Brain Malignancy in Adults (PDF) A Review 2023

Clinical Review & Education JAMA | Review Glioblastoma and Other Primary Brain Malignancies in Adults A Review Lauren R. Schaff, MD; Ingo K. Mellinghoff, MD Multimedia IMPORTANCE Malignant primary brain tumors cause more than 15 000 deaths per year in the United States. The annual incidence of prima...

Clinical Review & Education JAMA | Review Glioblastoma and Other Primary Brain Malignancies in Adults A Review Lauren R. Schaff, MD; Ingo K. Mellinghoff, MD Multimedia IMPORTANCE Malignant primary brain tumors cause more than 15 000 deaths per year in the United States. The annual incidence of primary malignant brain tumors is approximately 7 per 100 000 individuals and increases with age. Five-year survival is approximately 36%. OBSERVATIONS Approximately 49% of malignant brain tumors are glioblastomas, and 30% are diffusely infiltrating lower-grade gliomas. Other malignant brain tumors include primary central nervous system (CNS) lymphoma (7%) and malignant forms of ependymomas (3%) and meningiomas (2%). Symptoms of malignant brain tumors include headache (50%), seizures (20%-50%), neurocognitive impairment (30%-40%), and focal neurologic deficits (10%-40%). Magnetic resonance imaging before and after a gadolinium-based contrast agent is the preferred imaging modality for evaluating brain tumors. Diagnosis requires tumor biopsy with consideration of histopathological and molecular characteristics. Treatment varies by tumor type and often includes a combination of surgery, chemotherapy, and radiation. For patients with glioblastoma, the combination of temozolomide with radiotherapy improved survival when compared with radiotherapy alone (2-year survival, 27.2% vs 10.9%; 5-year survival, 9.8% vs 1.9%; hazard ratio [HR], 0.6 [95% CI, 0.5-0.7]; P <.001). In patients with anaplastic oligodendroglial tumors with 1p/19q codeletion, probable 20-year overall survival following radiotherapy without vs with the combination of procarbazine, lomustine, and vincristine was 13.6% vs 37.1% (80 patients; HR, 0.60 [95% CI, 0.35-1.03]; P =.06) in the EORTC 26951 trial and 14.9% vs 37% in the RTOG 9402 trial (125 patients; HR, 0.61 [95% CI, 0.40-0.94]; P =.02). Treatment of primary CNS lymphoma includes high-dose methotrexate-containing regimens, followed by consolidation therapy with myeloablative chemotherapy and autologous stem cell rescue, nonmyeloablative chemotherapy regimens, or whole brain radiation. CONCLUSIONS AND RELEVANCE The incidence of primary malignant brain tumors is approximately 7 per 100 000 individuals, and approximately 49% of primary malignant brain tumors are glioblastomas. Most patients die from progressive disease. First-line therapy for glioblastoma is surgery followed by radiation and the alkylating chemotherapeutic agent temozolomide. JAMA. 2023;329(7):574-587. doi:10.1001/jama.2023.0023 A pproximately 85 000 individuals in the United States are diagnosed with a primary brain tumor each year, of which approximately 29% are malignant.1 Approximately 80% to 85% of malignant brain tumors in adults are gliomas, which diffusely infiltrate the brain parenchyma. The fifth edition of the World Health Organization’s (WHO) classification of Tumors of the Central Nervous System (CNS), which provides the international standard for the classification of brain and spinal cord tumors, refers to this group of tumors as adulttype diffuse gliomas.2 The incidence of glioblastoma, the most common malignant primary brain tumor in adults, increases after the age of 40 and peaks in adults aged 75 to 84 years.1,3 Lowergrade diffuse gliomas usually affect patients younger than 50 years of age and are further subclassified into astrocytomas and oligodendrogliomas.4,5 574 Author Affiliations: Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York (Schaff, Mellinghoff); Department of Neurology, Weill Cornell Medicine, New York, New York (Schaff, Mellinghoff); Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York (Mellinghoff); Department of Pharmacology, Weill Cornell Medicine, New York, New York (Mellinghoff). Corresponding Author: Ingo K. Mellinghoff, MD, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 ([email protected]). Section Editor: Mary McGrae McDermott, MD, Deputy Editor. Less common malignant brain tumors in adults include primary central nervous system lymphoma (PCNSL) and malignant forms of meningiomas, ependymomas, and other rare brain tumor types.1 PCNSL is a rare variant of non-Hodgkin lymphoma that presents in the brain, eyes, or leptomeningeal space without evidence of extracranial disease. The incidence of PCNSL is approximately 0.5 per 100 000 individuals, and the incidence is increasing in patients older than 60 years.6,7 Approximately 5% of meningiomas, the most common primary CNS tumor in adults, are WHO grade 2 (atypical), and 1% to 2% are WHO grade 3 (malignant/anaplastic).1,8 Ependymomas are rare CNS tumors that arise in the supratentorial brain, posterior fossa, and spine. The incidence is approximately 0.2 to 0.4 per 100 000 individuals, and as a proportion of all primary brain cancers, they are more common in children. Ependymomas are classified according to a combination of histopathological and JAMA February 21, 2023 Volume 329, Number 7 (Reprinted) © 2023 American Medical Association. All rights reserved. Downloaded from jamanetwork.com by University of British Columbia user on 02/23/2024 jama.com Glioblastoma and Other Primary Brain Malignancies in Adults Review Clinical Review & Education molecular features as well as anatomic site and range in growth speed from benign to malignant.1,9 This review summarizes current evidence regarding diagnosis and treatment of primary malignant brain tumors in adults. Box. Commonly Asked Questions When Should a Headache Prompt Evaluation for Brain Tumor? Headaches with the following associated symptoms are concerning for the possibility of a brain tumor and warrant prompt evaluation. These symptoms include acute, severe headaches that represent a change from prior headache pattern, new headaches in older adults or children, headaches that are positional or worsen with exertion, and headaches associated with any new neurologic symptoms. Methods Two literature searches of PubMed, restricted to English-language articles published within the last 10 years, were performed on June 11, 2022, and updated on December 10, 2022, using the following MeSH terms: glioma, glioblastoma, malignant meningioma, and primary CNS lymphoma. Articles with the MeSH term pediatric were excluded. The search, which retrieved 3592 articles, was limited to clinical trials, meta-analyses, and systematic reviews. This review includes 110 articles of which 48 were clinical trials and 19 were metaanalyses or reviews. The remaining 43 articles were identified by the authors based on their knowledge of literature before 2012 and from review of citations in retrieved articles: 14 retrospective studies, 11 guideline or consensus papers, 8 original research studies, 4 epidemiologic studies, 3 case-control studies, 2 prospective cohort studies, and 1 editorial. What Causes Brain Tumors? Exposure to ionizing radiation, such as from prior treatment for another cancer, is the only known environmental risk factor for brain tumor development. Immunodeficiency is a risk factor for the development of primary central nervous system lymphoma. There is no clear link between brain tumor development and power lines, electronic devices, or cellular telephone use. Most brain tumors are not hereditary. What Is the Prognosis of a Malignant Primary Brain Tumor? Most malignant brain tumors are not curable, and the goal of treatment is disease control and symptom management. Prognosis varies based on histology, grade, and molecular markers. Glioblastoma has the worst prognosis with overall survival of approximately 15 months. Lower-grade gliomas, particularly oligodendrogliomas with 1p/19q codeletion, may be controlled for decades. Discussion and Observations Epidemiology Less than 5% of adults with a malignant brain tumor report a family history of brain tumors or have a cancer predisposition syndrome.10,11 However, the contribution of heritability to brain tumor formation is likely higher, based on germline sequencing12 and analysis using GCTA (Genome-wide Complex Trait Analysis).13 Prior exposure to ionizing radiation to the CNS, usually during treatment for another cancer such as childhood leukemia, is a risk factor for brain tumors (Box).14 Exposure to low-frequency electromagnetic fields is not an established risk factor.15 There is not high-quality evidence demonstrating an association between cellular telephone use and brain tumor formation.11,16 An update to the UK Million Women Study, a prospective study of 776 156 women, reported adjusted relative risks (RR) for ever vs never cellular telephone use of 0.97 (95% CI, 0.901.04) for all brain tumors; there was no increased risk for glioma, meningioma, pituitary tumors, or acoustic neuroma.17 In an international case-control study of 4533 glioma patients and 4171 controls, a history of respiratory allergies (meta-analysis odds ratio [OR], 0.72 [95% CI, 0.58-0.90]), asthma (meta-analysis OR, 0.77 [95% CI, 0.640.93]), or eczema (meta-analysis OR, 0.71 [95% CI, 0.56-0.89]) was associated with a statistically significant lower risk of glioma.18 Those with glioma (229 patients) are also less likely than controls (289 patients) to report a history of varicella virus (adjusted OR, 0.59 [95% CI, 0.40-0.86]) and have lower levels of immunoglobulin G to varicella virus.19 Immunodeficiency, including HIV/AIDS, is a risk factor for the development of PCNSL.20 Clinical Presentation Headache occurs in nearly 50% of patients with a newly diagnosed brain tumor.21 Patients with rapidly growing tumors may develop increased intracranial pressure and present with nausea, vomiting, or fatigue. Physical examination may reveal papill- edema. Transient increases in intracranial pressure can cause episodic loss of consciousness (plateau waves) and may be mistaken for seizures. Patients may develop focal neurologic deficits related to the location of the tumor (Figure 1). For example, tumors affecting the frontal lobes (24%)1,22 may cause lack of initiative and difficulties with processing information and responding appropriately to the environment. Tumors in the dominant hemisphere may present with speech difficulty while nondominant tumors may have more subtle symptoms of spatial distortion and constructional apraxia. Anosognosia, defined as inability to recognize one’s deficits, may contribute to delayed symptom reporting. Cranial neuropathies due to leptomeningeal dissemination of disease or increased intracranial pressure can present with ocular palsies, hearing loss, or dysphagia. Symptoms may arise over weeks to months. As many as 74% of patients with lower-grade gliomas present with seizures,23 but tumors can be present for years before symptoms occur or can be discovered incidentally. PCNSL preferentially affects deep matter structures, and many patients (≈40%) exhibit behavioral or cognitive changes. Patients with PCNSL who have involvement of the vitreoretinal space (≈25%) may present with blurred vision or floaters. Slit lamp examination should be performed in all patients with suspected PCNSL and vitreoretinal biopsy may be diagnostic.7 Diagnosis Contrast-enhanced magnetic resonance imaging (MRI) of the brain is the imaging modality of choice when a brain tumor is suspected, ideally using a standardized brain tumor imaging protocol. 24 Glioblastomas typically show contrast-enhancement on T1-weighted sequences. T2-weighted/fluid-attenuated inversion recovery (T2/FLAIR) reveals hyperintense cerebral edema. Central necrosis jama.com (Reprinted) JAMA February 21, 2023 Volume 329, Number 7 © 2023 American Medical Association. All rights reserved. Downloaded from jamanetwork.com by University of British Columbia user on 02/23/2024 575 Clinical Review & Education Review Glioblastoma and Other Primary Brain Malignancies in Adults Figure 1. Symptoms of Malignant Brain Tumors Related to the Location of the Tumor Patients with primary brain malignancies may experience generalized symptoms such as fatigue, seizures, and signs and symptoms related to increased intracranial pressure, such as headache, nausea, vomiting, or papilledema. CORPUS CALL OS U Corpus callosum M Cognitive decline Inattention Personality change Fatigue Focal neurologic deficits related to the location of the tumor may also develop. This figure lists some of the most common focal deficits. Thalamus Sella Thalamus Bitemporal hemianopia Headaches Symptoms of hormonal deficiencies, such as unexplained weight loss or gain, alopecia, menstrual change, and sexual dysfunction Contralateral sensory deficits Aphasia Sella Parietal lobe Contralateral sensory deficits Contralateral homonymous inferior quadrantanopia PA R I E TA L LOBE Frontal lobe Contralateral motor deficits Personality change Decline in cognition and executive functioning Dominant hemisphere Left-right confusion Acalculia Agraphia Alexia 10% of tumors F R O N TA L LOBE 25% of tumors Dominant hemisphere Expressive aphasia O C C I P I TA L LOBE 3% of tumors TEMPORAL LOBE Temporal lobe 18% of tumors Disturbance of auditory perception Memory impairment Seizures Contralateral homonymous superior quadrantanopia 5% of tumors Contralateral homonymous hemianopia AI 4% Brainstem Cerebellum ors tum of NS Abnormal gait Nausea Vomiting Headache TE M Diplopia Facial droop Dysphagia Limb weakness R Nondominant hemisphere Decreased musical abilities and tonal perception Occipital lobe CEREBELLUM B Dominant hemisphere Receptive aphasia Nondominant hemisphere Poor spatial reasoning Contralateral neglect Constructional apraxia Anosognosia Ipsilateral ataxia Incoordination Nystagmus Nausea Vomiting Dizziness Highlighted in this image are signs and symptoms that are related to the location of the tumor. Percent values1 were not available for some parts of the brain and therefore do not sum to 100. and signs of local mass effect may also be present. Lower-grade gliomas are often hypointense on T1-weighted imaging and hyperintense on T2/FLAIR. PCNSL may be multifocal and demonstrate homogeneous enhancement and diffusion restriction on diffusion-weighted imaging. Meningiomas typically demonstrate homogeneous contrast enhancement and adjacent dural thickening (Figure 2). Tumor tissue is required to establish the diagnosis. Patients with imaging findings suggestive of a brain malignancy should be referred to a center with advanced neurosurgical techniques.25 Procedures are typically performed under general anesthesia, and patients are observed in the hospital for several days to monitor for surgery-related complications. Preservation of neurologic function, also referred to as maximal safe surgical resection, is a priority, and patients may undergo awake craniotomies during which repetitive neurologic assessments guide the resection. When tumor resection is not feasible, a tumor biopsy should be performed. Accurate grading of CNS tumors is important for estimating patient prognosis and requires integration of histological features and molecular abnormalities2 (Figure 3). For instance, astrocytomas with 576 mutations in the genes isocitrate dehydrogenase (IDH) 1 (Genbank accession O75874) or IDH 2 (Genbank accession P48735) and homozygous loss of the genes cyclin-dependent kinase inhibitor 2A (Genbank accession P42771) and B (Genbank accession P42772) (CDKN2A/B) are considered grade 4 even if they lack histological features of a grade 4 tumor.2 Molecular testing is also required to diagnose glioma subtypes that are characterized by specific molecular alterations, such as diffuse midline glioma H3 K27-altered or diffuse hemispheric glioma H3 G34-mutant. Molecular testing can also help select the most appropriate treatment. For example, O6methylguanine-DNA-methyltransferase (MGMT) (Genbank accession P16455) promoter methylation is characteristic of glioblastomas that are more likely to respond to alkylating agents such as temozolomide.26 Many centers are using comprehensive DNA sequencing and methylation profiling to classify brain tumors.27,28 Referral to a cancer center should be considered for detailed molecular analysis and treatment planning. Patients with CNS lymphoma require a systemic work-up to differentiate PCNSL from secondary CNS involvement. Patients with ependymomas require craniospinal MRI and cerebrospinal JAMA February 21, 2023 Volume 329, Number 7 (Reprinted) © 2023 American Medical Association. All rights reserved. Downloaded from jamanetwork.com by University of British Columbia user on 02/23/2024 jama.com Glioblastoma and Other Primary Brain Malignancies in Adults Review Clinical Review & Education Figure 2. Imaging Features of Malignant Brain Tumors Low-grade diffuse glioma Primary CNS lymphoma Malignant meningioma T2-WEIGHTED FLAIR T1 POSTCONTRAST T1 PRECONTRAST Glioblastoma Representative brain magnetic resonance images are from patients with glioblastoma, isocitrate dehydrogenase IDH-mutant low-grade glioma, primary central nervous system (CNS) lymphoma, and malignant meningioma. Images include T1-weighted pregandolinium and postgadolinium and T2-weighted/fluid-attenuated inversion recovery (FLAIR). Magenta arrow indicates mass effect (left lateral ventricle obscured). Blue arrow indicates ring enhancement reflective of central necrosis often seen in glioblastoma. Black arrow indicates homogeneous enhancement characteristic of CNS lymphoma. Yellow arrow indicates the dural attachment (dural tail) common with meningiomas. Glioblastoma and malignant meningioma panels show vasogenic edema on T2/FLAIR sequence, indicated by white arrows. fluid cytology following surgery to assess for leptomeningeal dissemination. Cerebral edema is treated with corticosteroids.32 Dexamethasone is preferred due to its low mineralocorticoid activity and long half-life. For severe neurologic symptoms, such as gait impairment or altered consciousness, a bolus of dexamethasone 10 mg may be administered followed by 16 mg per day. Mild to moderate symptoms, such as headache or sensory deficits, can be managed with dexamethasone 4 to 8 mg per day without a loading dose. Once- or twice-a-day dosing is typically sufficient.33 The lowest dose required for symptom control should be administered,32 and tapering off corticosteroids should be attempted as soon as appropriate. A slow taper (eg, dose reduction every 3-4 days) is recommended to identify the minimal steroid dose required to control neurologic symptoms and to reduce the risk of adrenal insufficiency. Patients receiving the equivalent of prednisone 20 mg daily for more than a month (ie, approximately dexamethasone 3 mg daily) Treatment of Symptoms and Complications Seizures occur in as many as 75% of patients with glioma.29 Older antiepileptic drugs, such as phenobarbital, carbamazepine, or phenytoin stimulate the synthesis of hepatic cytochrome P450 enzymes and can affect the metabolism of concomitant drugs. Nonenzyme–inducing antiepileptic agents, such as levetiracetam, lacosamide, or clobazam are preferred due to fewer drug-drug interactions and improved adverse effect profiles.30 Tumor-directed treatments may reduce the risk of seizure recurrence.31 For patients who never had a seizure, routine anticonvulsant prophylaxis is not recommended.30 The use of antiepileptic drugs perioperatively is common, but evidence for this practice is scant.30 jama.com (Reprinted) JAMA February 21, 2023 Volume 329, Number 7 © 2023 American Medical Association. All rights reserved. Downloaded from jamanetwork.com by University of British Columbia user on 02/23/2024 577 Clinical Review & Education Review Glioblastoma and Other Primary Brain Malignancies in Adults Figure 3. Integration of Histological Features and Molecular Alterations in the Revised WHO Classification of Tumors of the Central Nervous System Adult-type diffuse gliomasa IDH1- or IDH2-mutantb IDH-wild type 1p/19q Intact 1p/19q Codeletion Glioblastomac Astrocytoma, NECd Astrocytoma Oligodendroglioma Astrocytic histology Astrocytic histology Astrocytic histology Oligodendroglial histology Oval-to-elongated nucleus Eosinphilic cytoplasm Oval-to-elongated nucleus Eosinphilic cytoplasm Oval-to-elongated nucleus Eosinphilic cytoplasm Round nucleus Perinuclear halos Branching capillary pattern Histopathological and molecular characteristics are used to generate an integrated diagnosis and assess WHO tumor grade WHO Grade 4 WHO Grade 2 WHO Grade 2 WHO Grade 2 High cellular density Marked nuclear atypia High mitotic activity Necrosis and/or microvascular proliferation Low or no mitotic activity Absence of necrosis and microvascular proliferation Low or no mitotic activity Absence of necrosis and microvascular proliferation CDKN2A and CDKN2B intact Low or no mitotic activity Necrosis and microvascular proliferation absent Or at least 1 of the following: WHO Grade 3 WHO Grade 3 WHO Grade 3 EGFR amplification TERT promoter mutation Concurrent gain of chromosome 7 and loss of chromosome 10 (+7/−10) Increased cellular density Nuclear atypia Increased mitotic activity Necrosis and microvascular proliferation absent Increased cellular density Nuclear atypia Increased mitotic activity Absence of necrosis and microvascular proliferation CDKN2A and CDKN2B intact Increased cellular density Nuclear atypia Increased mitotic activity Necrosis and/or microvascular proliferation WHO Grade 4 High cellular density Marked nuclear atypia High mitotic activity Necrosis and/or microvascular proliferation Or Homozygous deletion of CDKN2A and/or CDKN2B The WHO Classification of Tumours of the Central Nervous System was revised in 2021 (WHO CNS5). Tumors are graded on the basis of histological features and molecular abnormalities. Tumor grade is intended to reflect the expected natural history, with grade 4 tumors having the worst prognosis. Adult-type diffuse gliomas, described here, range from grades 2 to 4. a Shown are examples for the adult-type diffuse gliomas. This figure does not include pediatric-type diffuse high-grade gliomas, which can present in adults. b Immunohistochemistry with a highly sensitive and specific monoclonal antibody that recognizes the isocitrate dehydrogenase (IDH)1-R132H-mutant protein is widely used. The IDH1-R132H mutation accounts for approximately 90% of all IDH1 and IDH2 mutations in supratentorial adult-type diffuse glioma. Testing for non–IDH1-R132H mutations uses DNA sequence analysis and is necessary when immunohistochemistry for IDH1-R132H is negative. should receive prophylaxis for Pneumocystis jirovecii pneumonia (PCP)34 (Table 1). Trimethoprim/sulfamethoxazole prophylaxis reduces incidence of PCP in non-HIV immunocompromised individuals from 6.2% to 0.2% (RR, 0.15 [95% CI, 0.04-0.62]).34 Gastrointestinal prophylaxis with a proton pump inhibitor is recommended for patients receiving dexamethasone in doses greater than 8 mg per day in perioperative settings; it is also recommended for patients treated with anticoagulation, nonsteroidal inflammatory drugs, or a history of peptic ulcer disease. Myopathy is a common complication of corticosteroid use in patients with brain tumors. Patients with steroid-induced myopathy may report difficulty when rising from a seated position and climbing stairs. Symptoms may resolve after steroid discontinuation. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor A (VEGF-A), can im578 c IDH-wild-type glioblastomas lack mutations in IDH1 and IDH2. Absence of immunoreactivity for IDH1 R132H is sufficient to diagnose IDH-wild-type glioblastoma in patients aged 55 years and older with histologically classic glioblastoma. d The “not elsewhere classifiable” (NEC) designation indicates that appropriate diagnostic testing has been performed, and results do not allow for an alternative diagnosis per World Health Organization (WHO) criteria. Further molecular work-up should exclude the presence of genetic findings that are associated with pediatric-type diffuse gliomas and circumscribed astrocytic gliomas. prove cerebral edema in patients with brain tumors who did not respond to steroids or who are intolerant to steroids.32,35, Venous thromboembolism (VTE) occurs in as many as 30% of patients with glioma and CNS lymphoma,36,37 often shortly following diagnostic surgery.38 Hospitalized neurosurgical patients should receive prophylactic low-molecular-weight heparin (LMWH) or unfractionated heparin, ideally beginning 24 hours after surgery.39 There are no data to support maintenance of VTE prophylaxis after hospital discharge,40 and there are also only few prospective data to guide the treatment of VTE in patients with brain tumors. The risk of intracranial bleeding may increase with the use of anticoagulants, but these data are not definitive,40,41 and anticoagulation is generally recommended given the significant mortality associated with untreated VTE. Many neuro-oncologists favor LMWH over JAMA February 21, 2023 Volume 329, Number 7 (Reprinted) © 2023 American Medical Association. All rights reserved. Downloaded from jamanetwork.com by University of British Columbia user on 02/23/2024 jama.com Glioblastoma and Other Primary Brain Malignancies in Adults Review Clinical Review & Education Table 1. Management of Medical Complications of Glioblastoma and Other Primary Malignant Brain Tumors in Adults Dose Mechanism of action Adverse effectsa Comments Severe symptoms, bolus 10 mg, then 16 mg/d in divided doses Mild-moderate symptoms, 4-8 mg/d Long-acting corticosteroid, decreases inflammatory mediators, reverses vascular permeability Intravenous 10 mg/kg every 2 wk Vascular endothelial growth factor inhibition Hyperglycemia, psychiatric/behavioral disturbance, fluid retention, weight gain, gastritis, myopathy, increased infection risk Adverse effects are dose dependent and increase with prolonged exposure Hypertension (19%-42%), hemorrhage (0.4%-7%), proteinuria (5%-20%), arterial thromboembolism (5%), deep venous thrombosis (6%-9%), posterior reversible encephalopathy syndrome (0.5%) For maintence, the lowest dose possible for shortest amount of time should be prescribed Add PCP prophylaxis (see section below) if continuing ≥3 mg dexamethasone for ≥1 mo May be used for treatment of recurrent glioma or management of edema Hold ≥4 wk before and after any surgical procedures Oral tablet Double-strength trimethoprim 160 mg, sulfamethoxazole 800 mg 3×/ wk or Single-strength trimethoprim 80 mg, sulfamethoxazole 40 mg once/d 50 mg twice/d or 100 mg once/d Interference with bacterial folic acid synthesis Not to be used in patients Rash, urticaria, with sulfa allergy nausea/vomiting, hepatotoxicity, thrombocytopenia, hyponatremia Frequency of occurrence was not reported Para-aminobenzoic acid antagonist Methemoglobinemia, hemolytic anemia, hepatotoxicity, dermatologic toxicity Frequency of occurrence was not reported Rash (6.3%-39%), diarrhea (3.2%-42%), nausea (4.1%-26%), headache (16%-28%), erythema multiforme (