳定(SD)23例, 进展(PD)14例总有效率(CR+PR)22.92%, 疾病控制率(DCR)70.83%, 中位无进展生存期(TTP)6.7个月(1~22个月), 1年生存率.32/48(66.70%), 2年生存率21/48(43.75%)。治疗后主要不良反应为血液学毒性及手足综合征, 其次为胃肠道反应及脉管炎。  结论  [NX]方案是治疗ATRMBC的有效方案, 不良反应可以耐受。      

Two weekly vinorelbine: administration in patients who have received at least two prior chemotherapy regimes for advanced breast cancer

This study examined the response to and toxicity of two weekly vinorelbine administration in patients with at least two prior chemotherapeutic treatments for advanced breast cancer. This single centre study enrolled 20 patients, 19 of whom had received prior taxane treatment for advanced breast cancer. Taxane treatment was in the form of docetaxel for all but 1 patient who had received paclitaxel. All patients had received two or more prior chemotherapeutic regimes for advanced breast carcinoma, including anthracyclines (epirubicin) in 19 patients. Vinorelbine 25 mg/m2 two weekly was given for 6 months, until disease progression or toxicity precluded further treatment. 5 earlier studied patients started vinorelbine at 25 mg/m2/week; all changed to the two weekly schedule, limiting the incidence and severity of neutropenia. 7 partial responses (PRs) out of 20 assessable patients (35% overall response rate, 95% confidence interval 15-59%) were noted, all PRs occurring in taxane pretreated patients. The median duration of response was 4 months whilst the median time to progression was 2.75 months. Overall, there were 7 neutropenic events (35%) of 2 week median duration, spanning common toxicity criteria (CTC) grades 1-3 in severity. 5 neutropenia cases (25%) occurred in patients whilst on two weekly vinorelbine. 2 cases (10%) required granulocyte colony stimulating factor support, 1 having had febrile neutropenia (52%). One case of thrombocytopenia, neurotoxicity and nausea (each CTC grade 1) were recorded. Although this study involves a small number of cases, these preliminary results suggest that two weekly vinorelbine is effective in heavily pretreated (including taxane pretreated) advanced breast carcinoma. Response is comparable with that of traditionally used weekly regimes, with markedly less toxicity.     

A case of reversible posterior leukoencephalopathy syndrome(RPLS)induced by modified FOLFOX6

We report here a case of reversible posterior leukoencephalopathy syndrome(RPLS)induced by modified FOLFOX6(mFOLFOX6). The patient was a 43-year-old woman who had sigmoid colon cancer with multiple liver metastases. Treatment with mFOLFOX6 was started. Early in the morning of day 11, the patient was transported by ambulance to the hospital due to nausea with headache, disturbed consciousness, and visual disturbance. The patient experienced sudden, severe nausea and subsequently presented generalized tonic-chronic seizures. The seizures subsided after treatment. On the evening of day 11, another episode of generalized tonic-chronic seizures occurred. Status epilepticus developed and tracheal intubation was performed for airway protection. Cranial MRI showed increased signal intensity in both occipital lobes, centered on the boundary between the gray and white matter on FLAIR images. Her condition stabilized with no seizure recurrence following intubation. Although hypertension was present on admission to the emergency room, blood pressure gradually fell to within the normal range without antihypertensive treatment. She was extubated on day 18. There were no neurologic sequelae. Cranial MRI on day 40 showed that the increased intensity in both occipital lobes had almost disappeared. Because the patient's condition was characterized by a reversible central nervous system disorder, RPLS was diagnosed.     

High body mass index correlates with increased risk of venous irritation by vinorelbine infusion

BACKGROUND: Vinorelbine is currently one of the most active chemotherapeutic agents. However, it is also a moderate vesicant that is well known to cause venous irritation and phlebitis. We conducted this study to identify clinical risk factors related to the incidence of venous irritation caused by peripheral vinorelbine infusion. METHODS: Medical records were used to investigate retrospectively a total of 201 cases of non-small cell lung cancer treated with a chemotherapeutic regimen containing vinorelbine. Venous irritation was evaluated in every course and graded according to the National Cancer Institute Common Toxicity Criteria version 2.0. Gender, age, body mass index (BMI), chemotherapeutic regimen, dose of vinorelbine and prior chemotherapy were used as clinical variables. RESULTS: A total of 928 vinorelbine infusions were administered to the 201 patients, among whom venous irritation occurred in 63 (31%). The incidence of venous irritation was 28% in the normal BMI (<25) group and 45% in the high BMI (25 or more) group and the difference between the two groups was statistically significant (P = 0.037). There were no significant correlations between the incidence of venous irritation and the clinical variables except BMI. In the multivariate analysis BMI was also a significant independent variable that correlated with increased risk of venous irritation (P = 0.017). CONCLUSIONS: Care is required when using vinorelbine to treat patients with a high BMI, especially with regard to the development of venous irritation.     

长春瑞滨联合顺铂治疗晚期乳腺癌的临床观察

目的探讨长春瑞滨联合顺铂治疗经紫杉醇＋蒽环类联合化疗失败的局部晚期乳腺癌和复发转移乳腺癌的疗效及安全性。方法10例采用紫杉醇＋蒽环类化疗耐药的局部晚期乳腺癌和31例手术后紫杉醇＋蒽环类辅助治疗的转移性乳腺癌患者,应用长春瑞滨（25mg／m^2,第1,8天,静脉滴注）、顺铂（30mg／m^2,第1—3天,静脉滴注）化疗,对其疗效及不良反应进行分析。结果全组患者完全缓解6例（14．6％）,部分缓解17例（41．5％）。不良反应以骨髓抑制、消化道反应常见。结论长春瑞滨联合顺铂方案对蒽环类和（或）紫杉醇耐药的乳腺癌疗效较好,值得临床进一步研究。     

希罗达联合长春瑞宾二线治疗紫杉类及蒽环类失败复发转移性乳腺癌的疗效观察

目的观察希罗达联合长春瑞宾二线治疗复发转移乳腺癌的临床效果及不良反应发生情况。方法选择32例乳腺癌复发转移性患者,于第1、8天静脉滴注长春瑞宾25mg／m2;早晚2次口服希罗达2000mg／（m2·d）,连用2周,休息1周为1个周期。所有患者均行2个以上周期的治疗。结果32例患者中,5例完全缓解（CR）,12例部分缓解（PR）,11例病情稳定（SD）,4例病情进展（PD）,总有效率53．12％,临床获益患者（CR＋PR＋SD）28例（87．5％）。患者不良反应为恶心、呕吐、皮肤色素沉着、厌食、手足综合征和疲劳等,小部分患者有头晕、口腔炎、胸闷和腹泻发生,偶见谷丙转氨酶、胆红素轻度升高者,其中轻一中度白细胞下降及贫血者占36．4％。结论对紫杉类及蒽环类治疗失败的复发转移乳腺癌患者,希罗达联合长春瑞宾作为二线治疗方案治疗效果肯定,且不良反应轻,患者能耐受。     

A phase I pharmacokinetic study of bexarotene with vinorelbine and cisplatin in patients with advanced non-small-cell lung cancer (NSCLC)

Purpose

This is a phase I study of the retinoid X receptor agonist bexarotene (Targretin^®) in combination with the chemotherapeutic drugs cisplatin and vinorelbine and lipid-lowering therapy. This study looked for pharmacokinetic (PK) interactions between the agents in parallel with a phase III study of the combination.

Methods

Patients (n = 26) with advanced-stage non-small-cell lung cancer received intravenous cisplatin 100 mg/m² on day 1 and at 4-week intervals plus intravenous vinorelbine 25 mg/m² weekly. Continuous oral bexarotene therapy (400 mg/m²/day) was initiated at day 4. Lipid-lowering therapy was initiated in all patients due to hypertriglyceridemia associated with bexarotene use. PK profiles of the chemotherapeutic agents were obtained on day 1 (without bexarotene) and during cycles 2–4 (with bexarotene). Vinorelbine (n = 18) and free cisplatin (n = 17) PK parameters in evaluable patients were determined using non-compartmental methods.

Results

Mean vinorelbine and free cisplatin clearance and dose-corrected AUC values with bexarotene were within 20% of respective values without concomitant bexarotene. Bexarotene levels did not vary with or without co-administration of the chemotherapeutic agents. There was no evidence of increased toxicity when bexarotene was co-administered with the chemotherapeutic agents.

Conclusions

Bexarotene does not substantially affect vinorelbine or cisplatin PK, and the combination is well tolerated. The results are consistent with the mechanisms of elimination of vinorelbine (high metabolic clearance) and cisplatin (non-enzymatic and renal elimination).

     

RLIP76 transports vinorelbine and mediates drug resistance in non-small cell lung cancer

Vinorelbine (Navelbine), an amphiphilic semisynthetic Vinca alkaloid, has displayed superior activity and decreased resistance in the treatment of advanced non-small cell lung cancer (NSCLC) compared with other members of its class. Recently, vinorelbine and cisplatin combination chemotherapy has been shown for the first time to confer a significant survival advantage in early-stage lung cancer after surgical therapy. The biological mechanisms underlying the differential response of NSCLC to cytocidal activity of vinorelbine have yet to be elucidated. Our recent findings indicate a role of RLIP76, a non-ATP binding cassette transport protein, in catalyzing the ATP-dependent efflux of structurally and functionally unrelated chemotherapeutic agents such as doxorubicin and vinblastine in NSCLC. Present studies were conducted to assess whether RLIP76 mediates vinorelbine transport and resistance. Here we show that RLIP76 catalyzes the transport of vinorelbine in a saturable manner with respect to vinorelbine (K(m) 75 nmol/L) and ATP (K(m) = 3.4 mmol/L). Three-fold overexpression of RLIP76 in NSCLC and SCLC confers increased resistance to cytotoxicity. RLIP76 overexpression causes a sustained intracellular decrease in vinorelbine concentration because of increased efflux, and anti-RLIP76 antibodies sensitize lung cancer cells to vinorelbine by inhibiting its efflux. These studies for the first time show that RLIP76 mediates vinorelbine transport and is capable of conferring drug accumulation defect and resistance to lung cancer cells.