Chemotherapy induced reversible posterior leukoencephalopathy syndrome

The reversible posterior leukoencephalopathy syndrome (RPLES) is a condition characterised by reversible neurological and radiological findings that has been associated with use of immunosuppressive, chemotherapeutic and more recently novel targeted therapies. We describe the case of a 50-year-old woman with advanced non-small cell lung cancer who developed status epilepticus shortly after receiving cisplatin and gemcitabine chemotherapy. The clinical, radiological and EEG findings during and post event are presented and are in keeping with a diagnosis of RPLES. Early recognition of this rare syndrome, supportive management and withdrawal of the offending agent appear to result in a reversal of the manifestations described.     

Reversible posterior leukoencephalopathy syndrome induced by vinorelbine

Reversible posterior leukoencephalopathy syndrome (RPLS) was first described in 1996; clinical symptoms include the presence of headache, visual disturbance,seizure, hypertension, and encephalopathy. The syndrome is most commonly encountered in association with chemotherapeutic agents or targeted therapy. Many chemotherapeutic agents, such as cisplatin,gemcitabine, methotrexate, were reported to be associated with RPLS. Vinorelbine is commonly used for the treatment of metastatic breast cancer, but vinorelbine-induced RPLS has not been reported. We reported a 34-year-old woman, diagnosed with invasive ductal carcinoma of the left breast, who experienced acute hypertension after vinorelbine intravenous infusion. Accompanied symptoms included headache,seizure, and conscious disturbance. Magnetic resonance imaging of the brain showed symmetric signal hyperintensity with the cortical and subcortical white matter of bilateral frontal, parietal, and occipital (predominant) lobes. Vinorelbine is a semisynthetic vinca alkaloid and prevents cell division by inhibiting tubulin polymerization.Brain metastasis or leptomeningeal carcinomatosis is an important issue for patients with breast cancer who present with headache, seizure, or altered consciousness.However, now RPLS may be a new consideration,especially with the presentation of acute hypertension. Unlike brain or meningeal metastasis, RPLS is usually benign, and most patients recover within 2 weeks. Our case highlights an association between vinorelbine and RPLS, and the drug has not been described as a predisposing factor of RPLS in past reports. In the era of cancer treatment with chemotherapy or targeted therapy,clinicians should be aware of this syndrome.     

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.     

A case of oxaliplatin-related posterior reversible encephalopathy syndrome

We report the first case of oxaliplatin-related posterior reversible encephalopathy syndrome (PRES) in the medical literature. A 19-year-old woman with metastatic adenocarcinoma of the rectum received modified FOLFOX (5-fluorouracil/oxaliplatin) chemotherapy. Ten days after the fourth treatment, she presented to the hospital with seizures and altered mental status. Magnetic resonance imaging of the brain demonstrated hyperintensity in the white matter of the posterior hemispheres consistent with PRES. Herein, we briefly review the PRES syndrome and its management.     

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.     

A case of pseudomyxoma peritonei successfully treated with multidisciplinary treatment including modified FOLFOX6 regimen

We report a case of pseudomyxoma peritonei caused by carcinoma of the appendix, which was successfully treated with multidisciplinary treatment including modified FOLFOX6 regimen. A 45-year-old man was diagnosed as having peritoneal dissemination associated with cancer of the cecum or appendix. Seven cycles of mFOLFOX6 treatment resulted in a marked decrease in ascites and serum levels of carcinoembryonic antigen and carbohydrate antigen 19-9. At laparotomy, a diagnosis of pseudomyxoma peritonei caused by cancer of the appendix was made. Intraperitoneal lavarge with 10,000 mL 5% glucose was performed after right hemicolectomy, omentectomy and removed of mucinous peritoneal nodules. Intraperitoneal chemotherapy comprised of 3000 mL low molecule dextran and 80 mg cisplatin was added on postoperative days 7 and 14. Modified FOLFOX6 regimen was started again two months postoperatively and reached 28 cycles. The patient does not show any sign of recurrence 12 months postoperatively.     

Fifth-line chemotherapy for metastatic gastric cancer--a case responding to modified FOLFOX 6

According to the National Comprehensive Cancer Network (NCCN) clinical practice guideline for gastric cancer (2006, the first edition), 5-FU/Leucovorin (LV), 5-FU-based, cisplatin (CDDP)-based, oxaliplatin (L-OHP)-based, taxane-based, and irinotecan (CPT-11)-based, ECF are recommended. We used modified FOLFOX 6 (mFOLFOX 6) for pretreatment, that is oxaliplatin-based chemotherapy, for a patient who had received 5-FU-based, CDDPbased, taxane-based, and CPT-11-based treatment for an unresectable gastric cancer case responding to mFOLFOX 6. A 73-year-old male admitted to our hospital for treatment of advanced gastric cancer was diagnosed to be inoperable. A combination chemotherapy docetaxel and CDDP and S-1 as first-line treatment, CPT-11 and CDDP as second-line treatment, weekly paclitaxel treatment as third-line treatment, and MTX and 5-FU as fourth-line treatment were performed. He had progressed after 5-FU-based, CDDP-based, taxane-based, and CPT-11-based chemotherapy. There are no effective approved drugs for gastric cancer in Japan. Oxaliplatin was reportedly effective for metastatic gastric cancer, but it is still non-approved in Japan. After receiving an explanation of oxaliplatin-based therapy, he gave informed consent. Oxaliplatin-based therapy for this patient was then evaluated and approved under an institutional review board of Higashi Sapporo Hospital. mFOLFOX 6 used for the oxaliplatin-based therapy. After 2 courses of mFOLFOX 6, he showed a partial response. Oxaliplatin-based treatment was thought to be promising for previously CDDP-treated patients with unresectable gastric cancers.     

A case of recurrent rectal cancer with lymphangiosis carcinomatosa successfully treated with modified FOLFOX6 therapy

A 56-year-old woman with multiple lung metastases and lymphangiosis carcinomatosa due to recurrent rectal cancer was treated with chemotherapy of modified FOLFOX6 (mFOLFOX6) regimen: l-leucovorin (l-LV 200 mg/m(2)) and oxaliplatin (L-OHP 85 mg/m(2)) were given as a 2-hour infusion followed by bolus injection of 5-FU 400 mg/m(2) and a 46- hour infusion 5-FU 2,400 mg/m(2) every two weeks. Since partial response was achieved and dyspnea was remarkably improved, she was discharged without oxygen therapy after 5 courses.     

A case of advanced colon cancer with peritoneal dissemination effectively treated with modified FOLFOX6 chemotherapy

A 50-year-old woman was diagnosed with ascending colon cancer with bilateral ovarian metastases, carcinomatous peritonitis, and carcinomatous pleurisy. Nine courses of mFOLFOX6 treatment resulted in the disappearance of her ascites and pleural effusion and a marked decrease in her serum CEA and CA19-9 levels. Additionally, the primary tumor and ovarian metastases became smaller. Therefore, a right hemicolectomy with D3 lymph node dissection, total hysterectomy, and bilateral salpingo-oophorectomy were performed. Postoperatively, we changed the chemotherapy from mFOLFOX6 to bevacizumab+FOLFIRI because the patient had an allergic reaction to oxaliplatin, and we suspected lung metastasis. Because the lung metastasis grew after ten courses of bevacizumab+FOLFIRI, we changed to cetuximab+FOLFIRI. Unfortunately, 28 months after her diagnosis, the patient died of carcinomatous pleurisy.     

A case of neurotoxicity reduced with goshajinkigan in modified FOLFOX6 chemotherapy for advanced colon cancer

In performing FOLFOX (infusional 5-FU/LV with oxaliplatin) for advanced colorectal cancer, neurotoxicity of oxaliplatin (L-OHP) is the serious dose limiting factor. On the other hand, goshajinkigan is recently considered as an effective agent for the neurotoxicity of taxanes in Japan.We have applied goshajinkigan (TJ 107) for a case of advanced colon cancer with mFOLFOX 6, and experienced a reduction in numbness, the adverse effect of LOHP. A 57-year-old woman with descending colon cancer (H 1, P 3, Stage IV) underwent hemicolectomy D 2, rt.colectomy, bilateral oophorectomy, cholecystectomy and transverse colonostomy. After operation, mFOLFOX 6 was applied. In order to reduce the neurotoxicity of L-OHP, TJ 107 was used together from the third course. The severities of neurotoxicity before and after administration of TJ 107 were grade 2 and 1,respectively. TJ 107 could reduce or prevent the neurotoxicity of L-OHP.     

Sunitinib induced hypertension, thrombotic microangiopathy and reversible posterior leukencephalopathy syndrome.

A 54-year-old female with suboptimally controlled hypertension(RR 150/90) and an imatinib-resistant gastrointestinal stromalcell tumor, had been on treatment with sunitinib malate (Sutent,previously known as SU011248; Pfizer, NY), a vascular endothelialgrowth factor receptor (VEGFR)/c-kit/platelet-derived growthfactor receptor (PDGFR)/Flt3 tyrosine kinase inhibitor. Thedrug was given orally daily 50 mg for a 4-week-on, 2-week-offschedule since November 2005. During the 4-week-on cycles, thrombocytopeniawas present, but the platelet counts restored to normal valuesin the 2-week-off schedule (Figure 1). On treatment with sunitinib,20% regression of the tumor was seen. On 22 June 2006, in herlast week of     

A case report of hemolytic uremic syndrome (HUS) induced by antineoplastic agents

An autopsy case of hemolytic uremic syndrome after treatment with antineoplastic agents for advanced gastric carcinoma is reported. A 70 year-old woman underwent partial gastrectomy for gastric carcinoma on April 16, 1987 (P0H0S2N4, Stage IV). She was treated with Mitomycin C (MMC), UFT, OK-432 and PSK as post operative chemotherapy. Total doses were 60 mg of MMC, 33.9 g of UFT, 55 KE of OK-432 and (507 g) of PSK. She suffered from occult blood in urine in September 1987, thrombocytopenia and anemia in October, edema and hypertension in November and died due to acute renal failure and pulmonary failure on December 5, 1987. It seemed that the cause of death was hemolytic uremic syndrome induced by antineoplastic agents.     

Posterior reversible encephalopathy syndrome induced by anti-VEGF agents

Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiological entity that may occur in patients receiving anti-vascular endothelial growth factor (VEGF) agents such as bevacizumab and tyrosine kinase inhibitors. Little is known about the characteristics of patients at risk for PRES under anti-VEGF agents. We carried out a comprehensive review of reports documenting the occurrence of PRES in patients receiving anti-VEGF agents. Twenty-six patients are described with a majority of females (73.1%). Almost a third of patients had a past history of hypertension. The most common symptoms included headache, visual disturbance and seizure. A vast majority of patients had hypertension at the diagnosis of PRES, and proteinuria was detectable each time it was investigated. Neurological outcome was favorable in all cases with a symptomatic treatment including blood pressure control. The risk of PRES is increased when blood pressure is poorly controlled and when proteinuria is detectable. The clinical course appears favorable with a symptomatic treatment. PRES is a potentially severe but manageable toxicity of anti-VEGF agents.     

A case of leukoencephalopathy caused by HCFU

After a hysterectomy, a bilateral salpingo-oophorectomy, two courses of intra-peritoneal chemotherapy of Cisplatinum, Carmofur (HCFU, 600 mg/day [per os]) were given a patient who had ovarian granulosa cell tumor (malignant, stage Iai). Dizziness and loss of consciousness developed about 60 days after administration of HCFU, and leucoencephalopathy was diagnosed. A CT revealed a diffuse low density area in the white matter of the cerebrum. Myelin Basic Protein in the spinal fluid was found to amount to 9.8 mg/dl, which in norm. person is less than 4.0 mg/dl. Also, it showed parallel changes with the course of the clinical findings. HCFU easily dissolves to fat and changes to 5-FU without enzymes in the liver cell. Further HCFU also passes through Blood Brain Barrier to Produce 5-FU and its derivatives, in which the alpha-Fluoro-beta-Alanine is thought to be the culprit that brings on leucoencephalopathy. Even so, HCFU should be dosed when needed in spite of this risk. Other 5-FU modifiers also have been reported to produce the same effect in several cases.     

High-dose dexamethasone plus antihistamine prevents colorectal cancer patients treated with modified FOLFOX6 from hypersensitivity reactions induced by oxaliplatin

Background

Oxaliplatin is a third-generation platinum compound and a key agent for the management of colorectal cancer. Patients treated with oxaliplatin are at risk for hypersensitivity reactions. We designed a modified premedication regimen to prevent oxaliplatin-related hypersensitivity reactions and assessed if this approach is effective.

Methods

A retrospective cohort study of patients with advanced colorectal cancer who received modified FOLFOX6 (mFOLFOX6) was performed. Patients received routine premedication with dexamethasone 8?mg and granisetron 3?mg for the first five cycles of mFOLFOX6. From the sixth cycle onward, cohort 1 received the same premedication, and cohort 2 received modified premedication (diphenhydramine 50?mg orally, followed by dexamethasone 20?mg, granisetron 3?mg, and famotidine 20?mg). We compared the incidence of hypersensitivity reactions, duration of treatment, and reasons for treatment withdrawal between the two cohorts.

Results

A total of 181 patients were studied (cohort 1, 81; cohort 2, 100). Hypersensitivity reactions developed in 16 patients (20%) in cohort 1 and 7 (7.0%) in cohort 2 (P?=?0.0153). The median number of cycles increased from 9 in cohort 1 to 12 in cohort 2. Apart from progressive disease, neurotoxicity was the reason for discontinuing treatment in 20% of the patients in cohort 1, as compared with 53% in cohort 2.

Conclusion

Increased doses of dexamethasone and antihistamine significantly reduced oxaliplatin-related hypersensitivity reactions. This effective approach should be considered for all patients who receive FOLFOX, allowing treatment to be completed as planned.     

A phase I study of modified FOLFOX 6 therapy for advanced colorectal cancer

Oxaliplatin (L-OHP) has been established as a key drug for advanced colorectal cancer, and combination therapy with 5-FU/Leucovorin (LV)(FOLFOX regimen) is commonly used in Europe and the US. A phase I study of modified (m) FOLFOX 6 therapy was conducted to determine the recommended dose (RD) of 5-FU infused for 46 hours. Inclusion criteria were unresectable advanced colorectal cancer,measurable lesions, performance status (PS; ECOG) 0-2, age 20-75 years, and adequate organ functions. L-OHP and l-LV was administered over 2 hours and followed by bolus injection and continuous infusion of 5-FU for 46 hours every 2 weeks. Two cycles of mFOLFOX 6 therapy were performed. Doses of L-OHP, l-LV, and bolus injection of 5-FU were fixed at 85 mg/m(2), 200 mg/m(2), and 400 mg/m(2), respectively. The dose of continuous infused 5-FU was escalated from 1,600 mg/m(2), (level 1), 2,000 mg/m(2), (level 2), 2,400 mg/m(2), (level 3), and 2,800 mg/m(2), (level 4). RD was determined in a dose escalation manner, and safety was evaluated according to NCI-CTC Ver 2.0. A total of 13 patients were enrolled. Male/female=7/6, PS 0/1/2=2/4/7, mean age 64 years (range 55-75). Thrombocytopenia was not observed, and grade 2 of neutropenia and peripheral neuropathy was observed in 4 and 6 out of 13 patients. No dose-limiting toxicity (DLT) was observed at level 1 (n=3), 2 (n=4), and 3 (n=4), but at level 4 (n=2), 2 patients experienced DLT; grade 3 easy fatigue and anorexia required treatment delay over 7 days. Level 3 was therefore determined as RD. A phase II study is ongoing to evaluate the efficacy of mFOLFOX 6 therapy.