For cervical cancer awareness month, Lauren Bollinger, MD, discusses how the increase in research in the field of cervical cancer is driving the progress of treatment.
Despite significant advancements in prevention and screening, cervical cancer remains a fierce opponent, and the disease continues to affect many women worldwide. In 2022, an estimated 14,100 new cases of cervical cancer will be diagnosed, and 4,280 projected deaths will occur because of the disease in the United States alone.1
Approximately 40-50% of cervical cancer cases are diagnosed in the locally advanced stage, and women diagnosed with metastatic cervical cancer have a particularly poor prognosis, with a 5-year survival rate estimated at only 16%.2 These grim statistics are driving an urgent need for new treatment options.
Thankfully, there is renewed hope and tremendous excitement about the future, as over the last several years, clinical trials for patients with recurrent and metastatic cervical cancer have increased at a pace never experienced in the field of gynecologic oncology.
The cervical cancer landscape is dramatically changing for the better as new drug therapies, including antibody drug conjugates and immunotherapies, come into play vs traditional chemotherapy. Taking a closer look at what is driving all this excitement is worthwhile, as these developments will likely impact the standard of care for patients with cervical cancer for years to come.
There are a few interesting trials recently published or presented at various conferences that will hopefully contribute to our understanding of cervical cancer and help guide the path forward:
This international phase 3 randomized controlled trial is particularly exciting because it brings pembrolizumab (Keytruda) to the first-line treatment of patients with metastatic cervical cancer.3 Before this study, the standard of care was carboplatin or cisplatin with paclitaxel (Taxol), plus or minus bevacizumab (Avastin), which yielded a median overall survival (OS) ranging from approximately 13 to 17 months. Adding pembrolizumab to that regimen increased median OS to 24 months, which is very promising because this improvement in OS has not been seen before in this population of patients.
While progression free survival (PFS) improvements are often seen in clinical trials, they unfortunately do not always translate to OS. In the KEYNOTE-826 trial, adding pembrolizumab reduced the hazard of disease progression by 38% in patients with a PD-L1 combined positive score of 1 or more, and by 35% in the intention to treat population, additionally, the hazard of death was reduced by 36% and 33%, respectively.
OUTBACK Trial (NCT01414608)
OUTBACK was an international randomized phase 3 trial designed to determine the effects on survival of giving adjuvant chemotherapy after current standard of care chemoradiation.4 Participants were patients with locally advanced cervical cancer who traditionally would have received the standard of care chemoradiation with curative intent. Patients were randomly assigned to either standard chemoradiation or standard chemoradiation followed by adjuvant chemotherapy consisting of 4 cycles of carboplatin and paclitaxel. The primary endpoint was OS at 5 years, while secondary endpoints included PFS, adverse events, and patterns of disease recurrence.
Unfortunately, this turned out to be a negative trial, as the findings did not show that receiving adjuvant chemotherapy after standard chemoradiation improved OS or PFS. Additionally, the experimental therapy was also associated with more grade 3-5 adverse effects at less than one year from randomization. Beyond that point, adverse effects were similar between the two groups.
CALLA Trial (NCT03830866)
Results of the CALLA trial were presented at the International Gynecologic Cancer Society (IGCS) conference in September of 2022, and unfortunately, like the OUTBACK trial, the CALLA trial yielded negative results.5 A randomized phase 3 trial, CALLA examined an immunotherapy drug called durvalumab (Imfinzi) in combination with and following chemoradiation.
The study found durvalumab did not significantly improve PFS in patients with high-risk, locally advanced cervical cancer vs chemoradiation alone. The important point about this trial was that it used an immunotherapy drug in addition to chemotherapy in the upfront setting. Interestingly, the subgroup of patients at highest risk of progression and death, specifically the lymph node–positive stage III group, had a hazard ratio of 0.71.
Safety was comparable in both arms of the study, and no new or unexpected toxicities were noted. Although data is still immature, and results are not published yet, so far there has been no detriment to survival.
Studies in Cervical Cancer Actively Recruiting
Some interesting trials are still recruiting to look at treatments in this patient population:
40 InnovaTV 301/ENGOT-cx12/GOG-3057 (NCT04697628)
A randomized open label phase 3 trial, GOG-3057 is studying the drug tisotumab vedotin (Tivdak) vs choice chemotherapy in second-and third-line treatment of recurrent or metastatic cervical cancer.6 The encouraging point about this drug is that in phase 1 and 2 trials, it demonstrated a response in second-and third-line treatment for patients with recurrent cervical cancer where traditionally good options did not exist for these women. Based on these early results, the drug received an accelerated FDA approval for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. It will be highly interesting to see the phase 3 results, which are still a few years away.
This is a randomized, blinded, non-comparative 2-arm phase 2 study that will assess the efficacy and safety of anti-PD1 balstilimab with placebo or in combination with anti-CTLA-4 zalifrelimab for treatment of patients with advanced cervical cancer after relapse or progression following first-line platinum-based chemotherapy.7 Each arm will be evaluated against historical controls. The primary end point is objective response rate (ORR), but duration of response (DOR), PFS, OS, and quality of life outcomes will also be evaluated.
GOG 3047 (NCT04221945)
This is a randomized phase 3 study that will evaluate chemoradiation with or without the immunotherapy drug, pembrolizumab, for treatment of high-risk patients with locally advanced cervical cancer.8 Like pembrolizumab’s benefit in the KEYNOTE-826 study for patients with metastatic or recurrent disease, investigators are hoping that pembrolizumab plus chemoradiation is superior to standard of care chemoradiation with respect to progression free survival and overall survival.
GOG 3043 (NCT04831580)
This study is a randomized controlled surgical trial of robotic vs open radical hysterectomy for patients with cervical cancer.9 Surgeons had been routinely performing minimally invasive surgery for cervical cancer until the results of the Laparoscopic Approach to Cervical Cancer (LACC) trial showed inferior disease-free and overall survival for women undergoing minimally invasive surgery for cervical cancer.
Unfortunately, these results have led to gynecologic oncologists performing radical hysterectomies via laparotomy for all patients with cervical cancer. There is a great need for more data, and hopefully this study will provide some answers. It is focusing on robot-assisted radical hysterectomy with a surgical technique for tumor containment prior to opening the vagina during the hysterectomy procedure. Investigators hope to determine if this approach is noninferior to performing an open radical hysterectomy with respect to disease free survival.
Trials Closed for Patient Accrual
Several studies have completed accrual, so results should be coming soon that oncologists should look out for including the NRG-GY006 study (NCT02466971).10 This randomized phase 3 trial examines the efficacy of triapine in combination with traditional chemoradiationin women with stage IB2 (> 5 cm), II, IIIB or IVA squamous, adenocarcinoma, or adenosquamous carcinoma of the cervix.
Another randomized phase 3 trial to look out for is the GOG 263 study (NCT01101451).11 This study looks at postoperative adjuvant chemoradiation therapy compared to adjuvant radiation therapy alone in patients with stage I-IIA cervical cancer who have intermediate risk factors after treatment with radical hysterectomy.
Still too Soon to Predict Drug Approvals
While there are many trials in the works, it is difficult to foresee if any of the drugs under study will gain FDA approval anytime soon. There have been some negative trials associated with the immunotherapy drugs, so for now, everyone is in a wait-and-see mode to see which patients will benefit most from these therapies.
New Targets in Treating Cervical Cancer
Antibody drug conjugates are showing great promise for the future, and not just for patients with cervical cancer. Unlike chemotherapy, these biopharmaceutical drugs are designed to selectively kill tumor cells while sparing healthy cells, hopefully limiting toxicity. There has already been progress in antibody drug conjugates for treatment with patients with cervical cancer using the drug tisotumab vedotin (Tivdak).
The treatment is designed to target tissue factor (TF) using proprietary antibody drug conjugate technology. TF is highly expressed on many solid tumors, including ovarian, prostate, bladder, esophageal, endometrial, and lung tumors. As mentioned earlier, tisotumab vedotin is currently in phase 3 trials and received accelerated FDA approval in September 2021 after previous trials demonstrated a response in second-and third-line treatment for patients with recurrent cervical cancer.
Advice For the Community Oncologist
Community oncologists can play a vital role in prevention and early diagnosis of cervical cancer in their patients. Like other gynecologic malignancies, cervical cancer can often go unnoticed because there are no obvious signs of the disease. The most common symptoms are vaginal bleeding, unusual vaginal discharge, and pelvic pain. However, these symptoms might not be considered abnormal to a woman of reproductive age, so it is important for physicians to ask their patients if they are experiencing any of these possible warning signs. It is also critical to take women’s concerns seriously, especially those concerns related to their reproductive health.
Screening is also essential for these patients. Patients with cancer are often immunosuppressed, putting them at higher risk for cervical dysplasia and cervical cancer. Consequently, it is important to ask if patients are up to date on their cervical cancer pap screening, and if not, to make sure they have established OB-GYN care to manage their increased risk. Moreover, community oncologists who are treating adolescent and young adult cancer patients should be recommending the human papillomavirus (HPV) vaccine.
Pediatric adolescent and young adult patients undergoing cancer treatment, or receiving stem cell transplants, are at nearly three times the risk of developing a secondary HPV-associated malignancy, so it is very important for community oncologists to recommend the vaccine to this vulnerable population.
Most cervical cancer is caused by HPV 16 and 18, and those 2 types are protected against with the vaccine, which has proven to be extremely effective. For instance, a recently published population-based cohort study of more than 1.5 million adolescent and adult females from 10 to 30 years of age found the quadrivalent HPV vaccine was associated with a substantially reduced risk of invasive cervical cancer.12
We know that a recommendation by a trusted physician is the strongest predictor for HPV vaccination initiation and completion, so community oncologists can play an important role in making sure these young adults are educated and vaccinated.
Hope Is On the Horizon
Cervical cancer is the fourth most common cancer among women globally, with an estimated 604,000 new cases and 342,000 deaths in 2020.13 While cervical cancer is on the rise in some countries, in the United States progress is being made and we are seeing the incidence of cervical cancer declining, largely attributed to an increase in HPV vaccination. It is important to highlight that although HPV vaccination coverage continues to increase in the United States, it remains lower than coverage with most other routinely recommended vaccines and HPV vaccination coverage in other high-income countries.
For women who are facing a diagnosis of cervical cancer, there is much to be optimistic about today, as this is an unprecedented time for new trials that are leading to significant advancements and improvements in survival. This level of activity in cervical cancer clinical research has not been seen in the past decade. It is encouraging that this disease is finally getting the attention it deserves. Thanks to this dramatic increase in research, patients who previously had few treatment options now have promising therapies available to them, with many more on the horizon.
1. Cancer Stat Facts: Cervical Cancer. National Cancer Institute. December 30, 2020. Accessed: November 16, 2022. https://bit.ly/3jnteLM
2. Survival Rates for Cervical Cancer. American Cancer Society. March 1, 2022. Accessed: November 17, 2022. https://bit.ly/2GHnhVl
3. Shapira-Frommer R, Alexandre J, et al. KEYNOTE-826: A phase 3, randomized, double-blind, placebo-controlled study of pembrolizumab plus chemotherapy for first-line treatment of persistent, recurrent, or metastatic cervical cancer. J Clin Oncol. 2019;37(suppl 15). doi: 10.1200/JCO.2019.37.15_suppl.TPS5595
4. Mileshkin L, Moore K, et al. Adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone: The randomized phase III OUTBACK Trial (ANZGOG 0902, RTOG 1174, NRG 0274). J Clin Oncol. 2022;39(suppl 18). doi: 10.1200/JCO.2021.39.15_suppl.LBA3
5. Mayadev J, Nunes AT, Li M, et al. CALLA: Efficacy and safety of concurrent and adjuvant durvalumab with chemoradiotherapy versus chemoradiotherapy alone in women with locally advanced cervical cancer: a phase III, randomized, double-blind, multicenter study. Int J Gynecol Cancer. 2020 Jul;30(7):1065-1070. doi: 10.1136/ijgc-2019-001135
6. Vergote I, Randall L, et al. 40 InnovaTV 301/ENGOT-cx12/GOG-3057: tisotumab vedotin vs investigator’s choice chemo in second- or third-line recurrent or metastatic cervical cancer. Int J Gynecol Cancer. 2021;31(suppl 3). doi: 10.1136/ijgc-2021-ESGO.1
7. O’Malley DM, Randall LM, Jackson CG, et al. RaPiDS (GOG-3028): randomized Phase II study of balstilimab alone or in combination with zalifrelimab in cervical cancer. Future Oncol. 2021 Sep;17(26):3433-3443. doi: 10.2217/fon-2021-0529
8. Study of Chemoradiotherapy With or Without Pembrolizumab (MK-3475) For The Treatment of Locally Advanced Cervical Cancer (MK-3475-A18/KEYNOTE-A18/ENGOT-cx11/GOG-3047). National Cancer Institute. Accessed: December 12, 2022. https://bit.ly/3HTBVYb
9. Bixel KL, Leitao MM, et al. ROCC/GOG-3043: A randomized non-inferiority trial of robotic versus open radical hysterectomy for early-stage cervical cancer. J Clin Oncol. 2022; 40(suppl 16) TPS5605-TPS5605. doi: 10.1200/JCO.2022.40.16_suppl.TPS5605
10. Leath, C. A Randomized Phase III Trial of Radiation Therapy and Cisplatin Alone or in Combination with Intravenous Triapine in Women with Newly Diagnosed Bulky Stage IB2, Stage II, IIIB, or IVA Cancer of the Uterine Cervix or Stage II-IVA Vaginal Cancer. NRG Oncology. 2019. Accessed: December 12, 2022. https://bit.ly/3WHPOgt
11. Radiation Therapy With or Without Chemotherapy in Patients With Stage I-IIA Cervical Cancer Who Previously Underwent Surgery. NIH U.S. National Library of Medicine. Accessed: December 12, 2022. https://bit.ly/3GcuXw7
12. Lei J, Ploner A, Elfström K, et al. HPV Vaccination and the Risk of Invasive Cervical Cancer. N Engl J Med. 2020; 383:1340-1348. doi: 10.1056/NEJMoa1917338
13. Cervical Cancer Key Facts. World Health Organization. February 22, 2022. Accessed: November 17, 2022.https://bit.ly/3BVIGou
COVID-19 outbreak declared over at Petrolia’s hospital
A COVID-19 outbreak at Petrolia’s hospital has been declared over, Bluewater Health officials said Monday.
Diligent infection prevention and control measures were key in helping control the outbreak, declared Jan. 17, Bluewater Health officials said in a news release.
Hospital officials said the decision to declare the outbreak over was done in consultation with Lambton public health.
Bluewater Health Monday reported seven COVID-positive patients in Sarnia and Petrolia hospitals.
Bluewater Health’s policy allows a maximum of two visitors at the bedside at a time, officials said, noting visitors must wear masks and cannot have food or drink within patient rooms.
Diagnosis and acute management of migraine – CMAJ
See related review article at www.cmaj.ca/lookup/doi/10.1503/cmaj.221607 (to be published February 6, 2023) and a first-person account of the difficulty of finding migraine treatment at www.cmaj.ca/lookup/doi/10.1503/cmaj.221813
Migraine is a leading cause of disability across all age groups.
Routine imaging is not recommended in patients with migraine who have no red flags, atypical symptoms or abnormal findings on neurologic examination.
A stratified approach for acute migraine treatment empowers patients to choose from different treatment options depending on attack symptoms and severity and encourages patients to combine medications from different classes.
Effective acute migraine treatment includes acetaminophen, nonsteroidal anti-inflammatory drugs and triptans.
Ubrogepant and rimegepant are new, effective migraine treatments, suitable for patients with cardiovascular disease in whom triptans are contraindicated.
Migraine affects about 12% of adults, with a prevalence of 18% in women and 6% in men.1–3 Globally, in 2019, migraine was the second leading cause of disability among men and women across all age groups, and the leading cause of disability in women aged 15–49 years (expressed as years lived with disability). 4 In the United States, more than 70% of all migraine-related visits are to primary care providers,5 who play a central role in diagnosing and managing migraine. Recently, several new classes of migraine-specific medications have been shown to be effective and the evidence for the effectiveness of non-pharmacologic interventions is growing. In this article, we discuss the diagnosis and acute management of migraine, based on original research evidence, reviews and clinical practice guidelines (Box 1). We discuss prevention of migraine in a second article.6
Box 1: Evidence used in this review
We conducted a targeted search of Google Scholar and PubMed to identify original research, review articles and clinical practice guidelines published through November of 2021, using search terms that included, but were not limited to, “migraine acute treatment,” “migraine preventive treatment,” “migraine CGRP monoclonal antibodies,” “migraine 5-HT1F,” “migraine behavioural treatments” and “migraine neuromodulation.” We also consulted the most recent guidelines from the Canadian Headache Society and the American Headache Society, and the International Classification of Headache Disorders, 3rd edition.
What is the current understanding of migraine pathophysiology?
Migraine is characterized by neuronal hyperexcitability. Many genetic variants have been associated with increased susceptibility for migraine, suggesting a strong genetic basis.7 Migraine attacks can be broken down into 5 phases: prodrome, aura, headache, postdrome and interictal. However, not every migraine attack progresses through all phases (e.g., only one-third of people with migraine will experience aura) and the phases do not necessarily occur in succession (e.g., aura and headache can occur simultaneously).8,9
The pathophysiology of the headache phase is widely accepted to result from activation of the trigeminovascular pathway, which consists of peripheral trigeminal afferent nerves that innervate the dura and large cerebral arteries. When these neurons are stimulated, they release vasoactive neuropeptides such as calcitonin gene-related peptide (CGRP) and transmit nociceptive signals to the trigeminal nucleus caudalis. Nociceptive signals from the trigeminal nucleus caudalis and the dorsal horn of the upper cervical roots (C1–C2) converge at the trigeminal cervical complex before being relayed to central structures involved in pain processing (brain stem, thalamus, hypothalamus, basal ganglia and cortex).8,9 Levels of CGRP increase during a migraine attack and decrease with treatment and between attacks, and CGRP infusion can trigger a migraine attack.10 Calcitonin gene-related peptide facilitates migraines through various mechanisms, including arterial vasodilation, inflammation in the dura, facilitation of neuronal signalling and modulation of nociceptive signal transmission at the trigeminal cervical complex.10 The hypothesis that migraine can be aborted or prevented by blocking the action of CGRP has been central to the development of drugs that target the CGRP ligand or receptor.11
What are the diagnostic criteria for migraine?
In the third edition of the International Classification of Headache Disorders (ICHD-3), migraine is subclassified into 6 categories: migraine without aura, migraine with aura, chronic migraine, complications of migraine, probable migraine and episodic syndromes that may be associated with migraine.12
Changes from ICHD-2 include modification of migraine with aura so that aura symptoms must meet 3 of 6 aura characteristics (at least 1 aura symptom spreads gradually over 5 min or more, 2 or more aura symptoms occur in succession, each individual aura symptom lasts 5–60 min, at least 1 aura symptom is unilateral, at least 1 aura symptom is positive, the aura is accompanied — or followed within 60 min — by headache), to better distinguish migraine aura from symptoms of transient ischemic attack.13 The diagnosis previously known as basilar artery migraine has been renamed “migraine with brain stem aura,” to reflect the low likelihood that the basilar artery is involved.12 Chronic migraine has been reclassified as a subtype of migraine rather than a complication of migraine, highlighting that it is a distinct entity with unique treatments. Although the diagnostic criteria for chronic migraine still require that headache be present on 15 or more days per month for more than 3 consecutive months, migraine-type headache need be present on only 8 of the headache days each month, in recognition that patients can often experience a mixture of headache phenotypes, including tension-type.12
The Visual Aura Rating Scale (VARS) has been validated for use in distinguishing migraine with visual aura from nonspecific visual symptoms and it has a 91% sensitivity and 96% specificity for diagnosis of visual aura when the score is ≥ 5. The 5 characteristics of the visual symptoms that make up the the scale are duration 6–60 minutes (3 points), develops gradually over 5 minutes or more (2 points), scotoma present (2 points), zigzag line present (2 points) and unilateral (1 point).14
The ID Migraine Screener, a tool that has been validated in primary care, screens for 3 key migraine-associated features: photophobia, functional impairment and nausea (with the mnemonic “PIN the diagnosis”). The screen is positive for migraine if the patient has 2 or more of the features, and a study of 563 patients presenting for routine primary care appointments and reporting headaches in the past 3 months found the sensitivity to be 0.81 (95% confidence interval [CI] 0.77–0.85), specificity to be 0.75 (95% CI 0.64–0.84) and the positive predictive value to be 0.93 (95% CI 0.54–0.82).15
When should imaging be ordered in patients with migraine?
For patients with stable headaches who meet criteria for migraine and have a normal neurologic examination, guidelines from the American College of Radiology and the American Headache Society strongly recommend against routine neuroimaging.16,17 A meta-analysis found that in such patients, the prevalence of important intracranial abnormalities on neuroimaging ranged from 0% to 3.1%, with a combined prevalence of 0.18% (upper 95% CI 0.59%).18 This is comparable to the prevalence of abnormalities detected on neuroimaging among the general population (neoplastic abnormalities 0.7% [95% CI 0.47%–0.98%], nonneoplastic abnormalities 2% [95% CI 1.10%–3.15%]).19 The detection of incidental findings can trigger undue patient anxiety and unnecessary investigations and procedures.16,17
Neuroimaging should be ordered in patients with an abnormal neurologic examination or red flags on history. Headache red flags consist of patient characteristics, features of the headache, and clinical symptoms or signs that should be assessed in every patient presenting with headache. The mnemonic SNOOP4 is a widely used, simple, yet comprehensive way to remember the headache red flags (Table 1).20,21 Neuroimaging should also be ordered in patients with unilateral headache that always occurs on the same side (side-locked), a feature of trigeminal autonomic cephalalgias, which can be mimicked by underlying central nervous system pathologies such as pituitary tumours, intracranial dissections or aneurysms, and infections; aura symptoms that are unusual, prolonged or persistent, a feature that could indicate an underlying lesion or seizure; and post-traumatic headache, because of the increased risk for intracranial hemorrhage or vascular injuries.17
Magnetic resonance imaging (MRI) is preferred over computed tomography (CT) as it provides better visualization of the brain parenchyma and is more sensitive in detecting subtle lesions.22 The use of contrast can further help with visualizing the brain parenchyma and meninges and should be considered when intracranial mass, infection or inflammation are suspected.16 However, CT is preferred when hemorrhages or fractures are suspected and should be performed first when there is concern for an acute abnormality and when MRI is not readily available.22 When headache is accompanied by optic disc edema, CT or MRI with venogram is suggested to rule out cerebral venous sinus thrombosis as a cause of high intracranial pressure.16 In some patients, additional investigations such as lumbar puncture, electroencephalogram and blood work may be indicated, but this is beyond the scope of this review. A comprehensive review of neuroimaging and workup of secondary causes of headache was recently published.23
What is the approach to acute treatment of a migraine attack?
The goal of treatment of migraine attacks is to provide rapid relief from pain and other migraine-related symptoms, to restore patient function and to prevent recurrence. Ideally, treatment should be self-administered, effective, well tolerated and affordable, and require minimal redosing.24 A stratified approach to treatment that empowers patients to choose from different options, depending on attack symptoms and severity, and encourages them to combine medications from different classes (e.g., nonsteroidal anti-inflammatory drugs and triptans) for severe or prolonged attacks, is preferred.25,26 Migraine attacks associated with mild disability can be treated with simple analgesics, with an additional dose of the same or a different agent in the next 2–24 hours, if needed. The Traffic Light of Headache is a tool that can help patients make acute treatment decisions using a stratified treatment plan, according to their level of functional impairment.27 All patients should be educated and screened for medication overuse, which can lead to medication-overuse headache and is a risk factor for transformation of episodic to chronic migraine.25,26
Classic pharmacologic acute treatments for migraine
Guidelines from the Canadian Headache Society and American Headache Society both indicate that acetaminophen, acetylsalicylic acid, diclofenac, ibuprofen, naproxen sodium and triptans have the highest level of evidence for treatment of migraine attacks (Table 2).26,28 Dihydroergotamine, which has been available for decades, can be useful as a first-line agent in some patients (patients with severe attacks or who do not respond well to triptans, or both). However, the Canadian Headache Society recommends against routine use of dihydroergotamine, given potential drug interactions and a high risk of vascular adverse effects, such as bradycardia and prolonged vasoconstriction (coronary, peripheral and central).26 Dihydroergotamine is contraindicated in patients who are pregnant or have a history of peripheral vascular disease, coronary artery disease, uncontrolled hypertension, stroke, sepsis, and renal or hepatic dysfunction.24 The Canadian Headache Society also strongly recommends against the routine use of combination analgesics containing codeine or tramadol, opioids, and butalbital-containing medications, owing to the high risk of sedation, dependence and the development of medication overuse headache.22,26
New pharmacologic acute treatment of migraine
Two classes of orally administered small-molecule drugs have recently been approved by the US Food and Drug Administration for the treatment of migraine attacks with and without aura: ditans (lasmiditan) and gepants (ubrogepant and rimegepant) (Table 3). They can be used in patients with cardiovascular disease in whom triptans are contraindicated.29–31 The gepants are currently being considered by Health Canada, but at the present time, lasmiditan will not be marketed in Canada.
The safety and efficacy of each class of drug has been evaluated in phase 3, randomized, placebo-controlled trials, which assessed acute treatment response during a single migraine attack.29,30,32–35 Study design and inclusion and exclusion criteria were similar across the trials. The co-primary outcomes were freedom from pain at 2 hours and resolution of the most bothersome migraine symptom at 2 hours. Inclusion criteria were a minimum 1-year history of migraine or migraine with aura, onset before age 50 years and 2–8 moderate-to-severe migraine headaches per month. Patients were excluded if they had 15 or more headache days per month, a history of medication overuse or a change in their baseline preventive treatment within the previous 3 months. Although patients with cardiovascular risk factors (e.g., obesity, diabetes, dyslipidemia, smoking) were included in all trials, patients with clinically important cardiovascular disease were excluded from all studies except 1 trial that evaluated lasmiditan.30 This is the most notable limitation of these studies, given that the greatest potential advantage of the ditans and gepants is their suitability for use in patients with clinically important cardiovascular disease in whom triptans are contraindicated.
Trial participants had a mean age between 40 and 42 years, 84.0%–88.0% were women and 75.0%–82.5% were white. All 3 drugs met the co-primary outcomes (freedom from pain at 2 h and resolution of the most bothersome migraine symptom at 2 h) compared with placebo, and treatment-related adverse effects were mild and transient (Table 3).29,30,32–35 The most common adverse effects with the gepants were nausea, dizziness, dry mouth and dyspepsia.32,34 Open-label extension trials have not identified any long-term safety or tolerability concerns for up to 1 year.36,37 Dizziness and sedation were the most common adverse effects seen with lasmiditan, resulting in a label warning patients not to drive within 8 hours of its use (Table 3). Ongoing collection of real-world data is needed to monitor for emergence of additional potential adverse effects with use beyond 1 year.
No head-to-head studies have compared ditans or gepants with triptans. However, a recent systematic review and meta-analysis quantified the effect of lasmiditan, rimegepant and ubrogepant compared with triptans in treatment of migraine attacks.38 In terms of efficacy, triptans (except naratriptan 2.5 mg and almotriptan 6.25 mg) were more strongly associated with freedom from pain at 2 hours than lasmiditan (50 mg, 100 mg), rimegepant 75 mg and ubrogepant (50 mg, 100 mg). Patients treated with rizatriptan, sumatriptan and zolmitriptan had more adverse events than patients treated with rimegepant and ubrogepant.38 Patients treated with lasmiditan had more adverse events than most other treatments (triptans and gepants) at all doses, owing to a high incidence of dizziness and sedation. In summary, most triptans are more efficacious than the new drugs, but with similar or poorer tolerability than gepants. Lasmiditan appears to be associated with the most adverse events.
According to current evidence, triptans should remain the mainstay of acute treatment of migraines, while ditans and gepants can be alternatives for patients who cannot tolerate or do not respond well to triptans, as well as patients with cardiovascular disease in whom triptans are contraindicated. As of May 2021, rimegepant was also approved in the US for prevention for episodic migraine, making it the first oral medication with indications for both acute and preventive treatment, the latter being the subject of a subsequent article.6,33,35,39
What are the device- and procedure-related treatment options for migraine?
Neuromodulation devices and peripheral nerve blocks have a role in the management of a small number of patients with migraine. Evidence to support these is discussed in Appendix 1 (available at www.cmaj.ca/lookup/doi/10.1503/cmaj.211969/tab-related-content). Neuromodulation devices, of which 2 are available in Canada, can be used alone or together with pharmacotherapy for the acute treatment of migraine. They are noninvasive and have minimal adverse effects. Peripheral nerve blockade with local anesthetic injection can be performed at various nerve branches of the trigeminocervical system and it is covered by most provincial public health plans in Canada.
Migraine is a leading cause of disability. Treatment of migraine attacks should aim to provide rapid relief from headache pain and related symptoms, restore patient functioning and prevent recurrence. Older medications remain effective, although newer medications may be preferred for certain groups of patients. In Box 2, we provide a practical clinical approach to management of the patient with migraine. Nonpharmacologic and pharmacologic approaches to the prevention of migraine will be discussed in a separate article.6
Box 2: A clinical approach to managing migraine
Identify that the primary headache type is migraine.
Order brain imaging to exclude secondary causes of headache if red flags or abnormalities on physical examination are present.
Categorize the disorder (episodic v. chronic migraine).
Identify comorbidities and exacerbating factors.
Assess disability and attack characteristics.
Review previous treatments, unmet needs and patient’s treatment goals.
Formulate a treatment plan.
Take a stratified approach to acute migraine treatment.
Individualized drugs: choose the medication best suited for the patient; with oral prevention drugs, start low and go slow.
Consider comorbidities and coverage for migraine prevention (e.g., consider an antidepressant if patient has comorbid psychological symptoms, avoid divalproex acid in people of childbearing age, be aware that calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) and onabotulinumtoxinA require a trial of at least 2 oral preventatives before they can be covered by public or private funding and that CGRP mAbs are approved for both episodic and chronic migraine, while onabotulinumtoxinA is approved only for chronic migraine).
Competing interests: Werner Becker reports receiving consulting fees from AbbView, Novartis, Lundbeck, Eli Lilly, Teva and McKesson, and honoraria for lectures, presentations, manuscript writing and educational events from AbbVie, Novartis, Weber and Weber, Lundbeck and Teva. Dr. Becker serves as a volunteer member on the board of Migraine Canada and on the board of the Pain Society of Alberta. In the past, he has served on the boards of the Canadian Headache Society and the American Headache Society. Tommy Lik Hang Chan reports receiving unrestricted education grants from AbbVie, Teva and Novartis; honoraria from AbbVie, Eli Lilly, Miravo and Novartis; and travel stipends for attending conferences and meetings from AbbVie. Dr. Chan is on the advisory board for AbbVie, Eli Lilly, Teva, Lundbeck, Miravo and Novartis. No other competing interests were declared.
This article was solicited and has been peer reviewed.
Contributors: All of the authors contributed to the conception and design of the work, drafted the manuscript, revised it critically for important intellectual content, gave final approval of the version to be published and agreed to be accountable for all aspects of the work.
This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is noncommercial (i.e., research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/
BlackburnNews.com – CEE hospital COVID outbreak over – BlackburnNews.com
CEE hospital COVID outbreak over
January 30, 2023 12:20pm
A COVID-19 outbreak declared earlier this month at Charlotte Eleanor Englehart (CEE) Hospital in Petrolia is now over.
Bluewater Health, in consultation with Lambton Public Health, has declared an end to the outbreak in the Continuing Care Unit at CEE.
“Diligent infection prevention and control measures were key in helping control this outbreak. Bluewater Health is grateful for the support of all staff and professional staff, patients and families, and the community during this time,” read a news release.
Hospital visitors are reminded to sanitize their hands upon arrival, put on a hospital-provided mask and follow visitation rules, including maximum two visitors at a time.
There are currently seven COVID-positive patients in hospital in Sarnia and Petrolia.
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