Delayed Reversible Posterior Encephalopathy Syndrome Following Chemotherapy with Oxaliplatin

Reversible posterior leukoencephalopathy (RPLS), also known as posterior reversible encephalopathy syndrome, is characterized by magnetic resonance imaging (MRI) findings of reversible vasogenic subcortical edema without infarction. The clinical presentation is usually nonspecific and typically involves global encephalopathy, seizures, headache, or visual symptoms. MRI of the brain is essential to the diagnosis of RPLS. Typical findings of RPLS include high-intensity signal on T2-weighted images predominantly in the posterior lobes of the brain that is caused by subcortical white matter vasogenic edema. Fluid-attenuated inversion recovery (FLAIR) sequences on MRI improve sensitivity and detect subtle peripheral lesions. This clinical radiographic syndrome has been described in a number of medical conditions, with hypertensive encephalopathy, eclampsia, and the use of immunosuppressant drugs (most notably calcineurin inhibitors) being the most common. It has occasionally been reported with cisplatin and rarely with carboplatin. Its occurrence with oxaliplatin is very unusual. An extensive literature search including PUBMED and direct contact with the drug manufacturer yielded only 2 known case reports. Herein, we describe a case that had classic clinical and radiologic features of RPLS. We also briefly describe 2 other patients who have been described to have RPLS with oxaliplatin in the literature.     

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 following CHOP chemotherapy for diffuse large B-cell lymphoma

A 63-year-old female with stage IE diffuse large B-cell lymphomadeveloped reversible posterior leukoencephalopathy syndrome (RPLS)following CHOP chemotherapy, with typical clinical and radiologicalfindings. RPLS is a rare neurological syndrome characterised by visualdisturbances, seizures, headaches and altered conscious level which hasbeen associated with malignant hypertension, pre-eclampsia and somedrugs, including ciclosporin. It has not been previously reportedfollowing CHOP chemotherapy. Alternative treatment should be consideredfor patients who develop this rare complication.     

Computed tomography scan‐driven selection of treatment for retroperitoneal liposarcoma histologic subtypes

BACKGROUND:

Well differentiated (WD) and dedifferentiated (DD) retroperitoneal liposarcoma (RPLS) have distinct biologic behaviors. Consequently, the therapeutic approaches for these tumors differ and mandate an accurate preoperative diagnosis. The authors of this report evaluated whether computed tomography (CT) can be used to differentiate between WD and DD RPLS.

METHODS:

Imaging studies (CT, magnetic resonance imaging, and positron emission tomography‐CT) from 78 patients with RPLS who underwent surgery at the University of Texas M. D. Anderson Cancer Center (UTMDACC) between 2001 and 2007 were reviewed by a senior bone and soft tissue sarcoma radiologist who was blinded to the final histopathologic diagnosis. A focal nodular/water density area within an RPLS was interpreted as a marker suggestive of DD. Correlations between imaging diagnosis, histology, and clinical outcome were analyzed.

RESULTS:

The study radiologist identified 60 RPLS as DD and 17 RPLS as WD. A radiologic diagnosis of a WD was correlated with preoperative biopsy and postoperative histology in all patients (100%). Focal nodular/water density was a very sensitive marker of DD (97.8%); however, it had relatively low specificity (51.5%). Sixteen WD RPLS (48.5%) contained focal nodular/water density areas, leading to their misdiagnosis as DD; half of those tumors had hypercellular WD. Of 78 preoperative biopsies, 22 (28.2%) were performed at UTMDACC under CT guidance. Preoperative histologic diagnoses obtained from 12 biopsies derived from focal nodular/water density areas were confirmed as unchanged on final pathology; whereas, in 50% of biopsies that were not taken from a suspicious area, DD histology was misdiagnosed as WD.

CONCLUSIONS:

When CT features are suggestive of WD, no further diagnostic tests are needed for tumor characterization. Moreover, CT can accurately identify most DD, thereby rendering their under‐treatment unlikely; however, a CT‐guided biopsy is needed to differentiate between DD and WD RPLS that contain focal nodular/water density areas, thereby avoiding their over treatment. Cancer 2009. © 2009 American Cancer Society.     

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.     

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.     

Posterior Reversible Leukoencephalopathy Syndrome Associated with Pazopanib

A 62-year-old female patient with metastatic renal cell carcinoma under third-line treatment with pazopanib for 8 weeks suddenly developed severe headaches, grand mal seizures and paresis of the left arm in combination with gait instability as well as nausea and vomiting during her vacation abroad. The emergency physician measured systolic blood pressure values over 300 mm Hg and suspected a stroke. The CT imaging without contrast agent in a local hospital did not show any pathologic findings despite bone metastases. The colleagues suspected cerebral metastases or meningeosis carcinomatosa and referred the patient to our department for further diagnostics and treatment planning. An MRI scan ruled out the suspected cerebral metastases or meningeosis carcinomatosa, but showed signs of reversible posterior leukoencephalopathy syndrome (RPLS) in the form of band-like hyperintensities as a sign of cytotoxic edema in the gray and white matter of the left parietal lobe. The patient then reported that similar blood pressure values had been measured shortly after the start of a first-line therapy with sunitinib, so that we discontinued the current treatment with pazopanib. Within 6 days the neurologic symptoms vanished and the patient was discharged. An intermittent hypertension persisted. A follow-up MRI 3 weeks later showed an RPLS-typical cortical infarction in the affected area. RPLS should be considered as the actual reason for neurologic findings in hypertensive patients with known metastatic cancers under tyrosine kinase inhibitor therapy.Key words: Hypertension, Pazopanib, Posterior reversible encephalopathy syndrome, Reversible posterior leukoencephalopathy syndrome, Tyrosine kinase inhibitors     

A phase II multicentre study of ziv-aflibercept in combination with cisplatin and pemetrexed in patients with previously untreated advanced/metastatic non-squamous non-small cell lung cancer

Background:

This study evaluated the efficacy and safety of ziv-aflibercept in combination with cisplatin and pemetrexed in non-small cell lung cancer (NSCLC).

Methods:

This single arm, multicentre phase II trial enrolled patients with previously untreated, locally advanced or metastatic non-squamous NSCLC. Patients received intravenous ziv-aflibercept 6 mg kg⁻¹, pemetrexed 500 mg m⁻², and cisplatin 75 mg m⁻², every 21 days for up to six cycles. Maintenance administration of ziv-aflibercept was to continue until disease progression, intolerable toxicity or other cause for withdrawal. The co-primary end points were objective response rate (ORR) and progression-free survival (PFS). Planned sample size was 72 patients.

Results:

The study was closed prematurely because of three confirmed and two suspected cases of reversible posterior leukoencephalopathy syndrome (RPLS). A total of 42 patients were enrolled. Median age was 61.5 years; 55% were male, 86% Caucasian and 50% had Eastern Cooperative Oncology Group performance status (ECOG PS)=0. A median of four cycles of ziv-aflibercept was administered. The most common treatment-emergent adverse events (TEAEs) of any grade were nausea (69%) and fatigue (67%), with hypertension (36%) as the most common grade 3/4 TEAE. Of the 38 evaluable patients, ORR was 26% and median PFS was 5 months.

Conclusion:

Cases of RPLS had been observed in other studies in the ziv-aflibercept clinical development programme but the rate observed in this study was higher than previously observed. This might be related to declining renal function and/or hypertension. Although ORR and PFS were in accordance with most historical first-line NSCLC studies, this combination of ziv-aflibercept/cisplatin/pemetrexed will not be further explored in NSCLC.     

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.     

急性淋巴细胞白血病化疗后可逆性后部白质脑病综合征一例并文献复习

目的 探讨急性淋巴细胞白血病巩固化疗后可逆性后部白质脑病综合征(RPLS)的临床表现、诊治及其预后情况.方法 回顾分析1例急性淋巴细胞白血病患者的临床及影像学资料并结合文献进行复习.结果 该患者主要临床表现为腹胀、反复发热,伴乏力症状,经血常规及骨髓相关检查,诊断为早前B细胞性高危组急性淋巴细胞白血病,经诱导缓解化疗及巩固化疗后患者出现血压增高及神经系统症状,结合影像学检查诊断为RPLS,经积极治疗后完全恢复,影像学表现迅速改善.结论 RPLS可由多种病因产生,临床表现及影像学检查缺乏特异性,一般预后较好,早期作出正确诊治是关键.     

A phase I dose-escalation study of aflibercept administered in combination with pemetrexed and cisplatin in patients with advanced solid tumours

Background:

To evaluate the safety, pharmacokinetics (PKs), and pharmacodynamics of aflibercept, and to identify the recommended phase II dose (RP2D) of aflibercept in combination with pemetrexed and cisplatin.

Methods:

Aflibercept was administered at escalating doses of 2, 4, or 6 mg kg⁻¹ in combination with fixed doses of pemetrexed (500 mg m⁻²) plus cisplatin (75 mg m⁻²) every 3 weeks. Blood samples were collected for PK analyses. Serum antiaflibercept antibodies were quantified to assess their impact on systemic aflibercept concentrations.

Results:

Eighteen patients were enrolled. One patient dosed at 4 mg kg⁻¹ experienced grade 3 hypophosphatemia (dose-limiting toxicity; DLT), which prompted a cohort expansion. No further DLTs were observed in the 4 mg kg⁻¹ cohort or the 6 mg kg⁻¹ dose cohort. Most common adverse events (AEs) of all grades included (%): fatigue (89), anaemia (89), nausea (83), hyponatremia (78), and neutropenia (72). Grade ⩾3 AEs consistent with anti-vascular endothelial growth factor therapy included (%): hypertension (22), pulmonary embolism (11), and deep vein thrombosis (6). Five patients (28%) experienced mild neurocognitive disturbance. No episodes of reversible posterior leukoencephalopathy syndrome (RPLS) were noted.

Conclusion:

The results of this phase I study allowed further evaluation of the combination of aflibercept with pemetrexed and cisplatin in a phase II study. The RP2D of aflibercept was 6 mg kg⁻¹, to be administered intravenously every 3 weeks in combination with pemetrexed and cisplatin.     

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.     

Leukoencephalopathy after whole‐brain radiation therapy plus radiosurgery versus radiosurgery alone for metastatic lung cancer

BACKGROUND:

As systemic therapies improve and patients live longer, concerns mount about the toxicity of whole‐brain radiation therapy (WBRT) for treatment of brain metastases. Development of delayed white matter abnormalities indicative of leukoencephalopathy have been correlated with cognitive dysfunction. This study assesses the risk of imaging‐defined leukoencephalopathy in patients whose management included WBRT in addition to stereotactic radiosurgery (SRS). This risk is compared to patients who only underwent SRS.

METHODS:

We retrospectively compared 37 patients with non–small cell lung cancer who underwent WBRT plus SRS to 31 patients who underwent only SRS. All patients survived at least 1 year after treatment. We graded the development of delayed white matter changes on magnetic resonance imaging using a scale to evaluate T₂/FLAIR (fluid attenuated image recovery) images: grade 1 = little or no white matter hyperintensity; grade 2 = limited periventricular hyperintensity; and grade 3 = diffuse white matter hyperintensity.

RESULTS:

Patients treated with WBRT and SRS had a significantly greater incidence of delayed white matter leukoencephalopathy compared to patients who underwent SRS alone (P < .001). On final imaging, 36 of 37 patients (97.3%) treated by WBRT developed leukoencephalopathy (25% with grade 2; 70.8% with grade 3). Only 1 patient treated with SRS alone developed leukoencephalopathy.

CONCLUSIONS:

Risk of leukoencephalopathy in patients treated with SRS alone for brain metastases was significantly lower than that for patients treated with WBRT plus SRS. A prospective study is necessary to correlate these findings with neurocognition and quality of life. These data supplement existing reports regarding the differential effects of WBRT and SRS on normal brain structure and function. Cancer 2013. © 2012 American Cancer Society.     

Human papillomavirus detection in moroccan patients with nasopharyngeal carcinoma

Background  

Nasopharyngeal carcinoma (NPC) is a malignant tumor which arises in surface epithelium of the posterior wall of the nasopharynx. There's is evidence that Epstein Barr virus (EBV) is associated to NPC development. However, many epidemiologic studies point to a connection between viral infections by the human papillomavirus (HPV) and NPC.     

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.     

Role of bursectomy for advanced gastric cancer: Result of a case–control study from a large volume hospital

Aims

According to the recent Japanese Gastric Cancer Association's gastric cancer treatment guidelines, bursectomy is recommended for tumors penetrating the serosa of the posterior gastric wall. However, there is still little data to show whether bursectomy improves patient survival. The aim of this study is to evaluate the efficacy of bursectomy for subserosa or serosa-positive gastric cancer in terms of overall survival.

Method

From April 2001 to December 2006, 470 patients underwent curative resection for macroscopically subserosa or serosa-positive gastric cancer. These patients were grouped according to whether bursectomy was performed or not (bursectomy+/bursectomy−). Clinicopathological characteristics and incidence of complications were compared between the groups. The overall survival rates were analyzed using a Cox proportional hazards model.

Results

There was no significant difference in morbidity and mortality between the bursectomy+ and bursectomy− groups. In the multivariable analysis for overall survival, bursectomy was not a significant independent factor (p = 0.978). In the subgroup analysis for clinical and pathological stage III and IV, and tumors penetrating the serosa of the posterior gastric wall, bursectomy did not have significant effect on overall survival as well (p = 0.582, 0.453, and 0.532, respectively). In the propensity score-matched patients, bursectomy still showed no significant effect on overall survival (p = 0.804).

Conclusions

Bursectomy is unlikely to improve overall survival in patients with macroscopically subserosa or serosa-positive gastric cancer.     

Intensity modulated radiation-therapy for preoperative posterior abdominal wall irradiation of retroperitoneal liposarcomas

PURPOSE: Preoperative external-beam radiation therapy (preop RT) in the management of Retroperitoneal Liposarcomas (RPLS) typically involves the delivery of radiation to the entire tumor mass: yet this may not be necessary. The purpose of this study is to evaluate a new strategy of preop RT for RPLS in which the target volume is limited to the contact area between the tumoral mass and the posterior abdominal wall. METHODS AND MATERIALS: Between June 2000 and Jan 2005, 18 patients with the diagnosis of RPLS have been treated following a pilot protocol of pre-op RT, 50 Gy in 25 fractions of 2 Gy/day. The Clinical Target Volume (CTV) has been limited to the posterior abdominal wall, region at higher risk for local relapse. A Three-Dimensional conformal (3D-CRT) and an Intensity Modulated (IMRT) plan were generated and compared; toxicity was reported following the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events v3.0. RESULTS: All patients completed the planned treatment and the acute toxicity was tolerable: 2 patients experienced Grade 3 and 1 Grade 2 anorexia while 2 patients developed Grade 2 nausea. IMRT allows a better sparing of the ipsilateral and the contralateral kidney. All tumors were successfully resected without major complications. At a median follow-up of 27 months 2 patients developed a local relapse and 1 lung metastasis. CONCLUSIONS: Our strategy of preop RT is feasible and well tolerated: the rate of resectability is not compromised by limiting the preop CTV to the posterior abdominal wall and a better critical-structures sparing is obtained with IMRT.     

Parental occupational exposure to exhausts,solvents, glues and paints,and risk of childhood leukemia

Purpose  

It is unknown whether parental occupational exposure to chemicals before during and after pregnancy increases the risk of acute lymphoblastic leukemia (ALL) in the offspring. Few studies on this topic have assessed maternal exposures.     

Relationship between survivorship care plans and unmet information needs,quality of life,satisfaction with care,and propensity to engage with,and attend,follow-up care

Background

The impact of survivorship care plans (SCPs) on the proximal and distal outcomes of adult and childhood cancer survivors, and parent proxies, is unclear. This study aimed to determine the relationship between SCP receipt and these outcomes.

Methods

A cross-sectional survey of adult and childhood cancer survivors (and parent proxies for survivors aged younger than 16 years) across Australia and New Zealand was conducted. Multivariate regression models were fitted to measure the impact of SCP receipt on proximal (unmet information needs and propensity to engage with, and attend, cancer-related follow-up care) and distal outcomes (quality of life and satisfaction with cancer-related follow-up care) with control for cancer history and sociodemographic factors.

Results

Of 1123 respondents, 499 were adult cancer survivors and 624 were childhood cancer survivors (including 222 parent proxies). We found that SCP receipt was predictive of greater attendance at, and awareness of, cancer-related follow-up care (adult: odds ratio [OR], 2.46; 95% CI, 1.18–5.12; OR, 2.38; 95% CI, 1.07–5.29; child/parent: OR, 2.61; 95% CI, 1.63–4.17; OR, 1.63; 95% CI, 1.06–2.50; respectively). SCP receipt also predicted fewer unmet information needs related to “follow-up care required” and “possible late effects” (adult: OR, 0.44; 95% CI, 0.20–0.96; OR, 0.29; 95% CI, 0.13–0.64; child/parent: OR, 0.46; 95% CI, 0.30–0.72; OR, 0.57; 95% CI, 0.38–0.85; respectively). In terms of distal outcomes, SCP receipt predicted a better global quality of life for adult cancer survivors (β, 0.08; 95% CI, −0.01–7.93), proxy-reported health-related quality of life (β, 0.15; 95% CI, 0.44–7.12), and satisfaction with follow-up care for childhood cancer survivors (OR, 2.93; 95% CI, 1.64–5.23).

Conclusions

Previous studies have shown little impact of SCPs on distal end points. Results suggest that SCPs may be beneficial to cancer survivors’ proximal and distal outcomes.