Posterior Reversible Encephalopathy Syndrome in Patients With Cancer

Background.

Posterior reversible encephalopathy syndrome (PRES) is characterized by neurologic symptoms with typical lesions on neuroimaging and may be associated with chemotherapy and immunosuppressive agents used in patients with cancer. We described the spectrum of PRES at a major cancer center.

Methods.

We reviewed charts of adults with PRES between 2005 and 2011 at Memorial Sloan Kettering Cancer Center for clinical information and outcome.

Results.

We identified 21 women (68%) and 10 men (median cohort age: 58 years). Solid tumors (n = 22, 71%) were more common than hematologic (n = 8) or primary brain malignancies (n = 1). Prior brain irradiation (16%) and central nervous system metastases (10%) were uncommon. There were 55% who received chemotherapy or targeted therapy within the month preceding PRES, including 6 patients who received bevacizumab; PRES followed allogeneic stem cell transplantation in 5 (16%). Presenting symptoms included confusion (71%), seizure (58%), and headache (48%). Maximum systolic and diastolic blood pressures were similar among patients grouped by cancer type, chemotherapy or bevacizumab use, and atypical imaging. Moreover, 37% of patients with both magnetic resonance imaging (MRI) and computed tomography (CT) had normal CT concurrent with PRES on MRI, and 84% returned to neurologic baseline at a median of 7.5 days (range: 1–167 days) from onset. Successful anticonvulsant taper was achieved in 51%. Chemotherapy rechallenge was attempted in 41% without recurrent PRES. Autopsy revealed nonspecific changes isolated to radiographically affected areas in one of two patients.

Conclusion.

Recent chemotherapy, particularly bevacizumab, is common in cancer patients with PRES. Clinical and radiographic presentations may vary; MRI appears more sensitive than CT. Anticonvulsant taper and chemotherapy rechallenge is often possible.

Implications for Practice:

Posterior reversible encephalopathy syndrome is characterized by neurologic symptoms with typical lesions on neuroimaging and may be associated with chemotherapy and immunosuppressive agents used in patients with cancer. Clinical and radiographic presentations are protean, and magnetic resonance imaging is more sensitive than computed tomography. Recovery is common, and many patients can be successfully rechallenged with the apparently offending chemotherapy agent or regimen.     

Posterior Reversible Encephalopathy Syndrome: A Neurologic Phenomenon in Cancer Patients

Posterior reversible encephalopathy syndrome is a well-recognized entity associated with a variety of benign and malignant conditions. This syndrome typically manifests itself with headache, visual loss, and seizures. Radiographic abnormalities consist of white matter edema involving the posterior parietal and occipital lobes, manifested as increased T2 and fluid-attenuated inversion recovery signal intensity on magnetic resonance imaging. In the last decade, there has been a reported increase in the incidence of posterior reversible encephalopathy syndrome in cancer patients. The diagnosis can be challenging in this patient population. Early recognition and initiation of appropriate therapy with removal of the causative agent is essential in order to prevent permanent neurologic sequelae.     

Management of the Elderly Patients with High-Grade Serous Ovarian Cancer in the REAL-WORLD Setting

Treatment of elderly patients with neoplasia is challenging. Age is a known prognostic factor in ovarian cancer but the optimal treatment of elderly patients has not been determined. We undertook a retrospective analysis to determine clinical practice in advanced-stage ovarian cancer patients older than 70 years of age. Methods: Medical records of women with high-grade serous ovarian cancer, stage III and IV were retrospectively analyzed. Results: A total of 735 patients were identified with a median age of 61.5 years. 22.4% among them were older than 70 years of age at diagnosis. First-line Progression-Free Survival (PFS) and Overall Survival (OS) were significantly worse in elderly patients in comparison to the younger ones [mPFS 11.3 months vs. 14.8 months, (p < 0.001) and mOS 30.2 months vs. 45.6 months (p < 0.001)]. However, elderly patients were characterized by worse ECOG-Performance Status and they were more frequently treated with Neoadjuvant Chemotherapy followed by Interval Debulking Surgery, while often they were more frequently denied debulking surgery compared to patients under 70 years of age. Moreover, elderly patients received more frequently monotherapy with platinum as frontline treatment. In contrast, there was no significant difference in the outcome of the debulking surgery in comparison to the younger patients or the frequency that gBRCA test was performed. Age over 70 years did not retain its significance for either Progression-Free Survival or Overall Survival when adjusted for all other reported prognostic factors. Conclusions: Elderly ovarian cancer patients have a worse prognosis. Comprehensive geriatric assessment should be performed for the optimal treatment of these patients.     

Economic Evaluation of Adding Bevacizumab to Chemotherapy for Metastatic Colorectal Cancer (mCRC) Patients in Indonesia

Objective: Since 2016, bevacizumab has been widely used to treat metastatic colorectal cancer (mCRC) in Indonesia. Nevertheless, the high cost of bevacizumab has raised the question of whether the therapy is considered cost-effective and should be included in the national health insurance system. This study aimed to assess the cost-effectiveness of bevacizumab plus chemotherapy versus chemotherapy alone for the treatment of mCRC patients. Methods: A Markov model was applied using the perspective of the Indonesian healthcare system to assess cost-effectiveness. The health outcomes were expressed in terms of quality-adjusted life years (QALY) using the validated EuroQoL-5D-5L instrument. Data for medical costs were collected from hospital billings in four hospitals located in three different cities in Indonesia. Meanwhile, data for utility were obtained from interviewing 90 patients who came to the hospital. We compared those mCRC patients who received chemotherapy alone either with FOLFOX or FOLFIRI, versus patients who received the addition of bevacizumab. Results: With the perspective of societal, the incremental cost-effectiveness ratio (ICER) of adding bevacizumab was USD 49,312 per QALY gained using secondary data and USD 28,446 per QALY using real world data. Conclusion: Using either a healthcare or societal perspective, the addition of bevacizumab for mCRC treatment was considered not cost-effective.     

Long-Term Complete Remission with nab-Paclitaxel,Bevacizumab, and Gemcitabine Combination Therapy in a Patient with Triple-Negative Metastatic Breast Cancer

This is a case study of a 52-year-old female patient diagnosed in June 2007 with primary metastatic invasive ductal carcinoma of the left breast and synchronous metastases in the bone, lymph nodes, and lung. Biopsy results of the tumor tissue were negative for the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2). In November 2007, she participated in a phase II study of metastatic HER2-negative breast cancer. Treatment consisted of systemic chemotherapy with gemcitabine 1,500 mg/m², nab-paclitaxel 150 mg/m², and bevacizumab 10 mg/kg once every other week. The patient experienced pain relief in her sternum after 5 weeks of chemotherapy, and her analgesic therapy was discontinued. After 7 months, the patient achieved a complete radiographic response, which was maintained for nearly 2 additional years. She continued receiving treatment throughout this period, requiring 1 dose reduction due to fatigue. The patient experienced no other adverse events, including neuropathy, and continued working uninterrupted throughout her treatment. The patient was discontinued from the study in May 2010 after disease progression, almost a full 3 years after diagnosis. The patient showed minimal response to subsequent therapies but had disease stabilization and died from her disease in April 2012. Median overall survival for patients with metastatic triple-negative breast cancer is between 12 and 13.3 months. This patient survived nearly 5 years following diagnosis. This case exemplifies how therapy with nab-paclitaxel, bevacizumab, and gemcitabine may prolong survival, with minimal toxicity, in select patients with triple-negative metastatic breast cancer.Key words: Triple-negative breast cancer, Metastatic breast cancer, HER2 negative, nab-paclitaxel, Long-term response     

The imaging and neuropathological effects of Bevacizumab (Avastin) in patients with leptomeningeal carcinomatosis

Bevacizumab (Avastin, Genetech/Roche) is an anti-angiogenic drug approved for treating patients with malignant gliomas that reduces edema and mass effect, but has been suggested to promote multifocal tumor spread within the brain. Patients with systemic malignancies are also treated with bevacizumab, but there is limited information regarding effects of the drug on the neuroimaging or neuropathological features of metastatic CNS disease. We report 2 patients with non-small cell lung carcinomas who had received bevacizumab for their systemic cancers and then developed cognitive deficits consistent with white matter dementia. Diagnosis of leptomeningeal carcinomatosis (LC) was confounded and delayed by the finding of atypical neuroimaging features, including minimal to absent leptomeningeal enhancement and unusual perivascular and punctate hemorrhagic lesions and multifocal subgyral signal abnormalities suspicious for vasculitis or small vessel vasculopathy. Neuropathological assessment confirmed LC but, in the autopsy case also disclosed extraordinary perivascular spread of individual metastatic tumor cells to the depth of capillaries. The pattern was reminiscent of vascular “cooption” by tumor seen in experimental animals in preclinical trials of bevacizumab. Small infarctions were associated with perivascular tumor and vasculopathy, unusual features of LC in patients who do not receive bevacizumab. In the biopsied patient, multiple perivascular tumor nodules were identified in superficial cortex. In these two patients, bevacizumab appeared to alter neuroimaging characteristics of LC, confounded diagnosis and possibly also influenced the pattern of tumor spread of LC. More cases will need to be studied to confirm this latter finding.     

Clinical and Regulatory Considerations for the Use of Bevacizumab Biosimilars in Metastatic Colorectal Cancer

Biosimilars – biological medicines highly similar to a licensed reference product (RP) – can mitigate the risk of drug shortages by providing treatment alternatives and, with their lower costs, increase patient access to medication and reduce health care expenditure. However, limited knowledge of biosimilar approval processes and lack of confidence in their quality and efficacy can limit their uptake. Importantly, biosimilars are approved based on tightly controlled regulatory pathways to demonstrate that the physical, chemical, and biological properties of the proposed biosimilar are highly similar to the RP, with no clinically meaningful differences. Initially, a battery of highly sensitive in vitro studies are performed, comparing critical quality attributes between the proposed biosimilar and RP. Subsequently, in vivo pharmacodynamic studies compare the activity and physiologic effects of the biosimilar and RP. Finally, clinical studies are conducted, including a pharmacokinetic equivalence study and a confirmatory comparative clinical trial. The latter is performed in the most sensitive patient population for which the RP is licensed, to provide the greatest possibility of identifying any clinically meaningful differences between the proposed biosimilar and RP. When equivalent safety and efficacy have been demonstrated in one setting, the totality of evidence, together with scientific justification that there are no anticipated differences between the RP and proposed biosimilar in mechanism of action, pharmacokinetics, immunogenicity or toxicity, allows extrapolation into indications where clinical studies were not performed with the proposed biosimilar. Here, we review the approval process for biosimilars, focusing on the licensing of bevacizumab biosimilars and their extrapolation to metastatic colorectal cancer.     

Stratification of Length of Stay Prediction following Surgical Cytoreduction in Advanced High-Grade Serous Ovarian Cancer Patients Using Artificial Intelligence; the Leeds L-AI-OS Score

(1) Background: Length of stay (LOS) has been suggested as a marker of the effectiveness of short-term care. Artificial Intelligence (AI) technologies could help monitor hospital stays. We developed an AI-based novel predictive LOS score for advanced-stage high-grade serous ovarian cancer (HGSOC) patients following cytoreductive surgery and refined factors significantly affecting LOS. (2) Methods: Machine learning and deep learning methods using artificial neural networks (ANN) were used together with conventional logistic regression to predict continuous and binary LOS outcomes for HGSOC patients. The models were evaluated in a post-hoc internal validation set and a Graphical User Interface (GUI) was developed to demonstrate the clinical feasibility of sophisticated LOS predictions. (3) Results: For binary LOS predictions at differential time points, the accuracy ranged between 70–98%. Feature selection identified surgical complexity, pre-surgery albumin, blood loss, operative time, bowel resection with stoma formation, and severe postoperative complications (CD3–5) as independent LOS predictors. For the GUI numerical LOS score, the ANN model was a good estimator for the standard deviation of the LOS distribution by ± two days. (4) Conclusions: We demonstrated the development and application of both quantitative and qualitative AI models to predict LOS in advanced-stage EOC patients following their cytoreduction. Accurate identification of potentially modifiable factors delaying hospital discharge can further inform services performing root cause analysis of LOS.     

Long-Term Relapse-Free Survival by Interdisciplinary Collaboration in a Patient with Metastatic Pancreatic Cancer (UICC IV)

Introduction

The prognostic outlook for patients suffering from pancreatic cancer is generally poor. Particularly in cases of advanced and metastatic disease, long-term relapse-free survival may be achieved only in a few cases.

Case Report

A 45-year-old patient presented with metastatic pancreatic cancer. Liver metastases had been intra-operatively confirmed by histology. Prior to initiating treatment, a portacath was surgically implanted. Subsequently, the patient received a weekly dose of 1,000 mg/m² gemcitabine combined with 2,000 mg/m² high-dose 5-fluorouracil as a 24-hour infusion for palliative treatment. As the patient was suffering from a stenosis of the ductus hepaticus communis, an endoprosthesis was primarily implanted. After 18 applications of chemotherapy during which only low toxic side effects such as nausea, vomiting and alopecia (NCI-CTC grade 1) presented, a partial remission of the primary tumor was observed. In the course of chemotherapy treatment, the carbohydrate antigen 19-9 tumor marker value normalized. Thus, the interdisciplinary tumor board of the University of Erlangen decided to perform a laparoscopy to evaluate the status of liver metastases after palliative chemotherapy treatment. Subsequently, the primary tumor could be completely resected (pT2, pN0, pM0, L0, V0, G2, R0); liver metastases were not observed. Eight years after the initial diagnosis, the patient is relapse-free, professionally fully integrated and presents with an excellent performance status.

Conclusion

Patients suffering from metastatic pancreatic cancer may benefit from treatment combinations with palliative intent. In singular cases, patients may even have a curative treatment option, provided a close interdisciplinary collaboration exists.Key words: Pancreatic cancer, Chemotherapy with palliative intent, Gemcitabine, Weekly high-dose 5-FU as a 24-hour infusion     

Perturbation of Rb, p53, and Brca1 or Brca2 Cooperate in Inducing Metastatic Serous Epithelial Ovarian Cancer

The majority of human high-grade serous epithelial ovarian cancer (SEOC) is characterized by frequent mutations in p53 and alterations in the RB and FOXM1 pathways. A subset of human SEOC harbors a combination of germline and somatic mutations as well as epigenetic dysfunction for BRCA1/2. Using Cre-conditional alleles and intrabursal induction by Cre-expressing adenovirus in genetically engineered mice, we analyzed the roles of pathway perturbations in epithelial ovarian cancer initiation and progression. Inactivation of RB-mediated tumor suppression induced surface epithelial proliferation with progression to stage I carcinoma. Additional biallelic inactivation and/or missense p53 mutation in the presence or absence of Brca1/2 caused progression to stage IV disease. As in human SEOC, mice developed peritoneal carcinomatosis, ascites, and distant metastases. Unbiased gene expression and metabolomic profiling confirmed that Rb, p53, and Brca1/2-triple mutant tumors aligned with human SEOC, and not with other intraperitoneal cancers. Together, our findings provide a novel resource for evaluating disease etiology and biomarkers, therapeutic evaluation, and improved imaging strategies in epithelial ovarian cancer. Cancer Res; 72(16); 4141-53. ?2012 AACR.