Study Overview

Objective. To compare clinical outcomes and toxicities between combined nivolumab plus ipilimumab (N+I) versus ipilimumab alone (I) or nivolumab alone (N) in patients with advanced melanoma.

Design. Randomized controlled trial 1:1:1 of N+I (nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 weeks) versus N (3 mg/kg every 2 weeks) versus I plus placebo (3 mg/kg every 3 weeks for four doses).

Setting and participants. Adult patients with previously untreated stage III (unresectable) or stage IV melanoma and ECOG performance status of 0 or 1 (on a scale of 0–5 with higher score indicating greater disability). Patients with active brain metastases, ocular melanoma, or autoimmune disease were excluded. This study took place in academic and community practices across the United States, Europe, and Australia. 945 patients were randomized. If patients progressed, additional therapies were at clinician discretion.

Main outcome measures. Primary end points were progression-free survival and overall survival. Secondary end points were objective response rate, toxicity profile, and evaluation of PD-L1 (programmed death-ligand 1) as a predictive marker for progression-free survival and overall survival.

Main results. Baseline patient characteristics were published previously [1]. There were no significant differences among groups except that the I only group had a higher frequency of brian metastases (4.8%) vs the N only group (2.5%). At censored follow-up of a minimum of 36 months, median overall survival was not reached in the N+I group, was 37.6 months in the N only group and was 19.9 months in the I only group (hazard ratio [HR] for death 0.55 (P < 0.001) for N+I vs. I and 0.65 (P < 0.001) for N vs. I). Overall survival at 3 years was 58% in the N+I group vs. 52% in the N only group vs. 34% in the I only group. The rate of objective response was 58% in the N+I group vs. 44% in the N only group vs. 19% in the I only group. Progression-free survival at 3 years was 39% in the N+I group, 32% in the N only group and 10% in the I only group. The level of PD-L1 expression was not associated with response or overall survival. Grade 3 or 4 treatment-related adverse events occurred in 59% of the N+I group vs. 21% in N vs. 28% in I group. As therapy after progression was left to clinician discretion, crossover was common with 43% of the I only group receiving nivolumab as second-line therapy and 28% of the N only group receiving ipilimumab as second-line therapy.

Treatment-related events that lead to therapy discontinuation occurred much more frequently in those who received N+I (40%) vs. N (12%) vs. I (16%). However, among the N+I patients who discontinued after a median of 3 cycles of treatment, 67% were still alive at 3 years. In addition, when adverse events were treated with safety guidelines, most immune-mediated adverse events resolved within 3 to 4 weeks. The most common grade 3 or 4 adverse events in the N+I group were diarrhea (9%), elevated lipase (11%), and elevated liver transaminases (9%). A total of 2 treatment-related deaths were reported in the N+I group.

Conclusion. Both the combination therapy of nivolumab + ipilimumab and nivolumab alone offer superior 3-year overall survival and progression-free survival compared with ipilimumab alone in advanced melanoma, with acceptable toxicity profiles.

Commentary

Historically, unresectable and metastatic melanoma has had a dismal prognosis, with responses to chemotherapy in about 10% to 15% and rarely were these responses durable [2]. The previous standard of care was high-dose IL-2, a form of immunotherapy which leads to long-term survival in a small minority of patients (~15%) [3]. The encouraging results seen in this small minority lead to optimism for efficacy from additional immune-modifying agents.

The novel immunotherapy agents, known as checkpoint inhibitors, are antibodies directed against PD-1 (nivolumab and pembrolizumab), PD-L1 (atezolizumab, avelumab, and urvalumab), and CTLA-4 (ipilimumab). Each of these antigens are critical in a T cell process known as checkpoint inhibition. When these antigens are activated they inhibit T cells, a process critical for self recognition in the healthy human without cancer. However, many malignancies have developed molecular mechanisms to activate these checkpoint pathways and turn off T cell anti-tumor activity. By implementing checkpoint inhibitor antibodies, as done in this study, these drugs allow the T cells to be disinhibited and therefore exert anti-tumor activity. These drugs have been truly ground-breaking and are now FDA-approved in a number of malignancies, including bladder cancer, non–small cell lung cancer, head and neck squamous cell carcinoma, refractory Hodgkin lymphoma, mismatch repair–affected GI adenocarcinomas, renal cell carcinoma, and Merkel cell carcinoma. They offer the additional advantage of often an improved toxicity profile compared with traditional cytotoxic chemotherapy, as they are not typically associated with cytopenias, nausea, or hair loss, for example [4].

In this study, 3-year data from the CheckMate 067 trial is reported. As reported in this study, checkpoint inhibition has lead to truly remarkable improvements in outcomes for patients with advanced melanoma. In this study, the authors have demonstrated superiority of nivolumab plus ipilimumab and nivolumab alone versus ipilimumab alone. These results are similar to those seen in the KEYNOTE-006 trial which compared pemrolizumab (another anti-PD-1 antibody) to ipilimumab. In the KEYNOTE-006 trial, overall survival at 33 months was 50% in the pembrolizumab group versus 39% in the ipilimumab group.

In this study, the combination therapy was more toxic, requiring more frequent treatment discontinuation, though importantly, 3-year overall survival was 67% even among those who discontinued therapy. Grade 3 or 4 toxicity events seem to be associated with efficacy in this study. This is not surprising as this has been seen in some other tumor types as well [5], though it deserves more dedicated investigation as a prognostic marker in this population.

Applications for Clinical Practice

In this well-designed and -executed multicenter randomized trial, funded by Bristol-Myers Squibb and implemented in a selected population with good performance status, all 3 immunotherapies demonstrated impressive improvements in the management of advanced melanoma. The combination nivolumab and ipilimumab was the most effective, with markedly higher survival and response rates, but also with higher toxicity requiring treatment discontinuation, though this did not decrease the efficacy of the therapy. Both the combination nivolumab plus ipilimumab and nivolimab alone are acceptable treatments for patients with advanced melanoma and good performance status; cost and comorbidities will be critical in personalizing therapy.

—Matthew Painschab, MD, University of North Carolina, Chapel Hill, NC

Study Overview

Objective. To compare clinical outcomes and toxicities between combined nivolumab plus ipilimumab (N+I) versus ipilimumab alone (I) or nivolumab alone (N) in patients with advanced melanoma.

Design. Randomized controlled trial 1:1:1 of N+I (nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 weeks) versus N (3 mg/kg every 2 weeks) versus I plus placebo (3 mg/kg every 3 weeks for four doses).

Setting and participants. Adult patients with previously untreated stage III (unresectable) or stage IV melanoma and ECOG performance status of 0 or 1 (on a scale of 0–5 with higher score indicating greater disability). Patients with active brain metastases, ocular melanoma, or autoimmune disease were excluded. This study took place in academic and community practices across the United States, Europe, and Australia. 945 patients were randomized. If patients progressed, additional therapies were at clinician discretion.

Main outcome measures. Primary end points were progression-free survival and overall survival. Secondary end points were objective response rate, toxicity profile, and evaluation of PD-L1 (programmed death-ligand 1) as a predictive marker for progression-free survival and overall survival.

Main results. Baseline patient characteristics were published previously [1]. There were no significant differences among groups except that the I only group had a higher frequency of brian metastases (4.8%) vs the N only group (2.5%). At censored follow-up of a minimum of 36 months, median overall survival was not reached in the N+I group, was 37.6 months in the N only group and was 19.9 months in the I only group (hazard ratio [HR] for death 0.55 (P < 0.001) for N+I vs. I and 0.65 (P < 0.001) for N vs. I). Overall survival at 3 years was 58% in the N+I group vs. 52% in the N only group vs. 34% in the I only group. The rate of objective response was 58% in the N+I group vs. 44% in the N only group vs. 19% in the I only group. Progression-free survival at 3 years was 39% in the N+I group, 32% in the N only group and 10% in the I only group. The level of PD-L1 expression was not associated with response or overall survival. Grade 3 or 4 treatment-related adverse events occurred in 59% of the N+I group vs. 21% in N vs. 28% in I group. As therapy after progression was left to clinician discretion, crossover was common with 43% of the I only group receiving nivolumab as second-line therapy and 28% of the N only group receiving ipilimumab as second-line therapy.

Treatment-related events that lead to therapy discontinuation occurred much more frequently in those who received N+I (40%) vs. N (12%) vs. I (16%). However, among the N+I patients who discontinued after a median of 3 cycles of treatment, 67% were still alive at 3 years. In addition, when adverse events were treated with safety guidelines, most immune-mediated adverse events resolved within 3 to 4 weeks. The most common grade 3 or 4 adverse events in the N+I group were diarrhea (9%), elevated lipase (11%), and elevated liver transaminases (9%). A total of 2 treatment-related deaths were reported in the N+I group.

Conclusion. Both the combination therapy of nivolumab + ipilimumab and nivolumab alone offer superior 3-year overall survival and progression-free survival compared with ipilimumab alone in advanced melanoma, with acceptable toxicity profiles.

Commentary

Historically, unresectable and metastatic melanoma has had a dismal prognosis, with responses to chemotherapy in about 10% to 15% and rarely were these responses durable [2]. The previous standard of care was high-dose IL-2, a form of immunotherapy which leads to long-term survival in a small minority of patients (~15%) [3]. The encouraging results seen in this small minority lead to optimism for efficacy from additional immune-modifying agents.

The novel immunotherapy agents, known as checkpoint inhibitors, are antibodies directed against PD-1 (nivolumab and pembrolizumab), PD-L1 (atezolizumab, avelumab, and urvalumab), and CTLA-4 (ipilimumab). Each of these antigens are critical in a T cell process known as checkpoint inhibition. When these antigens are activated they inhibit T cells, a process critical for self recognition in the healthy human without cancer. However, many malignancies have developed molecular mechanisms to activate these checkpoint pathways and turn off T cell anti-tumor activity. By implementing checkpoint inhibitor antibodies, as done in this study, these drugs allow the T cells to be disinhibited and therefore exert anti-tumor activity. These drugs have been truly ground-breaking and are now FDA-approved in a number of malignancies, including bladder cancer, non–small cell lung cancer, head and neck squamous cell carcinoma, refractory Hodgkin lymphoma, mismatch repair–affected GI adenocarcinomas, renal cell carcinoma, and Merkel cell carcinoma. They offer the additional advantage of often an improved toxicity profile compared with traditional cytotoxic chemotherapy, as they are not typically associated with cytopenias, nausea, or hair loss, for example [4].

In this study, 3-year data from the CheckMate 067 trial is reported. As reported in this study, checkpoint inhibition has lead to truly remarkable improvements in outcomes for patients with advanced melanoma. In this study, the authors have demonstrated superiority of nivolumab plus ipilimumab and nivolumab alone versus ipilimumab alone. These results are similar to those seen in the KEYNOTE-006 trial which compared pemrolizumab (another anti-PD-1 antibody) to ipilimumab. In the KEYNOTE-006 trial, overall survival at 33 months was 50% in the pembrolizumab group versus 39% in the ipilimumab group.

In this study, the combination therapy was more toxic, requiring more frequent treatment discontinuation, though importantly, 3-year overall survival was 67% even among those who discontinued therapy. Grade 3 or 4 toxicity events seem to be associated with efficacy in this study. This is not surprising as this has been seen in some other tumor types as well [5], though it deserves more dedicated investigation as a prognostic marker in this population.

Applications for Clinical Practice

In this well-designed and -executed multicenter randomized trial, funded by Bristol-Myers Squibb and implemented in a selected population with good performance status, all 3 immunotherapies demonstrated impressive improvements in the management of advanced melanoma. The combination nivolumab and ipilimumab was the most effective, with markedly higher survival and response rates, but also with higher toxicity requiring treatment discontinuation, though this did not decrease the efficacy of the therapy. Both the combination nivolumab plus ipilimumab and nivolimab alone are acceptable treatments for patients with advanced melanoma and good performance status; cost and comorbidities will be critical in personalizing therapy.

—Matthew Painschab, MD, University of North Carolina, Chapel Hill, NC

Study Overview

Objective. To compare clinical outcomes and toxicities between combined nivolumab plus ipilimumab (N+I) versus ipilimumab alone (I) or nivolumab alone (N) in patients with advanced melanoma.

Design. Randomized controlled trial 1:1:1 of N+I (nivolumab 1 mg/kg + ipilimumab 3 mg/kg every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 weeks) versus N (3 mg/kg every 2 weeks) versus I plus placebo (3 mg/kg every 3 weeks for four doses).

Setting and participants. Adult patients with previously untreated stage III (unresectable) or stage IV melanoma and ECOG performance status of 0 or 1 (on a scale of 0–5 with higher score indicating greater disability). Patients with active brain metastases, ocular melanoma, or autoimmune disease were excluded. This study took place in academic and community practices across the United States, Europe, and Australia. 945 patients were randomized. If patients progressed, additional therapies were at clinician discretion.

Main outcome measures. Primary end points were progression-free survival and overall survival. Secondary end points were objective response rate, toxicity profile, and evaluation of PD-L1 (programmed death-ligand 1) as a predictive marker for progression-free survival and overall survival.

Main results. Baseline patient characteristics were published previously [1]. There were no significant differences among groups except that the I only group had a higher frequency of brian metastases (4.8%) vs the N only group (2.5%). At censored follow-up of a minimum of 36 months, median overall survival was not reached in the N+I group, was 37.6 months in the N only group and was 19.9 months in the I only group (hazard ratio [HR] for death 0.55 (P < 0.001) for N+I vs. I and 0.65 (P < 0.001) for N vs. I). Overall survival at 3 years was 58% in the N+I group vs. 52% in the N only group vs. 34% in the I only group. The rate of objective response was 58% in the N+I group vs. 44% in the N only group vs. 19% in the I only group. Progression-free survival at 3 years was 39% in the N+I group, 32% in the N only group and 10% in the I only group. The level of PD-L1 expression was not associated with response or overall survival. Grade 3 or 4 treatment-related adverse events occurred in 59% of the N+I group vs. 21% in N vs. 28% in I group. As therapy after progression was left to clinician discretion, crossover was common with 43% of the I only group receiving nivolumab as second-line therapy and 28% of the N only group receiving ipilimumab as second-line therapy.

Treatment-related events that lead to therapy discontinuation occurred much more frequently in those who received N+I (40%) vs. N (12%) vs. I (16%). However, among the N+I patients who discontinued after a median of 3 cycles of treatment, 67% were still alive at 3 years. In addition, when adverse events were treated with safety guidelines, most immune-mediated adverse events resolved within 3 to 4 weeks. The most common grade 3 or 4 adverse events in the N+I group were diarrhea (9%), elevated lipase (11%), and elevated liver transaminases (9%). A total of 2 treatment-related deaths were reported in the N+I group.

Conclusion. Both the combination therapy of nivolumab + ipilimumab and nivolumab alone offer superior 3-year overall survival and progression-free survival compared with ipilimumab alone in advanced melanoma, with acceptable toxicity profiles.

Commentary

Historically, unresectable and metastatic melanoma has had a dismal prognosis, with responses to chemotherapy in about 10% to 15% and rarely were these responses durable [2]. The previous standard of care was high-dose IL-2, a form of immunotherapy which leads to long-term survival in a small minority of patients (~15%) [3]. The encouraging results seen in this small minority lead to optimism for efficacy from additional immune-modifying agents.

The novel immunotherapy agents, known as checkpoint inhibitors, are antibodies directed against PD-1 (nivolumab and pembrolizumab), PD-L1 (atezolizumab, avelumab, and urvalumab), and CTLA-4 (ipilimumab). Each of these antigens are critical in a T cell process known as checkpoint inhibition. When these antigens are activated they inhibit T cells, a process critical for self recognition in the healthy human without cancer. However, many malignancies have developed molecular mechanisms to activate these checkpoint pathways and turn off T cell anti-tumor activity. By implementing checkpoint inhibitor antibodies, as done in this study, these drugs allow the T cells to be disinhibited and therefore exert anti-tumor activity. These drugs have been truly ground-breaking and are now FDA-approved in a number of malignancies, including bladder cancer, non–small cell lung cancer, head and neck squamous cell carcinoma, refractory Hodgkin lymphoma, mismatch repair–affected GI adenocarcinomas, renal cell carcinoma, and Merkel cell carcinoma. They offer the additional advantage of often an improved toxicity profile compared with traditional cytotoxic chemotherapy, as they are not typically associated with cytopenias, nausea, or hair loss, for example [4].

In this study, 3-year data from the CheckMate 067 trial is reported. As reported in this study, checkpoint inhibition has lead to truly remarkable improvements in outcomes for patients with advanced melanoma. In this study, the authors have demonstrated superiority of nivolumab plus ipilimumab and nivolumab alone versus ipilimumab alone. These results are similar to those seen in the KEYNOTE-006 trial which compared pemrolizumab (another anti-PD-1 antibody) to ipilimumab. In the KEYNOTE-006 trial, overall survival at 33 months was 50% in the pembrolizumab group versus 39% in the ipilimumab group.

In this study, the combination therapy was more toxic, requiring more frequent treatment discontinuation, though importantly, 3-year overall survival was 67% even among those who discontinued therapy. Grade 3 or 4 toxicity events seem to be associated with efficacy in this study. This is not surprising as this has been seen in some other tumor types as well [5], though it deserves more dedicated investigation as a prognostic marker in this population.

Applications for Clinical Practice

In this well-designed and -executed multicenter randomized trial, funded by Bristol-Myers Squibb and implemented in a selected population with good performance status, all 3 immunotherapies demonstrated impressive improvements in the management of advanced melanoma. The combination nivolumab and ipilimumab was the most effective, with markedly higher survival and response rates, but also with higher toxicity requiring treatment discontinuation, though this did not decrease the efficacy of the therapy. Both the combination nivolumab plus ipilimumab and nivolimab alone are acceptable treatments for patients with advanced melanoma and good performance status; cost and comorbidities will be critical in personalizing therapy.

—Matthew Painschab, MD, University of North Carolina, Chapel Hill, NC

Objective. To determine differences in all-cause and prostate cancer–specific mortality between subgroups of patients who underwent watchful waiting versus radical prostactectomy (RP) for early-stage prostate cancer.

Design. Randomized prospective multicenter trial (PIVOT study).

Setting and participants. Study participants were Department of Veterans Affairs (VA) patients younger than age 75 with biopsy-proven local prostate cancer (T1–T2, M0 by TNM staging and centrally confirmed by pathology laboratory in Baylor) between November 1994 and January 2002. They were patients at NCI medical center–associated VA facilities. Patients had to be eligible for RP and not limited by concomitant medical comorbidities. Patients were excluded if they had undergone therapy for prostate cancer other than transurethral resection of prostate cancer (TURP) for diagnostic purposes including radiation, androgen deprivation theory (ADT), chemotherapy, or definitive surgery. They were also excluded if they had a PSA > 50 ng/mL or a bone scan suggestive of metastatic disease.

Main outcome measures. The primary outcome of the study was all-cause mortality. The secondary outcome was prostate cancer–specific mortality. These were measured from date of diagnosis to August 2014 or until the patient died. A third-party end-points committee blinded to patient arm in the trial determined the cause of death from medical record assessment.

Main results. 731 men with a mean age of 67 were randomly assigned to RP or watchful waiting. The median PSA of patients was 7.8 ng/mL with 75% of patients having a Gleason score ≤ 7 and 74% of patients having low- or intermediate-risk prostate cancer. As of August 2014, 468 of 731 men had died; cause of death was unavailable in 7 patients (2 patients in the surgery arm and 5 in the observation arm). Median duration of follow-up to death or end of follow-up was 12.7 years. All-cause mortality was not significantly different between RP and observation arms (hazard ratio 0.84, 95% confidence interval [CI] 0.7–1.01, P = 0.06). The incidence of death at 19.5 years was 61.3% in patients assigned to surgery versus 66.8% in the watchful waiting arm (relative risk 0.92, 95% CI 0.82–1.02). Deaths from prostate cancer or treatment occurred in 69 patients in the study; 65 from prostate cancer and 4 from treatment. Prostate cancer–associated mortality was not significantly lower in the RP arm than in the watchful waiting arm (hazard ratio 0.63, 95% CI 0.39–1.02, P = 0.06). Mortality was not significantly reduced in any examined subgroup (age > or < 65, white or black ethnicity, PSA > 10 ng/mL or < 10 ng/mL, low/high/intermediate grade, Gleason score). Fewer men who underwent surgery (40.9%) had progression compared to those who underwent observation (68.4%). Most of these patients experienced local progression: 34.1% in the surgery arm and 61.9% in the observation arm. Distant progression was seen in 10.7% of patients treated with RP and 14.2% in the untreated arm. Treatment for progression (local, asymptomatic or by PSA rise) occurred in 59.7% of men assigned to observation and in 33.5% of men assigned to surgery. ADT was more frequently utilized as a treatment modality in men who were initially observed (44.4%) than in men who had up-front surgery (21.7%).

With regard to patient-related outcomes (PROs), more men assigned to RP reported bothersome symptoms such as physical discomfort and limitations in performing activities of daily living (ADLs) at 2 years than in men who did not undergo the intervention. This difference did not persist at later time points beyond 2 years. The use of incontinence pads was markedly higher in surgically treated men than in untreated men. 40% of patients in the treatment arm had to use at least 1 incontinence pad per day within 6 months of RP; this number remained unchanged at 10 years. Rates of erectile dysfunction were reported as lower at 2 (80% versus 45%), 5 (80% versus 55%) and 10 (85% versus 70%) years in men who were watched versus those who underwent surgery. Rates of optimal sexual function were reported as lower in resected men at 1 (35% versus 65%), 5 (38% versus 55%) and 10 (50% versus 70%) years than in men who were watched.

Conclusion. Patients with localized prostate cancer who were randomized to observation rather than RP did not experience greater all-cause mortality or prostate cancer–specific mortality than their surgical counterparts. Furthermore, they experienced less erectile dysfunction, less sexual function impairment, and less incontinence than patients who underwent surgery. Patients who underwent surgery had higher rates of ADL dysfunction and physical discomfort although these differences did not persist beyond 2 years.

Commentary

Nearly 162,000 men will be diagnosed with prostate cancer in 2017, and it is anticipated 27,000 will succumb to their disease [1]. This ratio of incident cases to annual mortality represents one of the lowest ratios amongst all cancer sites and suggests most prostate cancers are indolent. Localized prostate cancer is usually defined by low (Gleason score ≤ 6, PSA < 10 ng/mL and ≤ T2 stage) or intermediate (Gleason score ≤ 7, PSA 10–20 ng/mL, and ≤ T2b stage) risk characteristics. 70% of patients present with low-risk disease, which carries a mortality risk of close to 6% at 15 years [2]. Despite this, nearly 90% of these patients are treated with RP, external beam radiation, or brachytherapy. Some published studies suggest up to 60% of low-risk prostate cancer patients may be overtreated [3,4]. The decision to treat low-risk patients is controversial, as morbidities (eg, sexual dysfunction, erectile dysfunction, incontinence) from a radical prostatectomy or focal radiation therapy are significant while the potential gain may be minimal.

Two other trials in addition to current PIVOT follow-up study have sought to answer the question of whether observation (through either watchful waiting or active surveillance) or treatment (surgery or radiation) is the optimal approach in the management of patients with localized prostate cancer. The SPCG-4 trial [5], which began enrollment in the pre-PSA screening era, included Scandinavian patients with biopsy-proven prostate cancer who were < 75, and had life expectancy > 10 years, ≤ T2 lesions, and PSA < 50 ng/mL. Patients began enrollment in 1989 and were watched for more than 20 years. They were seen in clinic every 6 months for the first 2 years and annually thereafter. The primary outcomes of the trial were death from any cause, death from prostate cancer, or risk of bony and visceral metastases. 447 of 695 included men (200 men in the RP group and 247 men in the watchful waiting group) had died by 2012. The cumulative incidence of death from prostate cancer at the 18-year follow-up point was 17.7% in the surgery arm versus 28.7% in the observation arm. The incidence of distant metastases at the 18-year follow-up point was 26.1% in the radical prostatectomy arm and 38.3% in the watchful waiting group. 67.4% of men assigned to watchful waiting utilized ADT while 42.4% of men treated with prostatectomy utilized ADT palliatively post progression [5].

The ProtecT trial was a United Kingdom study that enrolled 1643 men with prostate cancer aged 50–69 years between 1999 and 2009. The trial randomized men to 3 arms: watchful waiting, RP, or radiation therapy. Patients were eligible for the study if they were < 70 and had ≤ T2 stage disease. 97% of patients had a Gleason score ≤ 7. The primary outcome was prostate cancer–associated mortality at 10 years. Secondary outcomes included death from any cause, rates of distant metastases, and clinical progression. At the end of follow-up, prostate cancer–specific survival was 98.8% in all groups with no significant differences between groups. There was no evidence that differences between prostate cancer–associated mortality varied between groups when stratified by Gleason score, age, PSA, or clinical stage. Additionally, all-cause mortality rates were equivalently distributed across groups [6].

One of the primary reasons why PIVOT and ProtecT may have had different outcomes than the SPCG-4 trial may relate to the aggressiveness of tumors in patients in the various studies. Median PSA levels in the PIVOT and ProtecT trials, respectively, were 7.8 ng/mL and 4.2 ng/mL, compared with 13.2 ng/mL in the SPCG-4 trial. 70% and 77% of patients in PIVOT and ProtecT, respectively, had Gleason score ≤ 6 compared with 57% in the SPCG-4 trial. It is possible that SPCG-4 demonstrated the benefit of RP compared to observation because more patients had higher-risk tumors. Other studies have assessed the economic cost of treatment versus observation in low-risk prostate cancer patients using outcomes such as quality-adjusted life events (QALEs). In a 2013 decision analysis, observation was more effective and less costly than up-front treatment with radiation therapy or RP. Specifically, amongst modes of observation, watchful waiting rather than active surveillance (with every-6-months PSA screening) was more effective and less expensive [7].

Some of the strengths of the PIVOT trial include its prospective randomized design, multicenter patient cohorts, central blinded pathology review, and prolonged follow-up time of nearly 20 years. The trial also had several important limitations. First, the trial included a smaller sample size of patients than the investigators originally intended (2000 patients) and was subsequently underpowered to detect the predetermined outcome of mortality difference between the arms. Second, nearly 20% of patients were not adherent with their treatment arm assignments, which could have potentially confounded the results. Finally, the trial included a patient population that was sicker than the average patient diagnosed in the community with prostate cancer. Trial patients were more likely to succumb to diseases other than prostate cancer and thus may not have been alive long enough to demonstrate a difference between the trial arms (20-year mortality rate was close to 50% in trial patients compared with 30% in the general population post prostatectomy).

Applications for Clinical Practice

The NCCN guidelines suggest that patients with low-risk or intermediate-risk prostate cancer with life expectancies < 10 years should proceed with observation alone. In patients with low-risk disease and life expectancies > 10 years, active surveillance, radiation therapy, or RP are all recommended options. In intermediate-risk patients with life expectancies of > 10 years, treatment with surgery or radiation is warranted. Based on the findings from the PIVOT trial and other trials mentioned above, observation seems to be the most reasonable approach in patients with low-risk prostate cancer. The risks of treatment with RP or radiation outweigh the potential benefits from therapy, particularly in the absence of long-term mortality benefit.

—Satya Das, MD, Vanderbilt Ingram Cancer Center, Nashville, TN

Objective. To determine differences in all-cause and prostate cancer–specific mortality between subgroups of patients who underwent watchful waiting versus radical prostactectomy (RP) for early-stage prostate cancer.

Design. Randomized prospective multicenter trial (PIVOT study).

Setting and participants. Study participants were Department of Veterans Affairs (VA) patients younger than age 75 with biopsy-proven local prostate cancer (T1–T2, M0 by TNM staging and centrally confirmed by pathology laboratory in Baylor) between November 1994 and January 2002. They were patients at NCI medical center–associated VA facilities. Patients had to be eligible for RP and not limited by concomitant medical comorbidities. Patients were excluded if they had undergone therapy for prostate cancer other than transurethral resection of prostate cancer (TURP) for diagnostic purposes including radiation, androgen deprivation theory (ADT), chemotherapy, or definitive surgery. They were also excluded if they had a PSA > 50 ng/mL or a bone scan suggestive of metastatic disease.

Main outcome measures. The primary outcome of the study was all-cause mortality. The secondary outcome was prostate cancer–specific mortality. These were measured from date of diagnosis to August 2014 or until the patient died. A third-party end-points committee blinded to patient arm in the trial determined the cause of death from medical record assessment.

Main results. 731 men with a mean age of 67 were randomly assigned to RP or watchful waiting. The median PSA of patients was 7.8 ng/mL with 75% of patients having a Gleason score ≤ 7 and 74% of patients having low- or intermediate-risk prostate cancer. As of August 2014, 468 of 731 men had died; cause of death was unavailable in 7 patients (2 patients in the surgery arm and 5 in the observation arm). Median duration of follow-up to death or end of follow-up was 12.7 years. All-cause mortality was not significantly different between RP and observation arms (hazard ratio 0.84, 95% confidence interval [CI] 0.7–1.01, P = 0.06). The incidence of death at 19.5 years was 61.3% in patients assigned to surgery versus 66.8% in the watchful waiting arm (relative risk 0.92, 95% CI 0.82–1.02). Deaths from prostate cancer or treatment occurred in 69 patients in the study; 65 from prostate cancer and 4 from treatment. Prostate cancer–associated mortality was not significantly lower in the RP arm than in the watchful waiting arm (hazard ratio 0.63, 95% CI 0.39–1.02, P = 0.06). Mortality was not significantly reduced in any examined subgroup (age > or < 65, white or black ethnicity, PSA > 10 ng/mL or < 10 ng/mL, low/high/intermediate grade, Gleason score). Fewer men who underwent surgery (40.9%) had progression compared to those who underwent observation (68.4%). Most of these patients experienced local progression: 34.1% in the surgery arm and 61.9% in the observation arm. Distant progression was seen in 10.7% of patients treated with RP and 14.2% in the untreated arm. Treatment for progression (local, asymptomatic or by PSA rise) occurred in 59.7% of men assigned to observation and in 33.5% of men assigned to surgery. ADT was more frequently utilized as a treatment modality in men who were initially observed (44.4%) than in men who had up-front surgery (21.7%).

With regard to patient-related outcomes (PROs), more men assigned to RP reported bothersome symptoms such as physical discomfort and limitations in performing activities of daily living (ADLs) at 2 years than in men who did not undergo the intervention. This difference did not persist at later time points beyond 2 years. The use of incontinence pads was markedly higher in surgically treated men than in untreated men. 40% of patients in the treatment arm had to use at least 1 incontinence pad per day within 6 months of RP; this number remained unchanged at 10 years. Rates of erectile dysfunction were reported as lower at 2 (80% versus 45%), 5 (80% versus 55%) and 10 (85% versus 70%) years in men who were watched versus those who underwent surgery. Rates of optimal sexual function were reported as lower in resected men at 1 (35% versus 65%), 5 (38% versus 55%) and 10 (50% versus 70%) years than in men who were watched.

Conclusion. Patients with localized prostate cancer who were randomized to observation rather than RP did not experience greater all-cause mortality or prostate cancer–specific mortality than their surgical counterparts. Furthermore, they experienced less erectile dysfunction, less sexual function impairment, and less incontinence than patients who underwent surgery. Patients who underwent surgery had higher rates of ADL dysfunction and physical discomfort although these differences did not persist beyond 2 years.

Commentary

Nearly 162,000 men will be diagnosed with prostate cancer in 2017, and it is anticipated 27,000 will succumb to their disease [1]. This ratio of incident cases to annual mortality represents one of the lowest ratios amongst all cancer sites and suggests most prostate cancers are indolent. Localized prostate cancer is usually defined by low (Gleason score ≤ 6, PSA < 10 ng/mL and ≤ T2 stage) or intermediate (Gleason score ≤ 7, PSA 10–20 ng/mL, and ≤ T2b stage) risk characteristics. 70% of patients present with low-risk disease, which carries a mortality risk of close to 6% at 15 years [2]. Despite this, nearly 90% of these patients are treated with RP, external beam radiation, or brachytherapy. Some published studies suggest up to 60% of low-risk prostate cancer patients may be overtreated [3,4]. The decision to treat low-risk patients is controversial, as morbidities (eg, sexual dysfunction, erectile dysfunction, incontinence) from a radical prostatectomy or focal radiation therapy are significant while the potential gain may be minimal.

Two other trials in addition to current PIVOT follow-up study have sought to answer the question of whether observation (through either watchful waiting or active surveillance) or treatment (surgery or radiation) is the optimal approach in the management of patients with localized prostate cancer. The SPCG-4 trial [5], which began enrollment in the pre-PSA screening era, included Scandinavian patients with biopsy-proven prostate cancer who were < 75, and had life expectancy > 10 years, ≤ T2 lesions, and PSA < 50 ng/mL. Patients began enrollment in 1989 and were watched for more than 20 years. They were seen in clinic every 6 months for the first 2 years and annually thereafter. The primary outcomes of the trial were death from any cause, death from prostate cancer, or risk of bony and visceral metastases. 447 of 695 included men (200 men in the RP group and 247 men in the watchful waiting group) had died by 2012. The cumulative incidence of death from prostate cancer at the 18-year follow-up point was 17.7% in the surgery arm versus 28.7% in the observation arm. The incidence of distant metastases at the 18-year follow-up point was 26.1% in the radical prostatectomy arm and 38.3% in the watchful waiting group. 67.4% of men assigned to watchful waiting utilized ADT while 42.4% of men treated with prostatectomy utilized ADT palliatively post progression [5].

The ProtecT trial was a United Kingdom study that enrolled 1643 men with prostate cancer aged 50–69 years between 1999 and 2009. The trial randomized men to 3 arms: watchful waiting, RP, or radiation therapy. Patients were eligible for the study if they were < 70 and had ≤ T2 stage disease. 97% of patients had a Gleason score ≤ 7. The primary outcome was prostate cancer–associated mortality at 10 years. Secondary outcomes included death from any cause, rates of distant metastases, and clinical progression. At the end of follow-up, prostate cancer–specific survival was 98.8% in all groups with no significant differences between groups. There was no evidence that differences between prostate cancer–associated mortality varied between groups when stratified by Gleason score, age, PSA, or clinical stage. Additionally, all-cause mortality rates were equivalently distributed across groups [6].

One of the primary reasons why PIVOT and ProtecT may have had different outcomes than the SPCG-4 trial may relate to the aggressiveness of tumors in patients in the various studies. Median PSA levels in the PIVOT and ProtecT trials, respectively, were 7.8 ng/mL and 4.2 ng/mL, compared with 13.2 ng/mL in the SPCG-4 trial. 70% and 77% of patients in PIVOT and ProtecT, respectively, had Gleason score ≤ 6 compared with 57% in the SPCG-4 trial. It is possible that SPCG-4 demonstrated the benefit of RP compared to observation because more patients had higher-risk tumors. Other studies have assessed the economic cost of treatment versus observation in low-risk prostate cancer patients using outcomes such as quality-adjusted life events (QALEs). In a 2013 decision analysis, observation was more effective and less costly than up-front treatment with radiation therapy or RP. Specifically, amongst modes of observation, watchful waiting rather than active surveillance (with every-6-months PSA screening) was more effective and less expensive [7].

Some of the strengths of the PIVOT trial include its prospective randomized design, multicenter patient cohorts, central blinded pathology review, and prolonged follow-up time of nearly 20 years. The trial also had several important limitations. First, the trial included a smaller sample size of patients than the investigators originally intended (2000 patients) and was subsequently underpowered to detect the predetermined outcome of mortality difference between the arms. Second, nearly 20% of patients were not adherent with their treatment arm assignments, which could have potentially confounded the results. Finally, the trial included a patient population that was sicker than the average patient diagnosed in the community with prostate cancer. Trial patients were more likely to succumb to diseases other than prostate cancer and thus may not have been alive long enough to demonstrate a difference between the trial arms (20-year mortality rate was close to 50% in trial patients compared with 30% in the general population post prostatectomy).

Applications for Clinical Practice

The NCCN guidelines suggest that patients with low-risk or intermediate-risk prostate cancer with life expectancies < 10 years should proceed with observation alone. In patients with low-risk disease and life expectancies > 10 years, active surveillance, radiation therapy, or RP are all recommended options. In intermediate-risk patients with life expectancies of > 10 years, treatment with surgery or radiation is warranted. Based on the findings from the PIVOT trial and other trials mentioned above, observation seems to be the most reasonable approach in patients with low-risk prostate cancer. The risks of treatment with RP or radiation outweigh the potential benefits from therapy, particularly in the absence of long-term mortality benefit.

—Satya Das, MD, Vanderbilt Ingram Cancer Center, Nashville, TN

Objective. To determine differences in all-cause and prostate cancer–specific mortality between subgroups of patients who underwent watchful waiting versus radical prostactectomy (RP) for early-stage prostate cancer.

Design. Randomized prospective multicenter trial (PIVOT study).

Setting and participants. Study participants were Department of Veterans Affairs (VA) patients younger than age 75 with biopsy-proven local prostate cancer (T1–T2, M0 by TNM staging and centrally confirmed by pathology laboratory in Baylor) between November 1994 and January 2002. They were patients at NCI medical center–associated VA facilities. Patients had to be eligible for RP and not limited by concomitant medical comorbidities. Patients were excluded if they had undergone therapy for prostate cancer other than transurethral resection of prostate cancer (TURP) for diagnostic purposes including radiation, androgen deprivation theory (ADT), chemotherapy, or definitive surgery. They were also excluded if they had a PSA > 50 ng/mL or a bone scan suggestive of metastatic disease.

Main outcome measures. The primary outcome of the study was all-cause mortality. The secondary outcome was prostate cancer–specific mortality. These were measured from date of diagnosis to August 2014 or until the patient died. A third-party end-points committee blinded to patient arm in the trial determined the cause of death from medical record assessment.

Main results. 731 men with a mean age of 67 were randomly assigned to RP or watchful waiting. The median PSA of patients was 7.8 ng/mL with 75% of patients having a Gleason score ≤ 7 and 74% of patients having low- or intermediate-risk prostate cancer. As of August 2014, 468 of 731 men had died; cause of death was unavailable in 7 patients (2 patients in the surgery arm and 5 in the observation arm). Median duration of follow-up to death or end of follow-up was 12.7 years. All-cause mortality was not significantly different between RP and observation arms (hazard ratio 0.84, 95% confidence interval [CI] 0.7–1.01, P = 0.06). The incidence of death at 19.5 years was 61.3% in patients assigned to surgery versus 66.8% in the watchful waiting arm (relative risk 0.92, 95% CI 0.82–1.02). Deaths from prostate cancer or treatment occurred in 69 patients in the study; 65 from prostate cancer and 4 from treatment. Prostate cancer–associated mortality was not significantly lower in the RP arm than in the watchful waiting arm (hazard ratio 0.63, 95% CI 0.39–1.02, P = 0.06). Mortality was not significantly reduced in any examined subgroup (age > or < 65, white or black ethnicity, PSA > 10 ng/mL or < 10 ng/mL, low/high/intermediate grade, Gleason score). Fewer men who underwent surgery (40.9%) had progression compared to those who underwent observation (68.4%). Most of these patients experienced local progression: 34.1% in the surgery arm and 61.9% in the observation arm. Distant progression was seen in 10.7% of patients treated with RP and 14.2% in the untreated arm. Treatment for progression (local, asymptomatic or by PSA rise) occurred in 59.7% of men assigned to observation and in 33.5% of men assigned to surgery. ADT was more frequently utilized as a treatment modality in men who were initially observed (44.4%) than in men who had up-front surgery (21.7%).

With regard to patient-related outcomes (PROs), more men assigned to RP reported bothersome symptoms such as physical discomfort and limitations in performing activities of daily living (ADLs) at 2 years than in men who did not undergo the intervention. This difference did not persist at later time points beyond 2 years. The use of incontinence pads was markedly higher in surgically treated men than in untreated men. 40% of patients in the treatment arm had to use at least 1 incontinence pad per day within 6 months of RP; this number remained unchanged at 10 years. Rates of erectile dysfunction were reported as lower at 2 (80% versus 45%), 5 (80% versus 55%) and 10 (85% versus 70%) years in men who were watched versus those who underwent surgery. Rates of optimal sexual function were reported as lower in resected men at 1 (35% versus 65%), 5 (38% versus 55%) and 10 (50% versus 70%) years than in men who were watched.

Conclusion. Patients with localized prostate cancer who were randomized to observation rather than RP did not experience greater all-cause mortality or prostate cancer–specific mortality than their surgical counterparts. Furthermore, they experienced less erectile dysfunction, less sexual function impairment, and less incontinence than patients who underwent surgery. Patients who underwent surgery had higher rates of ADL dysfunction and physical discomfort although these differences did not persist beyond 2 years.

Commentary

Nearly 162,000 men will be diagnosed with prostate cancer in 2017, and it is anticipated 27,000 will succumb to their disease [1]. This ratio of incident cases to annual mortality represents one of the lowest ratios amongst all cancer sites and suggests most prostate cancers are indolent. Localized prostate cancer is usually defined by low (Gleason score ≤ 6, PSA < 10 ng/mL and ≤ T2 stage) or intermediate (Gleason score ≤ 7, PSA 10–20 ng/mL, and ≤ T2b stage) risk characteristics. 70% of patients present with low-risk disease, which carries a mortality risk of close to 6% at 15 years [2]. Despite this, nearly 90% of these patients are treated with RP, external beam radiation, or brachytherapy. Some published studies suggest up to 60% of low-risk prostate cancer patients may be overtreated [3,4]. The decision to treat low-risk patients is controversial, as morbidities (eg, sexual dysfunction, erectile dysfunction, incontinence) from a radical prostatectomy or focal radiation therapy are significant while the potential gain may be minimal.

Two other trials in addition to current PIVOT follow-up study have sought to answer the question of whether observation (through either watchful waiting or active surveillance) or treatment (surgery or radiation) is the optimal approach in the management of patients with localized prostate cancer. The SPCG-4 trial [5], which began enrollment in the pre-PSA screening era, included Scandinavian patients with biopsy-proven prostate cancer who were < 75, and had life expectancy > 10 years, ≤ T2 lesions, and PSA < 50 ng/mL. Patients began enrollment in 1989 and were watched for more than 20 years. They were seen in clinic every 6 months for the first 2 years and annually thereafter. The primary outcomes of the trial were death from any cause, death from prostate cancer, or risk of bony and visceral metastases. 447 of 695 included men (200 men in the RP group and 247 men in the watchful waiting group) had died by 2012. The cumulative incidence of death from prostate cancer at the 18-year follow-up point was 17.7% in the surgery arm versus 28.7% in the observation arm. The incidence of distant metastases at the 18-year follow-up point was 26.1% in the radical prostatectomy arm and 38.3% in the watchful waiting group. 67.4% of men assigned to watchful waiting utilized ADT while 42.4% of men treated with prostatectomy utilized ADT palliatively post progression [5].

The ProtecT trial was a United Kingdom study that enrolled 1643 men with prostate cancer aged 50–69 years between 1999 and 2009. The trial randomized men to 3 arms: watchful waiting, RP, or radiation therapy. Patients were eligible for the study if they were < 70 and had ≤ T2 stage disease. 97% of patients had a Gleason score ≤ 7. The primary outcome was prostate cancer–associated mortality at 10 years. Secondary outcomes included death from any cause, rates of distant metastases, and clinical progression. At the end of follow-up, prostate cancer–specific survival was 98.8% in all groups with no significant differences between groups. There was no evidence that differences between prostate cancer–associated mortality varied between groups when stratified by Gleason score, age, PSA, or clinical stage. Additionally, all-cause mortality rates were equivalently distributed across groups [6].

One of the primary reasons why PIVOT and ProtecT may have had different outcomes than the SPCG-4 trial may relate to the aggressiveness of tumors in patients in the various studies. Median PSA levels in the PIVOT and ProtecT trials, respectively, were 7.8 ng/mL and 4.2 ng/mL, compared with 13.2 ng/mL in the SPCG-4 trial. 70% and 77% of patients in PIVOT and ProtecT, respectively, had Gleason score ≤ 6 compared with 57% in the SPCG-4 trial. It is possible that SPCG-4 demonstrated the benefit of RP compared to observation because more patients had higher-risk tumors. Other studies have assessed the economic cost of treatment versus observation in low-risk prostate cancer patients using outcomes such as quality-adjusted life events (QALEs). In a 2013 decision analysis, observation was more effective and less costly than up-front treatment with radiation therapy or RP. Specifically, amongst modes of observation, watchful waiting rather than active surveillance (with every-6-months PSA screening) was more effective and less expensive [7].

Some of the strengths of the PIVOT trial include its prospective randomized design, multicenter patient cohorts, central blinded pathology review, and prolonged follow-up time of nearly 20 years. The trial also had several important limitations. First, the trial included a smaller sample size of patients than the investigators originally intended (2000 patients) and was subsequently underpowered to detect the predetermined outcome of mortality difference between the arms. Second, nearly 20% of patients were not adherent with their treatment arm assignments, which could have potentially confounded the results. Finally, the trial included a patient population that was sicker than the average patient diagnosed in the community with prostate cancer. Trial patients were more likely to succumb to diseases other than prostate cancer and thus may not have been alive long enough to demonstrate a difference between the trial arms (20-year mortality rate was close to 50% in trial patients compared with 30% in the general population post prostatectomy).

Applications for Clinical Practice

The NCCN guidelines suggest that patients with low-risk or intermediate-risk prostate cancer with life expectancies < 10 years should proceed with observation alone. In patients with low-risk disease and life expectancies > 10 years, active surveillance, radiation therapy, or RP are all recommended options. In intermediate-risk patients with life expectancies of > 10 years, treatment with surgery or radiation is warranted. Based on the findings from the PIVOT trial and other trials mentioned above, observation seems to be the most reasonable approach in patients with low-risk prostate cancer. The risks of treatment with RP or radiation outweigh the potential benefits from therapy, particularly in the absence of long-term mortality benefit.

—Satya Das, MD, Vanderbilt Ingram Cancer Center, Nashville, TN

The ongoing discussion over the optimal management of infection in aneurysms and grafts takes center stage in the session, “New Developments in the Treatment of Infected Aneurysms, Prosthetic Arterial Grafts, and Aortic Endografts,” on Friday morning. The session includes two debates: one on mycotic abdominal aortic aneurysms and what to do about them, and the other on the optimal techniques for handling infected aortic grafts and endografts.

“The management of infected aortic grafts is challenging and controversial,” according to Dr. Keith Calligaro, co-moderator of the session. Different aspects of treatment will be discussed, said Dr. Calligaro, chief of the section of vascular surgery and endovascular therapy at Pennsylvania Hospital, and clinical professor of surgery, University of Pennsylvania School of Medicine.

The ongoing discussion over the optimal management of infection in aneurysms and grafts takes center stage in the session, “New Developments in the Treatment of Infected Aneurysms, Prosthetic Arterial Grafts, and Aortic Endografts,” on Friday morning. The session includes two debates: one on mycotic abdominal aortic aneurysms and what to do about them, and the other on the optimal techniques for handling infected aortic grafts and endografts.

“The management of infected aortic grafts is challenging and controversial,” according to Dr. Keith Calligaro, co-moderator of the session. Different aspects of treatment will be discussed, said Dr. Calligaro, chief of the section of vascular surgery and endovascular therapy at Pennsylvania Hospital, and clinical professor of surgery, University of Pennsylvania School of Medicine.

The ongoing discussion over the optimal management of infection in aneurysms and grafts takes center stage in the session, “New Developments in the Treatment of Infected Aneurysms, Prosthetic Arterial Grafts, and Aortic Endografts,” on Friday morning. The session includes two debates: one on mycotic abdominal aortic aneurysms and what to do about them, and the other on the optimal techniques for handling infected aortic grafts and endografts.

“The management of infected aortic grafts is challenging and controversial,” according to Dr. Keith Calligaro, co-moderator of the session. Different aspects of treatment will be discussed, said Dr. Calligaro, chief of the section of vascular surgery and endovascular therapy at Pennsylvania Hospital, and clinical professor of surgery, University of Pennsylvania School of Medicine.

Study Overview

Objective. To evaluate survival trends and differences in a large cohort of patients with stage IV differentiated thyroid cancer treated with radioactive iodine (RAI), external beam radiation therapy (EBRT), or no radiation following surgery.

Design. Multicenter retrospective cohort study using data from the National Cancer Database (NCDB) from 2002–2012.

Setting and participants. The study group consisted of a random sample of all inpatient discharges with a diagnosis of differentiated thyroid cancer (DTC). This yielded a cohort of 11,832 patients with stage IV DTC who underwent primary surgical treatment with thyroidecromy. Patients were stratified by cancer histology into follicular thyroid cancer (FTC) and papillary thyroid cancer (PTC). Patients were additionally stratified into 3 substage groups: IV-A, IV-B, and IV-C. Administrative censoring was implemented at 5 and 10 year marks of survival time.

Main outcome measures. The primary outcome was all-cause mortality. Survival was analyzed at 5 and 10 years. Multivariate analysis was performed on a number of covariates including age, sex, race, socioeconomic status, TNM stage, tumor grade, surgical length of stay, and surgical treatment variables such as neck dissection and lymph node surgery.

Main results. Most patients (91.24%) had PTC and 8.76% had FTC. The average age of patients in the RAI group was younger (FTC, age 66; PTC, age 58) than patients in the EBRT (FTC, age 69; PTC, age 65) or no RT groups. (FTC, age 73; PTC, age 61). In contrast to FTC patients, a large majority of PTC patients underwent surgical neck dissection. There were no significant differences in sex, ethnicity, primary payer, median income quartile, or education level among the 3 groups for patients with FTC. However, in PTC there was a majority of female and ethnically white/Caucasian patients in all 3 groups. In addition, patients with PTC who did not receive RT or received RAI were more likely to have private insurance versus those who underwent EBRT, who were more often covered under Medicare. These differences in primary payer were statistically significant (P < 0.001).

Statistically significant differences in mortality were observed at 5 and 10 years in both papillary and follicular thyroid cancer among the 3 groups. In the PTC groups, patients treated with EBRT had the highest mortality rates (46.6% at 5 years, 50.7% at 10 years), while patients with PTC receiving no RT had lower mortality rates (22.7% at 5 years, 25.5% at 10 years), and PTC patients receiving RAI had the lowest mortality rates (11.0% at 5 years, 14.0% at 10 years). Similar results were seen in patients with FTC, in which patients treated with EBRT had the highest mortality rates (51.4% at 5 years, 59.9% at 10 years), while patient with FTC receiving no RT had lower mortality rates (45.5% at 5 years, 51% at 10 years), and FTC patients receiving RAI had the lowest mortality rates (29.2% at 5 years, 36.8% at 10 years).

Using univariate analysis, EBRT showed a statistically significant increase in 5- and 10-year mortality for patients with PTC stage IV-A and IV-B as compared with no radiation. This was demonstrated in both stage IV-A and IV-B subgroups at 5 years (EBRT 5-year HR PTC stage IV-A = 2.04, 95% confidence interval [CI] 1.74–2.39, P < 0.001; EBRT 5-year HR PTC stage IV-B = 2.23, 95% CI 1.42–3.51, P < 0.001; and 10 years [EBRT 10-year HR PTC stage IV-A = 2.12, 95% CI 1.79-2.52 P < 0.001; EBRT 10-year HR PTC stage IV-B = 2.03, 95% CI 1.33-3.10, P < 0.001). RAI showed a statistically significant decrease in 5- and 10-year mortality in both PTC and FTC compared with no radiation, regardless of pathologic sub-stage. The largest reduction in risk was seen in FTC stage IV-B patients at 5 years [RAI 5 year HR FTC stage IV-B = 0.31, 95% CI 0.12-0.80, P < 0.05). Multivariate analysis was also performed and showed similar results to univariate analysis except that there was no longer a statistically significant difference in EBRT versus no RT in stage IV-A PTC at 5 and 10 years (EBRT 5-year HR PTC stage IV-A = 1.2, 95% CI 0.91–1.59, EBRT 10-year HR PTC stage IV-A = 1.29, 95% CI 0.93–1.79). Reductions in death hazard seen in all groups treated with RAI versus no RT previously observed in univariate analysis remained statistically significant in all groups on multivariate analysis.

Multivariate analysis revealed a number of significant covariates. Increase in age was noted to be associated with higher death hazard in all groups except FTC stage IV-B and stage IV-C. Every additional year of age increased the hazard of death by ~2% to 5%, up to a maximum of 9% per year. Females overall had a lower hazard of death compared with their male counterparts, most notably in PTC. African-American patients had improved survival in FTC (5 years) but lower survival in PTC (5 and 10 years) as compared with white patients. Tumor grade showed a dose response in models studied, with increasing death hazards with worsening tumor differentiation.

Conclusion. RAI was associated with improved survival in patients with stage IV DTC, while EBRT was associated with poorer survival outcomes.

Commentary

Radioiodine therapy has been used for treatment of DTC since the 1940s. Radioactive iodine (I-131) is largely taken up by thyroid follicular cells via their sodium-iodide transporter causing acute thyroid cell death by emission of short path length beta particles [1].

External beam radiation therapy (EBRT) is the most common radiation therapy approach to deliver radiation from a source outside of the patient. EBRT machines produce radiation by either radioactive decay of a nuclide or by acceleration of charged particles such as electrons or protons. Using a linear accelerator, charged particles are accelerated to a high enough energy to allow transmission of particles as an electron beam or x-ray, which is subsequently directed at the tumor [2].

This study by Yang and colleagues aimed to examine survival differences in patients with stage IV DTC who received one of these adjuvant radiation modalities post-thyroidectomy. All treatment groups showed improved survival, with RAI with decreases in death hazard in both univariate and multivariate analysis. Patients with stage IV DTC prolonged their survival by a factor of 1.53–4.66 in multivariate models and 1.63–4.92 in univariate models. This clearly supports the effectiveness of RAI as an adjuvant treatment to DTC following surgical resection.

However, this study has several limitations. As this was a retrospective cohort study, the lack of randomization introduces a potential source of bias. In addition, since data was collected via the National Cancer Database, there was limited information that could be obtained on the subjects studied. Disease-specific survival and recurrence rates were not reported and even histological grades were missing more than 50% of the time. Finally, older age and more advanced stage in the EBRT cohorts were likely confounders in the results of increased death hazard and mortality that were observed. It should be noted, however, that attempts to adjust for these covariates were made by the authors by analyzing the data using multivariate analysis.

There are a number of potential reasons as to why the RAI-treated patients did significantly better than the EBRT-treated patients. Based on the current literature and guidelines, EBRT is mainly recommended as a palliative treatment of locally advanced, unresectable, or metastatic disease in primarily noniodine-avid tumors. Therefore, it is certainly feasible that patients in this study who underwent treatment with EBRT had more aggressive disease and were thus at higher risk to begin with. Perhaps the indications to treat with EBRT inherently confer a poorer prognosis in advanced DTC patients. In addition, RAI is a systemic treatment modality whereas EBRT is only directed locally to the neck and thus may miss micro-metastatic lesions elsewhere in the body.

Applications for Clinical Practice

Current standard practice in thyroid cancer management involve the use of radioiodine therapy in treatment of selected intermediate-risk and all high-risk DTC patients after total thyroidectomy. These patients are treated with 131-I to destroy both remnant normal thyroid tissue and microscopic or subclinical disease remaining after surgery. The decision to administer radioactive iodine post-thyroidectomy in patients with DTC is based on risk stratification of clinicopathologic features of the tumor. The efficacy of RAI is dependent on many factors including sites of disease, patient preparation, tumor characteristics, and dose of radiation administered.

EBRT is currently used much less frequently than RAI in the management of differentiated thyroid cancer. Its main use has been for palliative treatment of locally advanced, unresectable, or metastatic disease in primarily noniodine-avid tumors. It has also been suggested for use in older patients (age 55 years or older) with gross extrathyroidal extension at the time of surgery (T4 disease), or in younger patients with T4b or extensive T4a disease and poor histologic features, with tumors that are strongly suspected to not concentrate iodine. The use of EBRT in other settings is not well established [3,4].

Treatment benefits of RAI in DTC have been extensively studied; however, this is the largest study that has examined long-term survival in a cohort of just under 12,000 patients with stage IV DTC. The results from this large cohort with advanced disease further demonstrates improved overall survival in stage IV DTC patients treated with RAI at 5 and 10 years. It is clear that RAI is the first-line adjuvant radiation therapy of DTC and should remain the standard of care in thyroid cancer management.

—Kayur Bhavsar, MD, University of Maryland School of Medicine
Baltimore, MD

Study Overview

Objective. To evaluate survival trends and differences in a large cohort of patients with stage IV differentiated thyroid cancer treated with radioactive iodine (RAI), external beam radiation therapy (EBRT), or no radiation following surgery.

Design. Multicenter retrospective cohort study using data from the National Cancer Database (NCDB) from 2002–2012.

Setting and participants. The study group consisted of a random sample of all inpatient discharges with a diagnosis of differentiated thyroid cancer (DTC). This yielded a cohort of 11,832 patients with stage IV DTC who underwent primary surgical treatment with thyroidecromy. Patients were stratified by cancer histology into follicular thyroid cancer (FTC) and papillary thyroid cancer (PTC). Patients were additionally stratified into 3 substage groups: IV-A, IV-B, and IV-C. Administrative censoring was implemented at 5 and 10 year marks of survival time.

Main outcome measures. The primary outcome was all-cause mortality. Survival was analyzed at 5 and 10 years. Multivariate analysis was performed on a number of covariates including age, sex, race, socioeconomic status, TNM stage, tumor grade, surgical length of stay, and surgical treatment variables such as neck dissection and lymph node surgery.

Main results. Most patients (91.24%) had PTC and 8.76% had FTC. The average age of patients in the RAI group was younger (FTC, age 66; PTC, age 58) than patients in the EBRT (FTC, age 69; PTC, age 65) or no RT groups. (FTC, age 73; PTC, age 61). In contrast to FTC patients, a large majority of PTC patients underwent surgical neck dissection. There were no significant differences in sex, ethnicity, primary payer, median income quartile, or education level among the 3 groups for patients with FTC. However, in PTC there was a majority of female and ethnically white/Caucasian patients in all 3 groups. In addition, patients with PTC who did not receive RT or received RAI were more likely to have private insurance versus those who underwent EBRT, who were more often covered under Medicare. These differences in primary payer were statistically significant (P < 0.001).

Statistically significant differences in mortality were observed at 5 and 10 years in both papillary and follicular thyroid cancer among the 3 groups. In the PTC groups, patients treated with EBRT had the highest mortality rates (46.6% at 5 years, 50.7% at 10 years), while patients with PTC receiving no RT had lower mortality rates (22.7% at 5 years, 25.5% at 10 years), and PTC patients receiving RAI had the lowest mortality rates (11.0% at 5 years, 14.0% at 10 years). Similar results were seen in patients with FTC, in which patients treated with EBRT had the highest mortality rates (51.4% at 5 years, 59.9% at 10 years), while patient with FTC receiving no RT had lower mortality rates (45.5% at 5 years, 51% at 10 years), and FTC patients receiving RAI had the lowest mortality rates (29.2% at 5 years, 36.8% at 10 years).

Using univariate analysis, EBRT showed a statistically significant increase in 5- and 10-year mortality for patients with PTC stage IV-A and IV-B as compared with no radiation. This was demonstrated in both stage IV-A and IV-B subgroups at 5 years (EBRT 5-year HR PTC stage IV-A = 2.04, 95% confidence interval [CI] 1.74–2.39, P < 0.001; EBRT 5-year HR PTC stage IV-B = 2.23, 95% CI 1.42–3.51, P < 0.001; and 10 years [EBRT 10-year HR PTC stage IV-A = 2.12, 95% CI 1.79-2.52 P < 0.001; EBRT 10-year HR PTC stage IV-B = 2.03, 95% CI 1.33-3.10, P < 0.001). RAI showed a statistically significant decrease in 5- and 10-year mortality in both PTC and FTC compared with no radiation, regardless of pathologic sub-stage. The largest reduction in risk was seen in FTC stage IV-B patients at 5 years [RAI 5 year HR FTC stage IV-B = 0.31, 95% CI 0.12-0.80, P < 0.05). Multivariate analysis was also performed and showed similar results to univariate analysis except that there was no longer a statistically significant difference in EBRT versus no RT in stage IV-A PTC at 5 and 10 years (EBRT 5-year HR PTC stage IV-A = 1.2, 95% CI 0.91–1.59, EBRT 10-year HR PTC stage IV-A = 1.29, 95% CI 0.93–1.79). Reductions in death hazard seen in all groups treated with RAI versus no RT previously observed in univariate analysis remained statistically significant in all groups on multivariate analysis.

Multivariate analysis revealed a number of significant covariates. Increase in age was noted to be associated with higher death hazard in all groups except FTC stage IV-B and stage IV-C. Every additional year of age increased the hazard of death by ~2% to 5%, up to a maximum of 9% per year. Females overall had a lower hazard of death compared with their male counterparts, most notably in PTC. African-American patients had improved survival in FTC (5 years) but lower survival in PTC (5 and 10 years) as compared with white patients. Tumor grade showed a dose response in models studied, with increasing death hazards with worsening tumor differentiation.

Conclusion. RAI was associated with improved survival in patients with stage IV DTC, while EBRT was associated with poorer survival outcomes.

Commentary

Radioiodine therapy has been used for treatment of DTC since the 1940s. Radioactive iodine (I-131) is largely taken up by thyroid follicular cells via their sodium-iodide transporter causing acute thyroid cell death by emission of short path length beta particles [1].

External beam radiation therapy (EBRT) is the most common radiation therapy approach to deliver radiation from a source outside of the patient. EBRT machines produce radiation by either radioactive decay of a nuclide or by acceleration of charged particles such as electrons or protons. Using a linear accelerator, charged particles are accelerated to a high enough energy to allow transmission of particles as an electron beam or x-ray, which is subsequently directed at the tumor [2].

This study by Yang and colleagues aimed to examine survival differences in patients with stage IV DTC who received one of these adjuvant radiation modalities post-thyroidectomy. All treatment groups showed improved survival, with RAI with decreases in death hazard in both univariate and multivariate analysis. Patients with stage IV DTC prolonged their survival by a factor of 1.53–4.66 in multivariate models and 1.63–4.92 in univariate models. This clearly supports the effectiveness of RAI as an adjuvant treatment to DTC following surgical resection.

However, this study has several limitations. As this was a retrospective cohort study, the lack of randomization introduces a potential source of bias. In addition, since data was collected via the National Cancer Database, there was limited information that could be obtained on the subjects studied. Disease-specific survival and recurrence rates were not reported and even histological grades were missing more than 50% of the time. Finally, older age and more advanced stage in the EBRT cohorts were likely confounders in the results of increased death hazard and mortality that were observed. It should be noted, however, that attempts to adjust for these covariates were made by the authors by analyzing the data using multivariate analysis.

There are a number of potential reasons as to why the RAI-treated patients did significantly better than the EBRT-treated patients. Based on the current literature and guidelines, EBRT is mainly recommended as a palliative treatment of locally advanced, unresectable, or metastatic disease in primarily noniodine-avid tumors. Therefore, it is certainly feasible that patients in this study who underwent treatment with EBRT had more aggressive disease and were thus at higher risk to begin with. Perhaps the indications to treat with EBRT inherently confer a poorer prognosis in advanced DTC patients. In addition, RAI is a systemic treatment modality whereas EBRT is only directed locally to the neck and thus may miss micro-metastatic lesions elsewhere in the body.

Applications for Clinical Practice

Current standard practice in thyroid cancer management involve the use of radioiodine therapy in treatment of selected intermediate-risk and all high-risk DTC patients after total thyroidectomy. These patients are treated with 131-I to destroy both remnant normal thyroid tissue and microscopic or subclinical disease remaining after surgery. The decision to administer radioactive iodine post-thyroidectomy in patients with DTC is based on risk stratification of clinicopathologic features of the tumor. The efficacy of RAI is dependent on many factors including sites of disease, patient preparation, tumor characteristics, and dose of radiation administered.

EBRT is currently used much less frequently than RAI in the management of differentiated thyroid cancer. Its main use has been for palliative treatment of locally advanced, unresectable, or metastatic disease in primarily noniodine-avid tumors. It has also been suggested for use in older patients (age 55 years or older) with gross extrathyroidal extension at the time of surgery (T4 disease), or in younger patients with T4b or extensive T4a disease and poor histologic features, with tumors that are strongly suspected to not concentrate iodine. The use of EBRT in other settings is not well established [3,4].

Treatment benefits of RAI in DTC have been extensively studied; however, this is the largest study that has examined long-term survival in a cohort of just under 12,000 patients with stage IV DTC. The results from this large cohort with advanced disease further demonstrates improved overall survival in stage IV DTC patients treated with RAI at 5 and 10 years. It is clear that RAI is the first-line adjuvant radiation therapy of DTC and should remain the standard of care in thyroid cancer management.

—Kayur Bhavsar, MD, University of Maryland School of Medicine
Baltimore, MD

Study Overview

Objective. To evaluate survival trends and differences in a large cohort of patients with stage IV differentiated thyroid cancer treated with radioactive iodine (RAI), external beam radiation therapy (EBRT), or no radiation following surgery.

Design. Multicenter retrospective cohort study using data from the National Cancer Database (NCDB) from 2002–2012.

Setting and participants. The study group consisted of a random sample of all inpatient discharges with a diagnosis of differentiated thyroid cancer (DTC). This yielded a cohort of 11,832 patients with stage IV DTC who underwent primary surgical treatment with thyroidecromy. Patients were stratified by cancer histology into follicular thyroid cancer (FTC) and papillary thyroid cancer (PTC). Patients were additionally stratified into 3 substage groups: IV-A, IV-B, and IV-C. Administrative censoring was implemented at 5 and 10 year marks of survival time.

Main outcome measures. The primary outcome was all-cause mortality. Survival was analyzed at 5 and 10 years. Multivariate analysis was performed on a number of covariates including age, sex, race, socioeconomic status, TNM stage, tumor grade, surgical length of stay, and surgical treatment variables such as neck dissection and lymph node surgery.

Main results. Most patients (91.24%) had PTC and 8.76% had FTC. The average age of patients in the RAI group was younger (FTC, age 66; PTC, age 58) than patients in the EBRT (FTC, age 69; PTC, age 65) or no RT groups. (FTC, age 73; PTC, age 61). In contrast to FTC patients, a large majority of PTC patients underwent surgical neck dissection. There were no significant differences in sex, ethnicity, primary payer, median income quartile, or education level among the 3 groups for patients with FTC. However, in PTC there was a majority of female and ethnically white/Caucasian patients in all 3 groups. In addition, patients with PTC who did not receive RT or received RAI were more likely to have private insurance versus those who underwent EBRT, who were more often covered under Medicare. These differences in primary payer were statistically significant (P < 0.001).

Statistically significant differences in mortality were observed at 5 and 10 years in both papillary and follicular thyroid cancer among the 3 groups. In the PTC groups, patients treated with EBRT had the highest mortality rates (46.6% at 5 years, 50.7% at 10 years), while patients with PTC receiving no RT had lower mortality rates (22.7% at 5 years, 25.5% at 10 years), and PTC patients receiving RAI had the lowest mortality rates (11.0% at 5 years, 14.0% at 10 years). Similar results were seen in patients with FTC, in which patients treated with EBRT had the highest mortality rates (51.4% at 5 years, 59.9% at 10 years), while patient with FTC receiving no RT had lower mortality rates (45.5% at 5 years, 51% at 10 years), and FTC patients receiving RAI had the lowest mortality rates (29.2% at 5 years, 36.8% at 10 years).

Using univariate analysis, EBRT showed a statistically significant increase in 5- and 10-year mortality for patients with PTC stage IV-A and IV-B as compared with no radiation. This was demonstrated in both stage IV-A and IV-B subgroups at 5 years (EBRT 5-year HR PTC stage IV-A = 2.04, 95% confidence interval [CI] 1.74–2.39, P < 0.001; EBRT 5-year HR PTC stage IV-B = 2.23, 95% CI 1.42–3.51, P < 0.001; and 10 years [EBRT 10-year HR PTC stage IV-A = 2.12, 95% CI 1.79-2.52 P < 0.001; EBRT 10-year HR PTC stage IV-B = 2.03, 95% CI 1.33-3.10, P < 0.001). RAI showed a statistically significant decrease in 5- and 10-year mortality in both PTC and FTC compared with no radiation, regardless of pathologic sub-stage. The largest reduction in risk was seen in FTC stage IV-B patients at 5 years [RAI 5 year HR FTC stage IV-B = 0.31, 95% CI 0.12-0.80, P < 0.05). Multivariate analysis was also performed and showed similar results to univariate analysis except that there was no longer a statistically significant difference in EBRT versus no RT in stage IV-A PTC at 5 and 10 years (EBRT 5-year HR PTC stage IV-A = 1.2, 95% CI 0.91–1.59, EBRT 10-year HR PTC stage IV-A = 1.29, 95% CI 0.93–1.79). Reductions in death hazard seen in all groups treated with RAI versus no RT previously observed in univariate analysis remained statistically significant in all groups on multivariate analysis.

Multivariate analysis revealed a number of significant covariates. Increase in age was noted to be associated with higher death hazard in all groups except FTC stage IV-B and stage IV-C. Every additional year of age increased the hazard of death by ~2% to 5%, up to a maximum of 9% per year. Females overall had a lower hazard of death compared with their male counterparts, most notably in PTC. African-American patients had improved survival in FTC (5 years) but lower survival in PTC (5 and 10 years) as compared with white patients. Tumor grade showed a dose response in models studied, with increasing death hazards with worsening tumor differentiation.

Conclusion. RAI was associated with improved survival in patients with stage IV DTC, while EBRT was associated with poorer survival outcomes.

Commentary

Radioiodine therapy has been used for treatment of DTC since the 1940s. Radioactive iodine (I-131) is largely taken up by thyroid follicular cells via their sodium-iodide transporter causing acute thyroid cell death by emission of short path length beta particles [1].

External beam radiation therapy (EBRT) is the most common radiation therapy approach to deliver radiation from a source outside of the patient. EBRT machines produce radiation by either radioactive decay of a nuclide or by acceleration of charged particles such as electrons or protons. Using a linear accelerator, charged particles are accelerated to a high enough energy to allow transmission of particles as an electron beam or x-ray, which is subsequently directed at the tumor [2].

This study by Yang and colleagues aimed to examine survival differences in patients with stage IV DTC who received one of these adjuvant radiation modalities post-thyroidectomy. All treatment groups showed improved survival, with RAI with decreases in death hazard in both univariate and multivariate analysis. Patients with stage IV DTC prolonged their survival by a factor of 1.53–4.66 in multivariate models and 1.63–4.92 in univariate models. This clearly supports the effectiveness of RAI as an adjuvant treatment to DTC following surgical resection.

However, this study has several limitations. As this was a retrospective cohort study, the lack of randomization introduces a potential source of bias. In addition, since data was collected via the National Cancer Database, there was limited information that could be obtained on the subjects studied. Disease-specific survival and recurrence rates were not reported and even histological grades were missing more than 50% of the time. Finally, older age and more advanced stage in the EBRT cohorts were likely confounders in the results of increased death hazard and mortality that were observed. It should be noted, however, that attempts to adjust for these covariates were made by the authors by analyzing the data using multivariate analysis.

There are a number of potential reasons as to why the RAI-treated patients did significantly better than the EBRT-treated patients. Based on the current literature and guidelines, EBRT is mainly recommended as a palliative treatment of locally advanced, unresectable, or metastatic disease in primarily noniodine-avid tumors. Therefore, it is certainly feasible that patients in this study who underwent treatment with EBRT had more aggressive disease and were thus at higher risk to begin with. Perhaps the indications to treat with EBRT inherently confer a poorer prognosis in advanced DTC patients. In addition, RAI is a systemic treatment modality whereas EBRT is only directed locally to the neck and thus may miss micro-metastatic lesions elsewhere in the body.

Applications for Clinical Practice

Current standard practice in thyroid cancer management involve the use of radioiodine therapy in treatment of selected intermediate-risk and all high-risk DTC patients after total thyroidectomy. These patients are treated with 131-I to destroy both remnant normal thyroid tissue and microscopic or subclinical disease remaining after surgery. The decision to administer radioactive iodine post-thyroidectomy in patients with DTC is based on risk stratification of clinicopathologic features of the tumor. The efficacy of RAI is dependent on many factors including sites of disease, patient preparation, tumor characteristics, and dose of radiation administered.

EBRT is currently used much less frequently than RAI in the management of differentiated thyroid cancer. Its main use has been for palliative treatment of locally advanced, unresectable, or metastatic disease in primarily noniodine-avid tumors. It has also been suggested for use in older patients (age 55 years or older) with gross extrathyroidal extension at the time of surgery (T4 disease), or in younger patients with T4b or extensive T4a disease and poor histologic features, with tumors that are strongly suspected to not concentrate iodine. The use of EBRT in other settings is not well established [3,4].

Treatment benefits of RAI in DTC have been extensively studied; however, this is the largest study that has examined long-term survival in a cohort of just under 12,000 patients with stage IV DTC. The results from this large cohort with advanced disease further demonstrates improved overall survival in stage IV DTC patients treated with RAI at 5 and 10 years. It is clear that RAI is the first-line adjuvant radiation therapy of DTC and should remain the standard of care in thyroid cancer management.

—Kayur Bhavsar, MD, University of Maryland School of Medicine
Baltimore, MD

From the Department of Neurology, Medstar Georgetown University Hospital, Washington, DC.

Abstract

• Objective: To review the epidemiology, pathophysiology, diagnosis, and treatment of migraine.
•  Methods: Review of the literature.
• Results: Migraine is a common disorder associated with significant morbidity. Diagnosis of migraine is performed according to the International Classification of Headache Disorders. Comorbidities are commonly seen with migraine and include mood disorders (depression, anxiety, post-traumatic stress disorder), musculoskeletal disorders (neck pain, fibromyalgia, Ehlors-Danlos syndrome), sleep disorders, asthma, allergies, thyroid dysfunction, obesity, irritable bowel syndrome, epilepsy, stroke, and heart disease. Comorbid conditions can increase migraine disability. Management of migraine with lifestyle modifications, trigger management, and acute and preventive medications can help reduce the frequency, duration, and severity of attacks. Overuse of medications such as opiates, barbiturates, and caffeine-containing medications can increase headache frequency. Educating patients about limiting use of these medications is important.
• Conclusion: Migraine is a common neurologic disease that can be very disabling. Recognizing the condition, making an accurate diagnosis, and starting patients on migraine-specific treatments can help improve patient outcomes.

Key words: migraine; migraine without aura; migraine with aura; management of migraine.

Migraine is a common neurologic disease that affects 1 in 10 people worldwide [1]. It is 2 to 3 times more prevalent in women than in men [2]. The prevalence of migraine peaks in both sexes during the most productive years of adulthood (age 25 to 55 years) [3]. The Global Burden of Diseases, Injuries, and Risk Factors Study considers it to be the 7th most disabling disease in the world [4]. Over 36 million people in the United States have migraine [5]. However, just 56% of migraineurs have ever been diagnosed [6].

Migraine is associated with a high rate of years lived with disability [7] and the rate has been steadily increasing since 1990. At least 50% of migraine sufferers are severely disabled, many requiring bed rest, during individual migraine attacks lasting hours to days [8]. The total U.S. annual economic costs from headache disorders, including the indirect costs from lost productivity and workplace performance, has been estimated at $31 billion [9,10].

Despite the profound impact of migraine on patients and society, there are numerous barriers to migraine care. Lipton et al [11] identified 3 steps that were minimally necessary to achieve guideline-defined appropriate acute pharmacologic therapy: (1) consulting a prescribing health care professional; (2) receiving a migraine diagnosis; and (3) using migraine-specific or other appropriate acute treatments. In a study they conducted in patients with episodic migraine, 45.5% had consulted health care professional for headache in the preceding year; of these, 86.7% reported receiving a medical diagnosis of migraine, and among the diagnosed consulters, 66.7% currently used acute migraine-specific treatments, resulting in only 26.3% individuals successfully completing all 3 steps. In the recent CaMEO study [12], the proportion patients with chronic migraine that overcame all 3 barriers was less than 5%.

The stigma of migraine often makes it difficult for people to discuss symptoms with their health care providers and family members [13]. When they do discuss their headaches with their provider, often they are not given a diagnosis [14] or do not understand what their diagnosis means [15]. It is important for health care providers to be vigilant about the diagnosis of migraine, discuss treatment goals and strategies, and prescribe appropriate migraine treatment. Migraine is often comorbid with a number of medical, neurological, and psychiatric conditions, and identifying and managing comorbidities is necessary to reduce headache burden and disability. In this article, we provide a review of the diagnosis and treatment of migraine, using a case illustration to highlight key points.

Case Study

Initial Presentation

A 24-year-old woman presents for an evaluation of her headaches.

History and Physical Examination

She initially noted headaches at age 19, which were not memorable and did not cause disability. Her current headaches are a severe throbbing pain over her right forehead. They are associated with light and sound sensitivity and stomach upset. Headaches last 6 to 7 hours without medications and occur 4 to 8 days per month.

She denies vomiting and autonomic symptoms such as runny nose or eye tearing. She also denies preceding aura. She reports headache relief with intake of tablets that contain acetaminophen/aspirin/caffeine and states that she takes between 4 to 15 tablets/month depending on headache frequency. She reports having tried acetaminophen and naproxen with no significant benefit. Aggravating factors include bright lights, strong smells, and soy/ high-sodium foods.

She had no significant past medical problems and denied a history of depression or anxiety. Family history was significant for both her father and sister having a history of headaches. The patient lived alone and denied any major life stressors. She exercises 2 times a week and denies smoking or alcohol use. Review of systems was positive for trouble sleeping, which she described as difficulty falling asleep.

On physical examination, vitals were within normal limits. BMI was 23. Chest, cardiac, abdomen, and general physical examination were all within normal limits. Neurological examination revealed no evidence of papilledema or focal neurological deficits.

• What is the pathophysiology of migraine?

Migraine was thought to be a primary vascular disorder of the brain, with the origins of the vascular theory of migraine dating back to 1684 [16]. Trials performed by Wolff concluded that migraine is of vascular origin [17], and this remained the predominant theory over several decades. Current evidence suggests that migraine is unlikely to be a pure vascular disorder and instead may be related to changes in the central or peripheral nervous system [18,19].

Migraine is complex brain network disorder with a strong genetic basis [19]. The trigemino-vascular system, along with neurogenically induced inflammation of the dura mater, mast cell degranulation and release of histamine, are the likely causes of migraine pain. Trigeminal fibers arise from neurons in the trigeminal ganglion that contain substance P and calcitonin gene-related peptide (CGRP) [20]. CGRP is a neuropeptide widely expressed in both peripheral and central neurons. Elevation of CGRP in migraine is linked to diminution of the inhibitory pathways which in turn leads to migraine susceptibility [21]. These findings have led to the development of new drugs that target the CGRP pathway.

In the brainstem, periaqueductal grey matter and the dorsolateral pons have been found to be “migraine generators,” or the driver of changes of cortical activity during migraine [22]. Brainstem nuclei are involved in modulating trigemino-vascular pain transmission and autonomic responses in migraine [23].

The hypothalamus has also been implicated in migraine pathogenesis, particularly its role in nociceptive and autonomic modulation in migraine patients. Schulte and May hypothesized that there is a network change between the hypothalamus and the areas of the brainstem generator leading to the migraine attacks [24].

The thalamus plays a central role for the processing and integration of pain stimuli from the dura mater and cutaneous regions. It maintains complex connections with the somatosensory, motor, visual, auditory, olfactory and limbic regions [25]. The structural and functional alterations in the system play a role in the development of migraine attacks, and also in the sensory hypersensitivity to visual stimuli and mechanical allodynia [26].

Experimental studies in rats show that cortical spreading depression can trigger neurogenic meningeal inflammation and subsequently activate the trigemino-vascular system [27]. It has been observed that between migraine episodes a time-dependent amplitude increase of scalp-evoked potentials to repeated stereotyped stimuli, such as visual, auditory, and somaticstimuli, occurs. This phenomenon is described as “deficient habituation.” In episodic migraine, studies show 2 characteristic changes: a deficient habituation between attacks and sensitization during the attack [28]. Genetic studies have hypothesized an involvement of glutamatergic neurotransmitters and synaptic dysplasticity in causing abnormal cortical excitability in migraine [27].

• What are diagnostic criteria for migraine?

Diagnosis of migraine is performed according to the International Classification of Headache Disorders (ICHD) [29]. Based on the number of headache days that the patient reports, migraine is classified into episodic or chronic migraine. Migraines that occur on fewer than 15 days/month are categorized as episodic migraines.

Episodic migraine is divided into 2 categories: migraine with aura (Table 1) and migraine without aura. Migraine without aura is described as recurrent headaches consisting of at least 5 attacks, each lasting 4 to 72 hours if left untreated. At least 2 of the following 4 characteristics must be present: unilateral location, pulsating quality, moderate or severe pain intensity, with aggravation by or causing avoidance of routine physical activity. During headache, at least 1 of nausea and/or vomiting or photophobia and phonophobia should be present.

In migraine with aura (Table 2), headache characteristics are the same, but in addition there are at least 2 lifetime attacks with fully reversible aura symptoms (visual, sensory, speech/language). In addition, these auras have at least 2 of the following 4 characteristics: at least 1 aura symptom spreads gradually over 5 minutes, and/or 2 or more symptoms occur in succession; each individual aura symptom lasts 5 to 60 minutes; aura symptom is unilateral; and aura is accompanied, or followed within 60 minutes, by headache. Migraine with aura is uncommon, occurring in 20% of patients with migraine [30]. Visual aura is the most common type of aura, occurring in up to 90% of patients [31]. There is also aura without migraine, called typical aura without headache. Patients can present with non-migraine headache with aura, categorized as typical aura with headache [29].

• What information should be elicited during the history?

Specific questions about the headaches can help with making an accurate diagnosis. These include:

• Length of attacks and their frequency
• Pain characteristics (location, quality, intensity)
• Actions that trigger or aggravate headaches (eg, stress, movement, bright lights, menses, certain foods and smells)
• Associated symptoms that accompany headaches (eg, nausea, vomiting)
• How the headaches impact their life (eg, missed days at work or school, missed life events, avoidance of social activities, emergency room visits due to headache)

To assess headache frequency, it is helpful to ask about the number of headache-free days in a month, eg, “how many days a month do you NOT have a headache.” To assist with headache assessment, patients can be asked to keep a calendar in which they mark days of use of medications, including over the counter medications, menses, and headache days. The calendar can be used to assess for migraine patterns, headache frequency, and response to treatment.

When asking about headache history, it is important for patients to describe their untreated headaches. Patients taking medications may have pain that is less severe or disabling or have reduced associated symptoms. Understanding what the headaches were like when they did not treat is important in making a diagnosis.

Other important questions include when was the first time they recall ever experiencing a headache. Migraine is often present early in life, and understanding the change in headache over time is important. Also ask patients about what they want to do when they have a headache. Often patients want to lie down in a cool dark room. Ask what they would prefer to do if they didn’t have any pending responsibilities.

Comorbidities

Comorbidities are commonly seen with migraine. Common comorbidities are mood disorders (depression, anxiety, post-traumatic stress disorder), musculoskeletal disorders (neck pain, fibromyalgia, Ehlors-Danlos syndrome), sleep disorders, asthma, allergies, thyroid dysfunction, obesity, irritable bowel syndrome, epilepsy, stroke, and heart disease.

Comorbid conditions can increase migraine disability and also can provide information about the pathophysiology of migraine and guide treatment. Management of the underlying comorbidity often leads to improved migraine outcomes. For example, serotonergic dysfunction is a possible pathway involved in both migraine and mood disorders. Treatment with medications that alter the serotonin system may help both migraine and coexisting mood disorders. Bigal et al proposed that activation of the HPA axis with reduced serotonin synthesis is a main pathway involved in affective disorders, migraine, and obesity [35].

In the early 1950s, Wolff conceptualized migraine as a psychophysiologic disorder [36]. The relationship between migraine and psychiatric conditions is complex, and comorbid psychiatric disorders are risk factors for headache progression and chronicity. Psychiatric conditions also play a role in nonadherence to headache medication, which contributes to poor outcome in these patients. Hence, there is a need for assessment and treatment of psychiatric disorders in people with migraine. A study by Guidetti et al found that headache patients with multiple psychiatric conditions have poor outcomes, with 86 % of these headache patients having no improvement and even deterioration in their headache [37]. Another study by Mongini et al concluded that psychiatric disorder appears to influence the result of treatment on a long-term basis [38].

In addition, migraine has been shown to impact mood disorders. Worsening headache was found to be associated with poorer prognosis for depression. Patients with active migraine not on medications with comorbid major depressive disorder (MDD) had more severe anxiety and somatic symptoms as compared with MDD patients without migraine [39].

Case Continued

Our patient has a normal neurologic examination and classic migraine headache history and stable frequency. The physician tells her she meets criteria for episodic migraine without aura. The patient asks if she needs a “brain scan” to see if something more serious may be causing her symptoms.

• What workup is recommended for patients with migraine?

If patient symptoms fit the criteria for migraine and there is a normal neurologic examination, the differential is often limited. When there are neurologic abnormalities on examination (eg, papilledema), or if the patient has concerning signs or symptoms (see below), then neuroimaging should be obtained to rule out secondary causes of headache.

In 2014, the American Academy of Neurology (AAN) published practice parameters on the evaluation of adults with recurrent headache based on guidelines published by the US Headache Consortium [40]. As per AAN guidelines, routine laboratory studies, lumbar puncture, and electroencephalogram are not recommended in the evaluation of non-acute migraines. Neuroimaging is not warranted in patients with migraine and a normal neurologic examination (grade B recommendation). Imaging may need to be considered in patients with non-acute headache and an unexplained abnormal finding on the neurologic examination (grade B recommendation).

When patients exhibit particular warning signs, or headache “red flags,” it is recommended that neuroimaging be considered. Red flags include patients with recurrent headaches and systemic symptoms (fever, weight loss), neurologic symptoms or abnormal signs (confusion, impaired alertness or consciousness), sudden onset, abrupt, or split second in nature, patients age > 50 with new onset or progressive headache, previous headache history with new or different headache (change in frequency, severity, or clinical features) and if there are secondary risk factors (HIV, cancer) [41].

Case Continued

Our patient has no red flags and can be reassured that given her normal physical examination and history suggestive of a migraine, a secondary cause of her headache is unlikely. The physician describes the treatments available, including implementing lifestyles changes and preventive and abortive medications. The patient expresses apprehension about being on prescription medications. She is concerned about side effects as well as the need to take daily medication over a long period of time. She reports that these were the main reasons she did not take the rizatriptan and propranolol that was prescribed by her previous doctor.

• How is migraine treated?

Migraine is managed with a combination of lifestyle changes and pharmacologic therapy. Pharmacologic management targets treating an attack when it occurs (abortive medication), as well as reducing the frequency and severity of future attacks (preventive medication).

Lifestyle Changes

Patients should be advised that making healthy lifestyle choices, eg, regular sleep, balanced meals, proper hydration, and regular exercise, can mitigate migraine [42–44]. Other lifestyle changes that can be helpful include weight loss in the obese population, as weight loss appears to result in migraine improvement. People who are obese also are at higher risk for the progression to chronic migraine.

Acute Therapy

There are varieties of abortive therapies [45] (Table 4) that are commonly used in clinical practice. Abortive therapy can be taken as needed and is most effective if used within the first 2 hours of headache. For patients with daily or frequent headache, these medications need to be restricted to 8 to 12 days a month of use and their use should be restricted to when headache is worsening. This usually works well in patients with moderate level pain, and especially in patients with no associated nausea. Selective migraine treatments, like triptans and ergots, are used when nonspecific treatments fail, or when headache is more severe. It is preferable that patients avoid opioids, butalbital, and caffeine-containing medications. In the real world, it is difficult to convince patient to stop these medications; it is more realistic to discuss use limitation with patients, who often run out their weekly limit for triptans.

Triptans are effective medications for acute management of migraine but headache recurrence rate is high, occurring in 15% to 40 % of patients taking oral triptans. It is difficult to predict the response to a triptan [46]. The choice of an abortive agent is often directed partially by patient preference (side effect profile, cost, non-sedating vs. prefers to sleep, long vs short half-life), comorbid conditions (avoid triptans and ergots in uncontrolled hypertension, cardiovascular disease, or peripheral vascular disease or stroke/aneurysm; avoid NSAIDS in patients with cardiovascular disease), and migraine-associated symptoms (nausea and/or vomiting). Consider non-oral formulations via subcutaneous or nasal routes in patients who have nausea or vomiting with their migraine attacks. Some patients may require more than one type of abortive medication. The high recurrence rate is similar across different triptans and so switching from one triptan to another has not been found to be useful. Adding NSAIDS to triptans has been found to be more useful than switching between triptans.Overuse of acute medications has been associated with transformation of headache from episodic to chronic (medication overuse headache or rebound headache). The risk of transformation appears to be greatest with medications containing caffeine, opiates, or barbiturates [47]. Use of acute medications should be limited based on the type of medication. Patients should take triptans for no more than 10 days a month. Combined medications and opioids should be used fewer than 8 days a month, and butalbital-containing medications should be avoided or used fewer than 5 days a month [48]. Use of acute therapy should be monitored with headache calendars. It is unclear if and to what degree NSAIDS and acetaminophen cause overuse headaches.

Medication overuse headache can be difficult to treat as patients have to stop using the medication causing rebound. Further, headaches often resemble migraine and it can be difficult to differentiate them from the patients’ routine headache. Vigilance with medication use in patients with frequent headache is an essential part of migraine management, and patients should receive clear instructions regarding how to use acute medications.

Prevention

Patients presenting with more than 4 headaches per month, or headaches that last longer than 12 hours, require preventive therapy. The goals of preventive therapy is to reduce attack frequency, severity, and duration, to improve responsiveness to treatment of acute attacks, to improve function and reduce disability, and to prevent progression or transformation of episodic migraine to chronic migraine. Preventive medications usually need to be taken daily to reduce frequency or severity of the headache. The goal in this approach is 50% reduction of headache frequency and severity. Migraine preventive medications usually belong to 1 of 3 categories of drugs: antihypertensives, antiepileptics, and antidepressants. At present there are many medications for migraine prevention with different levels of evidence [49] (Table 5). Onabotulinuma toxin is the only approved medication for chronic migraine based on promising results of the PREEMPT trial [50].

Other Considerations

A multidisciplinary approach to treatment may be warranted. Psychiatric evaluation and management of underlying depression and mood disorders can help reduce headache frequency and severity. Physical therapy should be prescribed for neck and shoulder pain. Sleep specialists should be consulted if ongoing sleep issues continue despite behavioral management.

• How common is nonadherence with migraine medication?

One third of patients who are prescribed triptans discontinue the medication within a year. Lack of efficacy and concerns over medication side effects are 2 of the most common reasons for poor adherence [51]. In addition, age plays a significant role in discontinuing medication, with the elderly population more likely to stop taking triptans [52]. Seng et al reported that among patients with migraine, being male, being single, having frequent headache, and having mild pain are all associated with medication nonadherence [53]. Formulary restrictions and type of insurance coverage also were associated with nonadherence. Among adherent patients, some individuals were found to be hoarding their tablets and waiting until they were sure it was a migraine. Delaying administration of abortive medications increases the chance of incomplete treatment response, leading to patients taking more medication and in turn have more side effects [53].

Educating patients about their medications and how they need to be taken (preventive vs. abortive, when to administer) can help with adherence (Table 6). Monitoring medication use and headache frequency is an essential part of continued care for migraine patients. Maintain follow up with patients to review how they are doing with the medication and avoid providing refills without visits. The patient may not be taking medication consistently or may be using more medication than prescribed.

• What is the role of nonpharmacologic therapy?

Most patients respond to pharmacologic treatment, but some patients with mood disorder, anxiety, difficulties or disability associated with headache, and patients with difficulty managing stress or other triggers may benefit from the addition of behavioral treatments (eg, relaxation, biofeedback, cognitive behavioral therapy, stress management) [54].

Cognitive behavioral therapy and mindfulness are techniques that have been found to be effective in decreasing intensity of pain and associated disability. The goal of these techniques is to manage the cognitive, affective, and behavioral precipitants of headache. In this process, patients are helped to identify the thoughts and behavior that play a role in generating headache. These techniques have been found to improve many headache-related outcomes like pain intensity, headache-related disability, measures of quality of life, mood and medication consumption [55]. A multidisciplinary intervention that included group exercise, stress management and relaxation lectures, and massage therapy was found to reduce self-perceived pain intensity, frequency, and duration of the headache, and improve functional status and quality of life in migraineurs [56]. A randomized controlled trial of yoga therapy compared with self care showed that yoga led to significant reduction in migraine headache frequency and improved overall outcome [57].

Overall, results from studies of nonpharmacologic techniques have been mixed [58,59]. A systematic review by Sullivan et al found a large range in the efficacy of psychological interventions for migraine [60]. A 2015 systematic review that examined if cognitive behavioral therapy (CBT) can reduce the physical symptoms of chronic headache and migraines obtained mixed results [58]. Holryod et al’s study [61] found that behavioral management combined with a ß blocker is useful in improving outcomes, but neither the ß blocker alone or behavioral migraine management alone was. Also, a trial by Penzien et al showed that nonpharmacological management helped reduce migraines by 40% to 50% and this was similar to results seen with preventive drugs [62].

Patient education may be helpful in improving outcomes. Smith et al reported a 50% reduction in headache frequency at 12 months in 46% of patients who received migraine education [63]. A randomized controlled trial by Rothrock et al involving 100 migraine patients found that patients who attended a “headache school” consisting of three 90-minute educational sessions focused on topics such as acute treatment and prevention of migraine had a significant reduction in mean migraine disability assessment score (MIDAS) than the group randomized to routine medical management only. The patients also experienced a reduction in functionally incapacitating headache days per month, less need for abortive therapy and were more compliant with prophylactic therapy [64].

Case Conclusion

Our patient is a young woman with a history of headaches suggestive of migraine without aura. Since her headache frequency ranges from 4-8 headaches month, she has episodic migraines. She also has a strong family history of headaches. She denies any other medical or psychiatric comorbidity. She reports an intake of a caffeine-containing medication of 4 to 15 tablets per month.

The physician recommended that she limit her intake of the caffeine-containing medication to 5 days or less per month given the risk of migraine transformation. The physician also recommended maintaining a good sleep schedule, limiting excessive caffeine intake, a stress reduction program, regular cardiovascular exercise, and avoiding skipping or delaying meals. The patient was educated about migraine and its underlying mechanisms and the benefits of taking medications, and her fears regarding medication use and side effects were allayed. Sumatriptan 100 mg oral tablets were prescribed to be taken at headache onset. She was hesitant to be started on an antihypertensive or antiseizure medication, so she was prescribed amitriptyline 30 mg at night for headache prevention. She was also asked to maintain a headache diary. The patient was agreeable with this plan.

Summary

Migraine is often underdiagnosed and undertreated. Primary care providers are often the first point of contact for these patients. Identifying the type and frequency of migraine and comorbidities is necessary to guide appropriate management in terms of medications and lifestyle modifications. Often no testing or imaging is required. Educating patients about this chronic disease, treatment expectations, and limiting intake of medication is essential.

Corresponding author: Pooja Mohan Rao, MBBS, MD, Georgetown University Hospital, 3800 Reservoir Rd. NW, 7 PHC, Washington, DC 20007, [email protected].

Financial disclosures: Dr. Ailani reports receiving honoraria for speaking and consulting for Allergan, Avanir, and Eli Lilly.

From the Department of Neurology, Medstar Georgetown University Hospital, Washington, DC.

Abstract

• Objective: To review the epidemiology, pathophysiology, diagnosis, and treatment of migraine.
•  Methods: Review of the literature.
• Results: Migraine is a common disorder associated with significant morbidity. Diagnosis of migraine is performed according to the International Classification of Headache Disorders. Comorbidities are commonly seen with migraine and include mood disorders (depression, anxiety, post-traumatic stress disorder), musculoskeletal disorders (neck pain, fibromyalgia, Ehlors-Danlos syndrome), sleep disorders, asthma, allergies, thyroid dysfunction, obesity, irritable bowel syndrome, epilepsy, stroke, and heart disease. Comorbid conditions can increase migraine disability. Management of migraine with lifestyle modifications, trigger management, and acute and preventive medications can help reduce the frequency, duration, and severity of attacks. Overuse of medications such as opiates, barbiturates, and caffeine-containing medications can increase headache frequency. Educating patients about limiting use of these medications is important.
• Conclusion: Migraine is a common neurologic disease that can be very disabling. Recognizing the condition, making an accurate diagnosis, and starting patients on migraine-specific treatments can help improve patient outcomes.

Key words: migraine; migraine without aura; migraine with aura; management of migraine.

Migraine is a common neurologic disease that affects 1 in 10 people worldwide [1]. It is 2 to 3 times more prevalent in women than in men [2]. The prevalence of migraine peaks in both sexes during the most productive years of adulthood (age 25 to 55 years) [3]. The Global Burden of Diseases, Injuries, and Risk Factors Study considers it to be the 7th most disabling disease in the world [4]. Over 36 million people in the United States have migraine [5]. However, just 56% of migraineurs have ever been diagnosed [6].

Migraine is associated with a high rate of years lived with disability [7] and the rate has been steadily increasing since 1990. At least 50% of migraine sufferers are severely disabled, many requiring bed rest, during individual migraine attacks lasting hours to days [8]. The total U.S. annual economic costs from headache disorders, including the indirect costs from lost productivity and workplace performance, has been estimated at $31 billion [9,10].

Despite the profound impact of migraine on patients and society, there are numerous barriers to migraine care. Lipton et al [11] identified 3 steps that were minimally necessary to achieve guideline-defined appropriate acute pharmacologic therapy: (1) consulting a prescribing health care professional; (2) receiving a migraine diagnosis; and (3) using migraine-specific or other appropriate acute treatments. In a study they conducted in patients with episodic migraine, 45.5% had consulted health care professional for headache in the preceding year; of these, 86.7% reported receiving a medical diagnosis of migraine, and among the diagnosed consulters, 66.7% currently used acute migraine-specific treatments, resulting in only 26.3% individuals successfully completing all 3 steps. In the recent CaMEO study [12], the proportion patients with chronic migraine that overcame all 3 barriers was less than 5%.

The stigma of migraine often makes it difficult for people to discuss symptoms with their health care providers and family members [13]. When they do discuss their headaches with their provider, often they are not given a diagnosis [14] or do not understand what their diagnosis means [15]. It is important for health care providers to be vigilant about the diagnosis of migraine, discuss treatment goals and strategies, and prescribe appropriate migraine treatment. Migraine is often comorbid with a number of medical, neurological, and psychiatric conditions, and identifying and managing comorbidities is necessary to reduce headache burden and disability. In this article, we provide a review of the diagnosis and treatment of migraine, using a case illustration to highlight key points.

Case Study

Initial Presentation

A 24-year-old woman presents for an evaluation of her headaches.

History and Physical Examination

She initially noted headaches at age 19, which were not memorable and did not cause disability. Her current headaches are a severe throbbing pain over her right forehead. They are associated with light and sound sensitivity and stomach upset. Headaches last 6 to 7 hours without medications and occur 4 to 8 days per month.

She denies vomiting and autonomic symptoms such as runny nose or eye tearing. She also denies preceding aura. She reports headache relief with intake of tablets that contain acetaminophen/aspirin/caffeine and states that she takes between 4 to 15 tablets/month depending on headache frequency. She reports having tried acetaminophen and naproxen with no significant benefit. Aggravating factors include bright lights, strong smells, and soy/ high-sodium foods.

She had no significant past medical problems and denied a history of depression or anxiety. Family history was significant for both her father and sister having a history of headaches. The patient lived alone and denied any major life stressors. She exercises 2 times a week and denies smoking or alcohol use. Review of systems was positive for trouble sleeping, which she described as difficulty falling asleep.

On physical examination, vitals were within normal limits. BMI was 23. Chest, cardiac, abdomen, and general physical examination were all within normal limits. Neurological examination revealed no evidence of papilledema or focal neurological deficits.

• What is the pathophysiology of migraine?

Migraine was thought to be a primary vascular disorder of the brain, with the origins of the vascular theory of migraine dating back to 1684 [16]. Trials performed by Wolff concluded that migraine is of vascular origin [17], and this remained the predominant theory over several decades. Current evidence suggests that migraine is unlikely to be a pure vascular disorder and instead may be related to changes in the central or peripheral nervous system [18,19].

Migraine is complex brain network disorder with a strong genetic basis [19]. The trigemino-vascular system, along with neurogenically induced inflammation of the dura mater, mast cell degranulation and release of histamine, are the likely causes of migraine pain. Trigeminal fibers arise from neurons in the trigeminal ganglion that contain substance P and calcitonin gene-related peptide (CGRP) [20]. CGRP is a neuropeptide widely expressed in both peripheral and central neurons. Elevation of CGRP in migraine is linked to diminution of the inhibitory pathways which in turn leads to migraine susceptibility [21]. These findings have led to the development of new drugs that target the CGRP pathway.

In the brainstem, periaqueductal grey matter and the dorsolateral pons have been found to be “migraine generators,” or the driver of changes of cortical activity during migraine [22]. Brainstem nuclei are involved in modulating trigemino-vascular pain transmission and autonomic responses in migraine [23].

The hypothalamus has also been implicated in migraine pathogenesis, particularly its role in nociceptive and autonomic modulation in migraine patients. Schulte and May hypothesized that there is a network change between the hypothalamus and the areas of the brainstem generator leading to the migraine attacks [24].

The thalamus plays a central role for the processing and integration of pain stimuli from the dura mater and cutaneous regions. It maintains complex connections with the somatosensory, motor, visual, auditory, olfactory and limbic regions [25]. The structural and functional alterations in the system play a role in the development of migraine attacks, and also in the sensory hypersensitivity to visual stimuli and mechanical allodynia [26].

Experimental studies in rats show that cortical spreading depression can trigger neurogenic meningeal inflammation and subsequently activate the trigemino-vascular system [27]. It has been observed that between migraine episodes a time-dependent amplitude increase of scalp-evoked potentials to repeated stereotyped stimuli, such as visual, auditory, and somaticstimuli, occurs. This phenomenon is described as “deficient habituation.” In episodic migraine, studies show 2 characteristic changes: a deficient habituation between attacks and sensitization during the attack [28]. Genetic studies have hypothesized an involvement of glutamatergic neurotransmitters and synaptic dysplasticity in causing abnormal cortical excitability in migraine [27].

• What are diagnostic criteria for migraine?

Diagnosis of migraine is performed according to the International Classification of Headache Disorders (ICHD) [29]. Based on the number of headache days that the patient reports, migraine is classified into episodic or chronic migraine. Migraines that occur on fewer than 15 days/month are categorized as episodic migraines.

Episodic migraine is divided into 2 categories: migraine with aura (Table 1) and migraine without aura. Migraine without aura is described as recurrent headaches consisting of at least 5 attacks, each lasting 4 to 72 hours if left untreated. At least 2 of the following 4 characteristics must be present: unilateral location, pulsating quality, moderate or severe pain intensity, with aggravation by or causing avoidance of routine physical activity. During headache, at least 1 of nausea and/or vomiting or photophobia and phonophobia should be present.

In migraine with aura (Table 2), headache characteristics are the same, but in addition there are at least 2 lifetime attacks with fully reversible aura symptoms (visual, sensory, speech/language). In addition, these auras have at least 2 of the following 4 characteristics: at least 1 aura symptom spreads gradually over 5 minutes, and/or 2 or more symptoms occur in succession; each individual aura symptom lasts 5 to 60 minutes; aura symptom is unilateral; and aura is accompanied, or followed within 60 minutes, by headache. Migraine with aura is uncommon, occurring in 20% of patients with migraine [30]. Visual aura is the most common type of aura, occurring in up to 90% of patients [31]. There is also aura without migraine, called typical aura without headache. Patients can present with non-migraine headache with aura, categorized as typical aura with headache [29].

• What information should be elicited during the history?

Specific questions about the headaches can help with making an accurate diagnosis. These include:

• Length of attacks and their frequency
• Pain characteristics (location, quality, intensity)
• Actions that trigger or aggravate headaches (eg, stress, movement, bright lights, menses, certain foods and smells)
• Associated symptoms that accompany headaches (eg, nausea, vomiting)
• How the headaches impact their life (eg, missed days at work or school, missed life events, avoidance of social activities, emergency room visits due to headache)

To assess headache frequency, it is helpful to ask about the number of headache-free days in a month, eg, “how many days a month do you NOT have a headache.” To assist with headache assessment, patients can be asked to keep a calendar in which they mark days of use of medications, including over the counter medications, menses, and headache days. The calendar can be used to assess for migraine patterns, headache frequency, and response to treatment.

When asking about headache history, it is important for patients to describe their untreated headaches. Patients taking medications may have pain that is less severe or disabling or have reduced associated symptoms. Understanding what the headaches were like when they did not treat is important in making a diagnosis.

Other important questions include when was the first time they recall ever experiencing a headache. Migraine is often present early in life, and understanding the change in headache over time is important. Also ask patients about what they want to do when they have a headache. Often patients want to lie down in a cool dark room. Ask what they would prefer to do if they didn’t have any pending responsibilities.

Comorbidities

Comorbidities are commonly seen with migraine. Common comorbidities are mood disorders (depression, anxiety, post-traumatic stress disorder), musculoskeletal disorders (neck pain, fibromyalgia, Ehlors-Danlos syndrome), sleep disorders, asthma, allergies, thyroid dysfunction, obesity, irritable bowel syndrome, epilepsy, stroke, and heart disease.

Comorbid conditions can increase migraine disability and also can provide information about the pathophysiology of migraine and guide treatment. Management of the underlying comorbidity often leads to improved migraine outcomes. For example, serotonergic dysfunction is a possible pathway involved in both migraine and mood disorders. Treatment with medications that alter the serotonin system may help both migraine and coexisting mood disorders. Bigal et al proposed that activation of the HPA axis with reduced serotonin synthesis is a main pathway involved in affective disorders, migraine, and obesity [35].

In the early 1950s, Wolff conceptualized migraine as a psychophysiologic disorder [36]. The relationship between migraine and psychiatric conditions is complex, and comorbid psychiatric disorders are risk factors for headache progression and chronicity. Psychiatric conditions also play a role in nonadherence to headache medication, which contributes to poor outcome in these patients. Hence, there is a need for assessment and treatment of psychiatric disorders in people with migraine. A study by Guidetti et al found that headache patients with multiple psychiatric conditions have poor outcomes, with 86 % of these headache patients having no improvement and even deterioration in their headache [37]. Another study by Mongini et al concluded that psychiatric disorder appears to influence the result of treatment on a long-term basis [38].

In addition, migraine has been shown to impact mood disorders. Worsening headache was found to be associated with poorer prognosis for depression. Patients with active migraine not on medications with comorbid major depressive disorder (MDD) had more severe anxiety and somatic symptoms as compared with MDD patients without migraine [39].

Case Continued

Our patient has a normal neurologic examination and classic migraine headache history and stable frequency. The physician tells her she meets criteria for episodic migraine without aura. The patient asks if she needs a “brain scan” to see if something more serious may be causing her symptoms.

• What workup is recommended for patients with migraine?

If patient symptoms fit the criteria for migraine and there is a normal neurologic examination, the differential is often limited. When there are neurologic abnormalities on examination (eg, papilledema), or if the patient has concerning signs or symptoms (see below), then neuroimaging should be obtained to rule out secondary causes of headache.

In 2014, the American Academy of Neurology (AAN) published practice parameters on the evaluation of adults with recurrent headache based on guidelines published by the US Headache Consortium [40]. As per AAN guidelines, routine laboratory studies, lumbar puncture, and electroencephalogram are not recommended in the evaluation of non-acute migraines. Neuroimaging is not warranted in patients with migraine and a normal neurologic examination (grade B recommendation). Imaging may need to be considered in patients with non-acute headache and an unexplained abnormal finding on the neurologic examination (grade B recommendation).

When patients exhibit particular warning signs, or headache “red flags,” it is recommended that neuroimaging be considered. Red flags include patients with recurrent headaches and systemic symptoms (fever, weight loss), neurologic symptoms or abnormal signs (confusion, impaired alertness or consciousness), sudden onset, abrupt, or split second in nature, patients age > 50 with new onset or progressive headache, previous headache history with new or different headache (change in frequency, severity, or clinical features) and if there are secondary risk factors (HIV, cancer) [41].

Case Continued

Our patient has no red flags and can be reassured that given her normal physical examination and history suggestive of a migraine, a secondary cause of her headache is unlikely. The physician describes the treatments available, including implementing lifestyles changes and preventive and abortive medications. The patient expresses apprehension about being on prescription medications. She is concerned about side effects as well as the need to take daily medication over a long period of time. She reports that these were the main reasons she did not take the rizatriptan and propranolol that was prescribed by her previous doctor.

• How is migraine treated?

Migraine is managed with a combination of lifestyle changes and pharmacologic therapy. Pharmacologic management targets treating an attack when it occurs (abortive medication), as well as reducing the frequency and severity of future attacks (preventive medication).

Lifestyle Changes

Patients should be advised that making healthy lifestyle choices, eg, regular sleep, balanced meals, proper hydration, and regular exercise, can mitigate migraine [42–44]. Other lifestyle changes that can be helpful include weight loss in the obese population, as weight loss appears to result in migraine improvement. People who are obese also are at higher risk for the progression to chronic migraine.

Acute Therapy

There are varieties of abortive therapies [45] (Table 4) that are commonly used in clinical practice. Abortive therapy can be taken as needed and is most effective if used within the first 2 hours of headache. For patients with daily or frequent headache, these medications need to be restricted to 8 to 12 days a month of use and their use should be restricted to when headache is worsening. This usually works well in patients with moderate level pain, and especially in patients with no associated nausea. Selective migraine treatments, like triptans and ergots, are used when nonspecific treatments fail, or when headache is more severe. It is preferable that patients avoid opioids, butalbital, and caffeine-containing medications. In the real world, it is difficult to convince patient to stop these medications; it is more realistic to discuss use limitation with patients, who often run out their weekly limit for triptans.

Triptans are effective medications for acute management of migraine but headache recurrence rate is high, occurring in 15% to 40 % of patients taking oral triptans. It is difficult to predict the response to a triptan [46]. The choice of an abortive agent is often directed partially by patient preference (side effect profile, cost, non-sedating vs. prefers to sleep, long vs short half-life), comorbid conditions (avoid triptans and ergots in uncontrolled hypertension, cardiovascular disease, or peripheral vascular disease or stroke/aneurysm; avoid NSAIDS in patients with cardiovascular disease), and migraine-associated symptoms (nausea and/or vomiting). Consider non-oral formulations via subcutaneous or nasal routes in patients who have nausea or vomiting with their migraine attacks. Some patients may require more than one type of abortive medication. The high recurrence rate is similar across different triptans and so switching from one triptan to another has not been found to be useful. Adding NSAIDS to triptans has been found to be more useful than switching between triptans.Overuse of acute medications has been associated with transformation of headache from episodic to chronic (medication overuse headache or rebound headache). The risk of transformation appears to be greatest with medications containing caffeine, opiates, or barbiturates [47]. Use of acute medications should be limited based on the type of medication. Patients should take triptans for no more than 10 days a month. Combined medications and opioids should be used fewer than 8 days a month, and butalbital-containing medications should be avoided or used fewer than 5 days a month [48]. Use of acute therapy should be monitored with headache calendars. It is unclear if and to what degree NSAIDS and acetaminophen cause overuse headaches.

Medication overuse headache can be difficult to treat as patients have to stop using the medication causing rebound. Further, headaches often resemble migraine and it can be difficult to differentiate them from the patients’ routine headache. Vigilance with medication use in patients with frequent headache is an essential part of migraine management, and patients should receive clear instructions regarding how to use acute medications.

Prevention

Patients presenting with more than 4 headaches per month, or headaches that last longer than 12 hours, require preventive therapy. The goals of preventive therapy is to reduce attack frequency, severity, and duration, to improve responsiveness to treatment of acute attacks, to improve function and reduce disability, and to prevent progression or transformation of episodic migraine to chronic migraine. Preventive medications usually need to be taken daily to reduce frequency or severity of the headache. The goal in this approach is 50% reduction of headache frequency and severity. Migraine preventive medications usually belong to 1 of 3 categories of drugs: antihypertensives, antiepileptics, and antidepressants. At present there are many medications for migraine prevention with different levels of evidence [49] (Table 5). Onabotulinuma toxin is the only approved medication for chronic migraine based on promising results of the PREEMPT trial [50].

Other Considerations

A multidisciplinary approach to treatment may be warranted. Psychiatric evaluation and management of underlying depression and mood disorders can help reduce headache frequency and severity. Physical therapy should be prescribed for neck and shoulder pain. Sleep specialists should be consulted if ongoing sleep issues continue despite behavioral management.

• How common is nonadherence with migraine medication?

One third of patients who are prescribed triptans discontinue the medication within a year. Lack of efficacy and concerns over medication side effects are 2 of the most common reasons for poor adherence [51]. In addition, age plays a significant role in discontinuing medication, with the elderly population more likely to stop taking triptans [52]. Seng et al reported that among patients with migraine, being male, being single, having frequent headache, and having mild pain are all associated with medication nonadherence [53]. Formulary restrictions and type of insurance coverage also were associated with nonadherence. Among adherent patients, some individuals were found to be hoarding their tablets and waiting until they were sure it was a migraine. Delaying administration of abortive medications increases the chance of incomplete treatment response, leading to patients taking more medication and in turn have more side effects [53].

Educating patients about their medications and how they need to be taken (preventive vs. abortive, when to administer) can help with adherence (Table 6). Monitoring medication use and headache frequency is an essential part of continued care for migraine patients. Maintain follow up with patients to review how they are doing with the medication and avoid providing refills without visits. The patient may not be taking medication consistently or may be using more medication than prescribed.

• What is the role of nonpharmacologic therapy?

Most patients respond to pharmacologic treatment, but some patients with mood disorder, anxiety, difficulties or disability associated with headache, and patients with difficulty managing stress or other triggers may benefit from the addition of behavioral treatments (eg, relaxation, biofeedback, cognitive behavioral therapy, stress management) [54].

Cognitive behavioral therapy and mindfulness are techniques that have been found to be effective in decreasing intensity of pain and associated disability. The goal of these techniques is to manage the cognitive, affective, and behavioral precipitants of headache. In this process, patients are helped to identify the thoughts and behavior that play a role in generating headache. These techniques have been found to improve many headache-related outcomes like pain intensity, headache-related disability, measures of quality of life, mood and medication consumption [55]. A multidisciplinary intervention that included group exercise, stress management and relaxation lectures, and massage therapy was found to reduce self-perceived pain intensity, frequency, and duration of the headache, and improve functional status and quality of life in migraineurs [56]. A randomized controlled trial of yoga therapy compared with self care showed that yoga led to significant reduction in migraine headache frequency and improved overall outcome [57].

Overall, results from studies of nonpharmacologic techniques have been mixed [58,59]. A systematic review by Sullivan et al found a large range in the efficacy of psychological interventions for migraine [60]. A 2015 systematic review that examined if cognitive behavioral therapy (CBT) can reduce the physical symptoms of chronic headache and migraines obtained mixed results [58]. Holryod et al’s study [61] found that behavioral management combined with a ß blocker is useful in improving outcomes, but neither the ß blocker alone or behavioral migraine management alone was. Also, a trial by Penzien et al showed that nonpharmacological management helped reduce migraines by 40% to 50% and this was similar to results seen with preventive drugs [62].

Patient education may be helpful in improving outcomes. Smith et al reported a 50% reduction in headache frequency at 12 months in 46% of patients who received migraine education [63]. A randomized controlled trial by Rothrock et al involving 100 migraine patients found that patients who attended a “headache school” consisting of three 90-minute educational sessions focused on topics such as acute treatment and prevention of migraine had a significant reduction in mean migraine disability assessment score (MIDAS) than the group randomized to routine medical management only. The patients also experienced a reduction in functionally incapacitating headache days per month, less need for abortive therapy and were more compliant with prophylactic therapy [64].

Case Conclusion

Our patient is a young woman with a history of headaches suggestive of migraine without aura. Since her headache frequency ranges from 4-8 headaches month, she has episodic migraines. She also has a strong family history of headaches. She denies any other medical or psychiatric comorbidity. She reports an intake of a caffeine-containing medication of 4 to 15 tablets per month.

The physician recommended that she limit her intake of the caffeine-containing medication to 5 days or less per month given the risk of migraine transformation. The physician also recommended maintaining a good sleep schedule, limiting excessive caffeine intake, a stress reduction program, regular cardiovascular exercise, and avoiding skipping or delaying meals. The patient was educated about migraine and its underlying mechanisms and the benefits of taking medications, and her fears regarding medication use and side effects were allayed. Sumatriptan 100 mg oral tablets were prescribed to be taken at headache onset. She was hesitant to be started on an antihypertensive or antiseizure medication, so she was prescribed amitriptyline 30 mg at night for headache prevention. She was also asked to maintain a headache diary. The patient was agreeable with this plan.

Summary

Migraine is often underdiagnosed and undertreated. Primary care providers are often the first point of contact for these patients. Identifying the type and frequency of migraine and comorbidities is necessary to guide appropriate management in terms of medications and lifestyle modifications. Often no testing or imaging is required. Educating patients about this chronic disease, treatment expectations, and limiting intake of medication is essential.

Corresponding author: Pooja Mohan Rao, MBBS, MD, Georgetown University Hospital, 3800 Reservoir Rd. NW, 7 PHC, Washington, DC 20007, [email protected].

Financial disclosures: Dr. Ailani reports receiving honoraria for speaking and consulting for Allergan, Avanir, and Eli Lilly.

From the Department of Neurology, Medstar Georgetown University Hospital, Washington, DC.

Abstract

• Objective: To review the epidemiology, pathophysiology, diagnosis, and treatment of migraine.
•  Methods: Review of the literature.
• Results: Migraine is a common disorder associated with significant morbidity. Diagnosis of migraine is performed according to the International Classification of Headache Disorders. Comorbidities are commonly seen with migraine and include mood disorders (depression, anxiety, post-traumatic stress disorder), musculoskeletal disorders (neck pain, fibromyalgia, Ehlors-Danlos syndrome), sleep disorders, asthma, allergies, thyroid dysfunction, obesity, irritable bowel syndrome, epilepsy, stroke, and heart disease. Comorbid conditions can increase migraine disability. Management of migraine with lifestyle modifications, trigger management, and acute and preventive medications can help reduce the frequency, duration, and severity of attacks. Overuse of medications such as opiates, barbiturates, and caffeine-containing medications can increase headache frequency. Educating patients about limiting use of these medications is important.
• Conclusion: Migraine is a common neurologic disease that can be very disabling. Recognizing the condition, making an accurate diagnosis, and starting patients on migraine-specific treatments can help improve patient outcomes.

Key words: migraine; migraine without aura; migraine with aura; management of migraine.

Migraine is a common neurologic disease that affects 1 in 10 people worldwide [1]. It is 2 to 3 times more prevalent in women than in men [2]. The prevalence of migraine peaks in both sexes during the most productive years of adulthood (age 25 to 55 years) [3]. The Global Burden of Diseases, Injuries, and Risk Factors Study considers it to be the 7th most disabling disease in the world [4]. Over 36 million people in the United States have migraine [5]. However, just 56% of migraineurs have ever been diagnosed [6].

Migraine is associated with a high rate of years lived with disability [7] and the rate has been steadily increasing since 1990. At least 50% of migraine sufferers are severely disabled, many requiring bed rest, during individual migraine attacks lasting hours to days [8]. The total U.S. annual economic costs from headache disorders, including the indirect costs from lost productivity and workplace performance, has been estimated at $31 billion [9,10].

Despite the profound impact of migraine on patients and society, there are numerous barriers to migraine care. Lipton et al [11] identified 3 steps that were minimally necessary to achieve guideline-defined appropriate acute pharmacologic therapy: (1) consulting a prescribing health care professional; (2) receiving a migraine diagnosis; and (3) using migraine-specific or other appropriate acute treatments. In a study they conducted in patients with episodic migraine, 45.5% had consulted health care professional for headache in the preceding year; of these, 86.7% reported receiving a medical diagnosis of migraine, and among the diagnosed consulters, 66.7% currently used acute migraine-specific treatments, resulting in only 26.3% individuals successfully completing all 3 steps. In the recent CaMEO study [12], the proportion patients with chronic migraine that overcame all 3 barriers was less than 5%.

The stigma of migraine often makes it difficult for people to discuss symptoms with their health care providers and family members [13]. When they do discuss their headaches with their provider, often they are not given a diagnosis [14] or do not understand what their diagnosis means [15]. It is important for health care providers to be vigilant about the diagnosis of migraine, discuss treatment goals and strategies, and prescribe appropriate migraine treatment. Migraine is often comorbid with a number of medical, neurological, and psychiatric conditions, and identifying and managing comorbidities is necessary to reduce headache burden and disability. In this article, we provide a review of the diagnosis and treatment of migraine, using a case illustration to highlight key points.

Case Study

Initial Presentation

A 24-year-old woman presents for an evaluation of her headaches.

History and Physical Examination

She initially noted headaches at age 19, which were not memorable and did not cause disability. Her current headaches are a severe throbbing pain over her right forehead. They are associated with light and sound sensitivity and stomach upset. Headaches last 6 to 7 hours without medications and occur 4 to 8 days per month.

She denies vomiting and autonomic symptoms such as runny nose or eye tearing. She also denies preceding aura. She reports headache relief with intake of tablets that contain acetaminophen/aspirin/caffeine and states that she takes between 4 to 15 tablets/month depending on headache frequency. She reports having tried acetaminophen and naproxen with no significant benefit. Aggravating factors include bright lights, strong smells, and soy/ high-sodium foods.

She had no significant past medical problems and denied a history of depression or anxiety. Family history was significant for both her father and sister having a history of headaches. The patient lived alone and denied any major life stressors. She exercises 2 times a week and denies smoking or alcohol use. Review of systems was positive for trouble sleeping, which she described as difficulty falling asleep.

On physical examination, vitals were within normal limits. BMI was 23. Chest, cardiac, abdomen, and general physical examination were all within normal limits. Neurological examination revealed no evidence of papilledema or focal neurological deficits.

• What is the pathophysiology of migraine?

Migraine was thought to be a primary vascular disorder of the brain, with the origins of the vascular theory of migraine dating back to 1684 [16]. Trials performed by Wolff concluded that migraine is of vascular origin [17], and this remained the predominant theory over several decades. Current evidence suggests that migraine is unlikely to be a pure vascular disorder and instead may be related to changes in the central or peripheral nervous system [18,19].

Migraine is complex brain network disorder with a strong genetic basis [19]. The trigemino-vascular system, along with neurogenically induced inflammation of the dura mater, mast cell degranulation and release of histamine, are the likely causes of migraine pain. Trigeminal fibers arise from neurons in the trigeminal ganglion that contain substance P and calcitonin gene-related peptide (CGRP) [20]. CGRP is a neuropeptide widely expressed in both peripheral and central neurons. Elevation of CGRP in migraine is linked to diminution of the inhibitory pathways which in turn leads to migraine susceptibility [21]. These findings have led to the development of new drugs that target the CGRP pathway.

In the brainstem, periaqueductal grey matter and the dorsolateral pons have been found to be “migraine generators,” or the driver of changes of cortical activity during migraine [22]. Brainstem nuclei are involved in modulating trigemino-vascular pain transmission and autonomic responses in migraine [23].

The hypothalamus has also been implicated in migraine pathogenesis, particularly its role in nociceptive and autonomic modulation in migraine patients. Schulte and May hypothesized that there is a network change between the hypothalamus and the areas of the brainstem generator leading to the migraine attacks [24].

The thalamus plays a central role for the processing and integration of pain stimuli from the dura mater and cutaneous regions. It maintains complex connections with the somatosensory, motor, visual, auditory, olfactory and limbic regions [25]. The structural and functional alterations in the system play a role in the development of migraine attacks, and also in the sensory hypersensitivity to visual stimuli and mechanical allodynia [26].

Experimental studies in rats show that cortical spreading depression can trigger neurogenic meningeal inflammation and subsequently activate the trigemino-vascular system [27]. It has been observed that between migraine episodes a time-dependent amplitude increase of scalp-evoked potentials to repeated stereotyped stimuli, such as visual, auditory, and somaticstimuli, occurs. This phenomenon is described as “deficient habituation.” In episodic migraine, studies show 2 characteristic changes: a deficient habituation between attacks and sensitization during the attack [28]. Genetic studies have hypothesized an involvement of glutamatergic neurotransmitters and synaptic dysplasticity in causing abnormal cortical excitability in migraine [27].

• What are diagnostic criteria for migraine?

Diagnosis of migraine is performed according to the International Classification of Headache Disorders (ICHD) [29]. Based on the number of headache days that the patient reports, migraine is classified into episodic or chronic migraine. Migraines that occur on fewer than 15 days/month are categorized as episodic migraines.

Episodic migraine is divided into 2 categories: migraine with aura (Table 1) and migraine without aura. Migraine without aura is described as recurrent headaches consisting of at least 5 attacks, each lasting 4 to 72 hours if left untreated. At least 2 of the following 4 characteristics must be present: unilateral location, pulsating quality, moderate or severe pain intensity, with aggravation by or causing avoidance of routine physical activity. During headache, at least 1 of nausea and/or vomiting or photophobia and phonophobia should be present.

In migraine with aura (Table 2), headache characteristics are the same, but in addition there are at least 2 lifetime attacks with fully reversible aura symptoms (visual, sensory, speech/language). In addition, these auras have at least 2 of the following 4 characteristics: at least 1 aura symptom spreads gradually over 5 minutes, and/or 2 or more symptoms occur in succession; each individual aura symptom lasts 5 to 60 minutes; aura symptom is unilateral; and aura is accompanied, or followed within 60 minutes, by headache. Migraine with aura is uncommon, occurring in 20% of patients with migraine [30]. Visual aura is the most common type of aura, occurring in up to 90% of patients [31]. There is also aura without migraine, called typical aura without headache. Patients can present with non-migraine headache with aura, categorized as typical aura with headache [29].

• What information should be elicited during the history?

Specific questions about the headaches can help with making an accurate diagnosis. These include:

• Length of attacks and their frequency
• Pain characteristics (location, quality, intensity)
• Actions that trigger or aggravate headaches (eg, stress, movement, bright lights, menses, certain foods and smells)
• Associated symptoms that accompany headaches (eg, nausea, vomiting)
• How the headaches impact their life (eg, missed days at work or school, missed life events, avoidance of social activities, emergency room visits due to headache)

To assess headache frequency, it is helpful to ask about the number of headache-free days in a month, eg, “how many days a month do you NOT have a headache.” To assist with headache assessment, patients can be asked to keep a calendar in which they mark days of use of medications, including over the counter medications, menses, and headache days. The calendar can be used to assess for migraine patterns, headache frequency, and response to treatment.

When asking about headache history, it is important for patients to describe their untreated headaches. Patients taking medications may have pain that is less severe or disabling or have reduced associated symptoms. Understanding what the headaches were like when they did not treat is important in making a diagnosis.

Other important questions include when was the first time they recall ever experiencing a headache. Migraine is often present early in life, and understanding the change in headache over time is important. Also ask patients about what they want to do when they have a headache. Often patients want to lie down in a cool dark room. Ask what they would prefer to do if they didn’t have any pending responsibilities.

Comorbidities

Comorbidities are commonly seen with migraine. Common comorbidities are mood disorders (depression, anxiety, post-traumatic stress disorder), musculoskeletal disorders (neck pain, fibromyalgia, Ehlors-Danlos syndrome), sleep disorders, asthma, allergies, thyroid dysfunction, obesity, irritable bowel syndrome, epilepsy, stroke, and heart disease.

Comorbid conditions can increase migraine disability and also can provide information about the pathophysiology of migraine and guide treatment. Management of the underlying comorbidity often leads to improved migraine outcomes. For example, serotonergic dysfunction is a possible pathway involved in both migraine and mood disorders. Treatment with medications that alter the serotonin system may help both migraine and coexisting mood disorders. Bigal et al proposed that activation of the HPA axis with reduced serotonin synthesis is a main pathway involved in affective disorders, migraine, and obesity [35].

In the early 1950s, Wolff conceptualized migraine as a psychophysiologic disorder [36]. The relationship between migraine and psychiatric conditions is complex, and comorbid psychiatric disorders are risk factors for headache progression and chronicity. Psychiatric conditions also play a role in nonadherence to headache medication, which contributes to poor outcome in these patients. Hence, there is a need for assessment and treatment of psychiatric disorders in people with migraine. A study by Guidetti et al found that headache patients with multiple psychiatric conditions have poor outcomes, with 86 % of these headache patients having no improvement and even deterioration in their headache [37]. Another study by Mongini et al concluded that psychiatric disorder appears to influence the result of treatment on a long-term basis [38].

In addition, migraine has been shown to impact mood disorders. Worsening headache was found to be associated with poorer prognosis for depression. Patients with active migraine not on medications with comorbid major depressive disorder (MDD) had more severe anxiety and somatic symptoms as compared with MDD patients without migraine [39].

Case Continued

Our patient has a normal neurologic examination and classic migraine headache history and stable frequency. The physician tells her she meets criteria for episodic migraine without aura. The patient asks if she needs a “brain scan” to see if something more serious may be causing her symptoms.

• What workup is recommended for patients with migraine?

If patient symptoms fit the criteria for migraine and there is a normal neurologic examination, the differential is often limited. When there are neurologic abnormalities on examination (eg, papilledema), or if the patient has concerning signs or symptoms (see below), then neuroimaging should be obtained to rule out secondary causes of headache.

In 2014, the American Academy of Neurology (AAN) published practice parameters on the evaluation of adults with recurrent headache based on guidelines published by the US Headache Consortium [40]. As per AAN guidelines, routine laboratory studies, lumbar puncture, and electroencephalogram are not recommended in the evaluation of non-acute migraines. Neuroimaging is not warranted in patients with migraine and a normal neurologic examination (grade B recommendation). Imaging may need to be considered in patients with non-acute headache and an unexplained abnormal finding on the neurologic examination (grade B recommendation).

When patients exhibit particular warning signs, or headache “red flags,” it is recommended that neuroimaging be considered. Red flags include patients with recurrent headaches and systemic symptoms (fever, weight loss), neurologic symptoms or abnormal signs (confusion, impaired alertness or consciousness), sudden onset, abrupt, or split second in nature, patients age > 50 with new onset or progressive headache, previous headache history with new or different headache (change in frequency, severity, or clinical features) and if there are secondary risk factors (HIV, cancer) [41].

Case Continued

Our patient has no red flags and can be reassured that given her normal physical examination and history suggestive of a migraine, a secondary cause of her headache is unlikely. The physician describes the treatments available, including implementing lifestyles changes and preventive and abortive medications. The patient expresses apprehension about being on prescription medications. She is concerned about side effects as well as the need to take daily medication over a long period of time. She reports that these were the main reasons she did not take the rizatriptan and propranolol that was prescribed by her previous doctor.

• How is migraine treated?

Migraine is managed with a combination of lifestyle changes and pharmacologic therapy. Pharmacologic management targets treating an attack when it occurs (abortive medication), as well as reducing the frequency and severity of future attacks (preventive medication).

Lifestyle Changes

Patients should be advised that making healthy lifestyle choices, eg, regular sleep, balanced meals, proper hydration, and regular exercise, can mitigate migraine [42–44]. Other lifestyle changes that can be helpful include weight loss in the obese population, as weight loss appears to result in migraine improvement. People who are obese also are at higher risk for the progression to chronic migraine.

Acute Therapy

There are varieties of abortive therapies [45] (Table 4) that are commonly used in clinical practice. Abortive therapy can be taken as needed and is most effective if used within the first 2 hours of headache. For patients with daily or frequent headache, these medications need to be restricted to 8 to 12 days a month of use and their use should be restricted to when headache is worsening. This usually works well in patients with moderate level pain, and especially in patients with no associated nausea. Selective migraine treatments, like triptans and ergots, are used when nonspecific treatments fail, or when headache is more severe. It is preferable that patients avoid opioids, butalbital, and caffeine-containing medications. In the real world, it is difficult to convince patient to stop these medications; it is more realistic to discuss use limitation with patients, who often run out their weekly limit for triptans.

Triptans are effective medications for acute management of migraine but headache recurrence rate is high, occurring in 15% to 40 % of patients taking oral triptans. It is difficult to predict the response to a triptan [46]. The choice of an abortive agent is often directed partially by patient preference (side effect profile, cost, non-sedating vs. prefers to sleep, long vs short half-life), comorbid conditions (avoid triptans and ergots in uncontrolled hypertension, cardiovascular disease, or peripheral vascular disease or stroke/aneurysm; avoid NSAIDS in patients with cardiovascular disease), and migraine-associated symptoms (nausea and/or vomiting). Consider non-oral formulations via subcutaneous or nasal routes in patients who have nausea or vomiting with their migraine attacks. Some patients may require more than one type of abortive medication. The high recurrence rate is similar across different triptans and so switching from one triptan to another has not been found to be useful. Adding NSAIDS to triptans has been found to be more useful than switching between triptans.Overuse of acute medications has been associated with transformation of headache from episodic to chronic (medication overuse headache or rebound headache). The risk of transformation appears to be greatest with medications containing caffeine, opiates, or barbiturates [47]. Use of acute medications should be limited based on the type of medication. Patients should take triptans for no more than 10 days a month. Combined medications and opioids should be used fewer than 8 days a month, and butalbital-containing medications should be avoided or used fewer than 5 days a month [48]. Use of acute therapy should be monitored with headache calendars. It is unclear if and to what degree NSAIDS and acetaminophen cause overuse headaches.

Medication overuse headache can be difficult to treat as patients have to stop using the medication causing rebound. Further, headaches often resemble migraine and it can be difficult to differentiate them from the patients’ routine headache. Vigilance with medication use in patients with frequent headache is an essential part of migraine management, and patients should receive clear instructions regarding how to use acute medications.

Prevention

Patients presenting with more than 4 headaches per month, or headaches that last longer than 12 hours, require preventive therapy. The goals of preventive therapy is to reduce attack frequency, severity, and duration, to improve responsiveness to treatment of acute attacks, to improve function and reduce disability, and to prevent progression or transformation of episodic migraine to chronic migraine. Preventive medications usually need to be taken daily to reduce frequency or severity of the headache. The goal in this approach is 50% reduction of headache frequency and severity. Migraine preventive medications usually belong to 1 of 3 categories of drugs: antihypertensives, antiepileptics, and antidepressants. At present there are many medications for migraine prevention with different levels of evidence [49] (Table 5). Onabotulinuma toxin is the only approved medication for chronic migraine based on promising results of the PREEMPT trial [50].

Other Considerations

A multidisciplinary approach to treatment may be warranted. Psychiatric evaluation and management of underlying depression and mood disorders can help reduce headache frequency and severity. Physical therapy should be prescribed for neck and shoulder pain. Sleep specialists should be consulted if ongoing sleep issues continue despite behavioral management.

• How common is nonadherence with migraine medication?

One third of patients who are prescribed triptans discontinue the medication within a year. Lack of efficacy and concerns over medication side effects are 2 of the most common reasons for poor adherence [51]. In addition, age plays a significant role in discontinuing medication, with the elderly population more likely to stop taking triptans [52]. Seng et al reported that among patients with migraine, being male, being single, having frequent headache, and having mild pain are all associated with medication nonadherence [53]. Formulary restrictions and type of insurance coverage also were associated with nonadherence. Among adherent patients, some individuals were found to be hoarding their tablets and waiting until they were sure it was a migraine. Delaying administration of abortive medications increases the chance of incomplete treatment response, leading to patients taking more medication and in turn have more side effects [53].

Educating patients about their medications and how they need to be taken (preventive vs. abortive, when to administer) can help with adherence (Table 6). Monitoring medication use and headache frequency is an essential part of continued care for migraine patients. Maintain follow up with patients to review how they are doing with the medication and avoid providing refills without visits. The patient may not be taking medication consistently or may be using more medication than prescribed.

• What is the role of nonpharmacologic therapy?

Most patients respond to pharmacologic treatment, but some patients with mood disorder, anxiety, difficulties or disability associated with headache, and patients with difficulty managing stress or other triggers may benefit from the addition of behavioral treatments (eg, relaxation, biofeedback, cognitive behavioral therapy, stress management) [54].

Cognitive behavioral therapy and mindfulness are techniques that have been found to be effective in decreasing intensity of pain and associated disability. The goal of these techniques is to manage the cognitive, affective, and behavioral precipitants of headache. In this process, patients are helped to identify the thoughts and behavior that play a role in generating headache. These techniques have been found to improve many headache-related outcomes like pain intensity, headache-related disability, measures of quality of life, mood and medication consumption [55]. A multidisciplinary intervention that included group exercise, stress management and relaxation lectures, and massage therapy was found to reduce self-perceived pain intensity, frequency, and duration of the headache, and improve functional status and quality of life in migraineurs [56]. A randomized controlled trial of yoga therapy compared with self care showed that yoga led to significant reduction in migraine headache frequency and improved overall outcome [57].

Overall, results from studies of nonpharmacologic techniques have been mixed [58,59]. A systematic review by Sullivan et al found a large range in the efficacy of psychological interventions for migraine [60]. A 2015 systematic review that examined if cognitive behavioral therapy (CBT) can reduce the physical symptoms of chronic headache and migraines obtained mixed results [58]. Holryod et al’s study [61] found that behavioral management combined with a ß blocker is useful in improving outcomes, but neither the ß blocker alone or behavioral migraine management alone was. Also, a trial by Penzien et al showed that nonpharmacological management helped reduce migraines by 40% to 50% and this was similar to results seen with preventive drugs [62].

Patient education may be helpful in improving outcomes. Smith et al reported a 50% reduction in headache frequency at 12 months in 46% of patients who received migraine education [63]. A randomized controlled trial by Rothrock et al involving 100 migraine patients found that patients who attended a “headache school” consisting of three 90-minute educational sessions focused on topics such as acute treatment and prevention of migraine had a significant reduction in mean migraine disability assessment score (MIDAS) than the group randomized to routine medical management only. The patients also experienced a reduction in functionally incapacitating headache days per month, less need for abortive therapy and were more compliant with prophylactic therapy [64].

Case Conclusion

Our patient is a young woman with a history of headaches suggestive of migraine without aura. Since her headache frequency ranges from 4-8 headaches month, she has episodic migraines. She also has a strong family history of headaches. She denies any other medical or psychiatric comorbidity. She reports an intake of a caffeine-containing medication of 4 to 15 tablets per month.

The physician recommended that she limit her intake of the caffeine-containing medication to 5 days or less per month given the risk of migraine transformation. The physician also recommended maintaining a good sleep schedule, limiting excessive caffeine intake, a stress reduction program, regular cardiovascular exercise, and avoiding skipping or delaying meals. The patient was educated about migraine and its underlying mechanisms and the benefits of taking medications, and her fears regarding medication use and side effects were allayed. Sumatriptan 100 mg oral tablets were prescribed to be taken at headache onset. She was hesitant to be started on an antihypertensive or antiseizure medication, so she was prescribed amitriptyline 30 mg at night for headache prevention. She was also asked to maintain a headache diary. The patient was agreeable with this plan.

Summary

Migraine is often underdiagnosed and undertreated. Primary care providers are often the first point of contact for these patients. Identifying the type and frequency of migraine and comorbidities is necessary to guide appropriate management in terms of medications and lifestyle modifications. Often no testing or imaging is required. Educating patients about this chronic disease, treatment expectations, and limiting intake of medication is essential.

Corresponding author: Pooja Mohan Rao, MBBS, MD, Georgetown University Hospital, 3800 Reservoir Rd. NW, 7 PHC, Washington, DC 20007, [email protected].

Financial disclosures: Dr. Ailani reports receiving honoraria for speaking and consulting for Allergan, Avanir, and Eli Lilly.

BOSTON—The antiamyloid antibody aducanumab may slow cognitive decline and reduce amyloid burden in patients with Alzheimer’s disease, according to results presented at the 10th Edition of Clinical Trials on Alzheimer’s Disease (CTAD). The results are 36-month data from the phase Ib PRIME trial.

Patients who have been taking the highest dose of aducanumab, 10 mg/kg, for the duration of the study declined the least on two measures of cognition, the Mini-Mental State Exam (MMSE) and the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB). Some of the participants taking the 10-mg/kg dose became amyloid negative on PET by 24 months and stayed at a low level of amyloid until month 36, said Samantha Budd Haeberlein, PhD, Vice President of Clinical Development at Biogen in Cambridge, Massachusetts.

It is likely that the high-dose group continued to have amyloid, despite the imaging findings, said Dr. Haeberlein. “I would challenge the idea that [aducanumab] completely removed amyloid, since I think the instrument is not perfect,” she said, adding that the decreased level represents a drop below the threshold for positivity set by Eli Lilly, maker of the imaging agent florbetapir. “But we have to say that we are in a different realm here, where it can be difficult to determine whether an individual is positive or negative for amyloid pathology.”

The 36-month data support the continued development of aducanumab, said Dr. Haeberlein. The antibody is now being tested in two phase III studies, ENGAGE and EMERGE.

“The aducanumab data reported at CTAD are good news for safety and good news for the signals we need to see in the phase III trials,” said Maria Carillo, PhD, Chief Science Officer of the Alzheimer’s Association. “These are hopeful signs, but based on what we have learned from past Alzheimer’s studies, we need to wait for the phase III trial results.”

Study Examined Four Doses

Aducanumab is a monoclonal human antibody derived from B cells collected from a cohort of cognitively normal elderly subjects and cognitively impaired elderly subjects who exhibited unusually slow decline, according to Biogen. It binds to fibrillar and oligomeric amyloid aggregates, thus directly reducing amyloid plaques in the brain.

Investigators enrolled 165 patients with prodromal or mild Alzheimer’s disease into the PRIME study. All of the participants had brain amyloid on PET imaging. PRIME is the first randomized trial of an antiamyloid compound to rely solely on PET to establish participants’ amyloid positivity. These patients were randomized to placebo or 1 mg/kg, 3 mg/kg, 6 mg/kg, or 10 mg/kg of aducanumab for one year. The treatment period was followed by a two-year open-label extension. Patients who had been randomized to placebo or 1 mg/kg of aducanumab were switched to 3 mg/kg of aducanumab or to a 3-mg/kg to 6-mg/kg titration regimen in the long-term extension. Patients randomized to aducanumab at 3 mg/kg, 6 mg/kg, 10 mg/kg, or titration in the placebo-controlled period continued to receive the same dose.

The PRIME trial’s primary outcomes are safety and tolerability. The cognitive and functional outcomes, which are not usually assessed in a phase Ib study, are exploratory. The numbers in each dosing group are quite small, said Dr. Haeberlein. Of the original cohort, 117 entered the extension study, and 50 continued until 166 weeks, at which time 10 to 16 patients were in each of the dosage cohorts.

Amyloid Burden Decreased in Some Patients

At 36 months, the mean change in amyloid plaque level was greatest for the 10-mg/kg group, which, on average, no longer met the threshold of amyloid positivity on florbetapir PET. The amyloid level in the 6-mg/kg group declined to the threshold, but did not fall below it. The 1-mg/kg and 3-mg/kg groups declined at similar rates, but the decreases were not as large as in the higher-dose group.

All participants declined on the MMSE and CDR-SB. The decline, however, was clearly attenuated in some of the active groups, where the best results were seen in the 10 patients who received the 10-mg/kg dose. The average decline from baseline on the CDR-SB was 2.84 points among those patients. In the other groups, declines from baseline on the CDR-SB were 5.28 points in those who switched from placebo to 3 mg/kg, 6.11 points in those who switched from 1 mg/kg to 3 mg/kg, 3.86 points in the 3-mg/kg treatment group, and 4.49 points in the 6-mg/kg treatment group.

Patients taking 10 mg/kg also fared best on the MMSE, declining 4.10 points on average. Declines in the other groups were 7.98 points in those who switched from placebo to 3 mg/kg, 6.35 points in those who switched from 1 mg/kg to 3 mg/kg, 4.83 points in the 3-mg/kg treatment group, and 8.97 points in the 6-mg/kg treatment group. These differences were not statistically significant, said Dr. Haeberlein. “In this extension trial, we are not talking about statistical significance.”

Investigators Observed Cases of ARIA

The incidence of amyloid-related imaging abnormalities (ARIA), however, did not follow this dose-dependent pattern. All eight cases of edematous ARIA (ARIA-E) in the long-term extension phase occurred in the placebo group that switched to 1 mg/kg and in the 1-mg/kg group that was titrated to 3 mg/kg. All cases occurred early in the extension phase, no new cases occurred during the past year, and all but one case occurred in carriers of APOE4.

Hemorrhagic ARIA occurred in two controls who switched to 1 mg/kg of aducanumab, five participants taking 3 mg/kg, two participants taking 6 mg/kg, and one patient taking 10 mg/kg. These cases occurred early in the trial. All of the ARIA cases, regardless of etiology, were considered mild and resolved spontaneously. In all, 46 patients in the PRIME trial have experienced ARIA, and six have had more than one episode.

The most common adverse events in the long-term extension phase were falls, headache, and ARIA. Two patients in the extension phase died, one in the 6-mg/kg group and one in the 10-mg/kg group. Neither death was considered to be related to the study medication.

—Michele G. Sullivan

BOSTON—The antiamyloid antibody aducanumab may slow cognitive decline and reduce amyloid burden in patients with Alzheimer’s disease, according to results presented at the 10th Edition of Clinical Trials on Alzheimer’s Disease (CTAD). The results are 36-month data from the phase Ib PRIME trial.

Patients who have been taking the highest dose of aducanumab, 10 mg/kg, for the duration of the study declined the least on two measures of cognition, the Mini-Mental State Exam (MMSE) and the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB). Some of the participants taking the 10-mg/kg dose became amyloid negative on PET by 24 months and stayed at a low level of amyloid until month 36, said Samantha Budd Haeberlein, PhD, Vice President of Clinical Development at Biogen in Cambridge, Massachusetts.

It is likely that the high-dose group continued to have amyloid, despite the imaging findings, said Dr. Haeberlein. “I would challenge the idea that [aducanumab] completely removed amyloid, since I think the instrument is not perfect,” she said, adding that the decreased level represents a drop below the threshold for positivity set by Eli Lilly, maker of the imaging agent florbetapir. “But we have to say that we are in a different realm here, where it can be difficult to determine whether an individual is positive or negative for amyloid pathology.”

The 36-month data support the continued development of aducanumab, said Dr. Haeberlein. The antibody is now being tested in two phase III studies, ENGAGE and EMERGE.

“The aducanumab data reported at CTAD are good news for safety and good news for the signals we need to see in the phase III trials,” said Maria Carillo, PhD, Chief Science Officer of the Alzheimer’s Association. “These are hopeful signs, but based on what we have learned from past Alzheimer’s studies, we need to wait for the phase III trial results.”

Study Examined Four Doses

Aducanumab is a monoclonal human antibody derived from B cells collected from a cohort of cognitively normal elderly subjects and cognitively impaired elderly subjects who exhibited unusually slow decline, according to Biogen. It binds to fibrillar and oligomeric amyloid aggregates, thus directly reducing amyloid plaques in the brain.

Investigators enrolled 165 patients with prodromal or mild Alzheimer’s disease into the PRIME study. All of the participants had brain amyloid on PET imaging. PRIME is the first randomized trial of an antiamyloid compound to rely solely on PET to establish participants’ amyloid positivity. These patients were randomized to placebo or 1 mg/kg, 3 mg/kg, 6 mg/kg, or 10 mg/kg of aducanumab for one year. The treatment period was followed by a two-year open-label extension. Patients who had been randomized to placebo or 1 mg/kg of aducanumab were switched to 3 mg/kg of aducanumab or to a 3-mg/kg to 6-mg/kg titration regimen in the long-term extension. Patients randomized to aducanumab at 3 mg/kg, 6 mg/kg, 10 mg/kg, or titration in the placebo-controlled period continued to receive the same dose.

The PRIME trial’s primary outcomes are safety and tolerability. The cognitive and functional outcomes, which are not usually assessed in a phase Ib study, are exploratory. The numbers in each dosing group are quite small, said Dr. Haeberlein. Of the original cohort, 117 entered the extension study, and 50 continued until 166 weeks, at which time 10 to 16 patients were in each of the dosage cohorts.

Amyloid Burden Decreased in Some Patients

At 36 months, the mean change in amyloid plaque level was greatest for the 10-mg/kg group, which, on average, no longer met the threshold of amyloid positivity on florbetapir PET. The amyloid level in the 6-mg/kg group declined to the threshold, but did not fall below it. The 1-mg/kg and 3-mg/kg groups declined at similar rates, but the decreases were not as large as in the higher-dose group.

All participants declined on the MMSE and CDR-SB. The decline, however, was clearly attenuated in some of the active groups, where the best results were seen in the 10 patients who received the 10-mg/kg dose. The average decline from baseline on the CDR-SB was 2.84 points among those patients. In the other groups, declines from baseline on the CDR-SB were 5.28 points in those who switched from placebo to 3 mg/kg, 6.11 points in those who switched from 1 mg/kg to 3 mg/kg, 3.86 points in the 3-mg/kg treatment group, and 4.49 points in the 6-mg/kg treatment group.

Patients taking 10 mg/kg also fared best on the MMSE, declining 4.10 points on average. Declines in the other groups were 7.98 points in those who switched from placebo to 3 mg/kg, 6.35 points in those who switched from 1 mg/kg to 3 mg/kg, 4.83 points in the 3-mg/kg treatment group, and 8.97 points in the 6-mg/kg treatment group. These differences were not statistically significant, said Dr. Haeberlein. “In this extension trial, we are not talking about statistical significance.”

Investigators Observed Cases of ARIA

The incidence of amyloid-related imaging abnormalities (ARIA), however, did not follow this dose-dependent pattern. All eight cases of edematous ARIA (ARIA-E) in the long-term extension phase occurred in the placebo group that switched to 1 mg/kg and in the 1-mg/kg group that was titrated to 3 mg/kg. All cases occurred early in the extension phase, no new cases occurred during the past year, and all but one case occurred in carriers of APOE4.

Hemorrhagic ARIA occurred in two controls who switched to 1 mg/kg of aducanumab, five participants taking 3 mg/kg, two participants taking 6 mg/kg, and one patient taking 10 mg/kg. These cases occurred early in the trial. All of the ARIA cases, regardless of etiology, were considered mild and resolved spontaneously. In all, 46 patients in the PRIME trial have experienced ARIA, and six have had more than one episode.

The most common adverse events in the long-term extension phase were falls, headache, and ARIA. Two patients in the extension phase died, one in the 6-mg/kg group and one in the 10-mg/kg group. Neither death was considered to be related to the study medication.

—Michele G. Sullivan

BOSTON—The antiamyloid antibody aducanumab may slow cognitive decline and reduce amyloid burden in patients with Alzheimer’s disease, according to results presented at the 10th Edition of Clinical Trials on Alzheimer’s Disease (CTAD). The results are 36-month data from the phase Ib PRIME trial.

Patients who have been taking the highest dose of aducanumab, 10 mg/kg, for the duration of the study declined the least on two measures of cognition, the Mini-Mental State Exam (MMSE) and the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB). Some of the participants taking the 10-mg/kg dose became amyloid negative on PET by 24 months and stayed at a low level of amyloid until month 36, said Samantha Budd Haeberlein, PhD, Vice President of Clinical Development at Biogen in Cambridge, Massachusetts.

It is likely that the high-dose group continued to have amyloid, despite the imaging findings, said Dr. Haeberlein. “I would challenge the idea that [aducanumab] completely removed amyloid, since I think the instrument is not perfect,” she said, adding that the decreased level represents a drop below the threshold for positivity set by Eli Lilly, maker of the imaging agent florbetapir. “But we have to say that we are in a different realm here, where it can be difficult to determine whether an individual is positive or negative for amyloid pathology.”

The 36-month data support the continued development of aducanumab, said Dr. Haeberlein. The antibody is now being tested in two phase III studies, ENGAGE and EMERGE.

“The aducanumab data reported at CTAD are good news for safety and good news for the signals we need to see in the phase III trials,” said Maria Carillo, PhD, Chief Science Officer of the Alzheimer’s Association. “These are hopeful signs, but based on what we have learned from past Alzheimer’s studies, we need to wait for the phase III trial results.”

Study Examined Four Doses

Aducanumab is a monoclonal human antibody derived from B cells collected from a cohort of cognitively normal elderly subjects and cognitively impaired elderly subjects who exhibited unusually slow decline, according to Biogen. It binds to fibrillar and oligomeric amyloid aggregates, thus directly reducing amyloid plaques in the brain.

Investigators enrolled 165 patients with prodromal or mild Alzheimer’s disease into the PRIME study. All of the participants had brain amyloid on PET imaging. PRIME is the first randomized trial of an antiamyloid compound to rely solely on PET to establish participants’ amyloid positivity. These patients were randomized to placebo or 1 mg/kg, 3 mg/kg, 6 mg/kg, or 10 mg/kg of aducanumab for one year. The treatment period was followed by a two-year open-label extension. Patients who had been randomized to placebo or 1 mg/kg of aducanumab were switched to 3 mg/kg of aducanumab or to a 3-mg/kg to 6-mg/kg titration regimen in the long-term extension. Patients randomized to aducanumab at 3 mg/kg, 6 mg/kg, 10 mg/kg, or titration in the placebo-controlled period continued to receive the same dose.

The PRIME trial’s primary outcomes are safety and tolerability. The cognitive and functional outcomes, which are not usually assessed in a phase Ib study, are exploratory. The numbers in each dosing group are quite small, said Dr. Haeberlein. Of the original cohort, 117 entered the extension study, and 50 continued until 166 weeks, at which time 10 to 16 patients were in each of the dosage cohorts.

Amyloid Burden Decreased in Some Patients

At 36 months, the mean change in amyloid plaque level was greatest for the 10-mg/kg group, which, on average, no longer met the threshold of amyloid positivity on florbetapir PET. The amyloid level in the 6-mg/kg group declined to the threshold, but did not fall below it. The 1-mg/kg and 3-mg/kg groups declined at similar rates, but the decreases were not as large as in the higher-dose group.

All participants declined on the MMSE and CDR-SB. The decline, however, was clearly attenuated in some of the active groups, where the best results were seen in the 10 patients who received the 10-mg/kg dose. The average decline from baseline on the CDR-SB was 2.84 points among those patients. In the other groups, declines from baseline on the CDR-SB were 5.28 points in those who switched from placebo to 3 mg/kg, 6.11 points in those who switched from 1 mg/kg to 3 mg/kg, 3.86 points in the 3-mg/kg treatment group, and 4.49 points in the 6-mg/kg treatment group.

Patients taking 10 mg/kg also fared best on the MMSE, declining 4.10 points on average. Declines in the other groups were 7.98 points in those who switched from placebo to 3 mg/kg, 6.35 points in those who switched from 1 mg/kg to 3 mg/kg, 4.83 points in the 3-mg/kg treatment group, and 8.97 points in the 6-mg/kg treatment group. These differences were not statistically significant, said Dr. Haeberlein. “In this extension trial, we are not talking about statistical significance.”

Investigators Observed Cases of ARIA

The incidence of amyloid-related imaging abnormalities (ARIA), however, did not follow this dose-dependent pattern. All eight cases of edematous ARIA (ARIA-E) in the long-term extension phase occurred in the placebo group that switched to 1 mg/kg and in the 1-mg/kg group that was titrated to 3 mg/kg. All cases occurred early in the extension phase, no new cases occurred during the past year, and all but one case occurred in carriers of APOE4.

Hemorrhagic ARIA occurred in two controls who switched to 1 mg/kg of aducanumab, five participants taking 3 mg/kg, two participants taking 6 mg/kg, and one patient taking 10 mg/kg. These cases occurred early in the trial. All of the ARIA cases, regardless of etiology, were considered mild and resolved spontaneously. In all, 46 patients in the PRIME trial have experienced ARIA, and six have had more than one episode.

The most common adverse events in the long-term extension phase were falls, headache, and ARIA. Two patients in the extension phase died, one in the 6-mg/kg group and one in the 10-mg/kg group. Neither death was considered to be related to the study medication.

—Michele G. Sullivan

Today we are witnessing unprecedented rapid development and dissemination of new scientific information regarding vascular diseases, and it is becoming increasingly difficult for busy practitioners to keep up with the avalanche of information, according to Dr. Bruce A. Perler.

To help practitioners differentiate the hype from reality, the “Progress in the Medical Treatments of Vascular Disease; Vascular Diseases and Risk Prediction” session on Friday will bring together internationally respected experts in the field. These faculty will present “the latest and most important advances in the perioperative and long-term medical management of our patients in a succinct and easily digestible fashion,” said Dr. Perler of Johns Hopkins University School of Medicine, who will co-moderate the session with Dr. Caron B. Rockman of New York University School of Medicine.

Today we are witnessing unprecedented rapid development and dissemination of new scientific information regarding vascular diseases, and it is becoming increasingly difficult for busy practitioners to keep up with the avalanche of information, according to Dr. Bruce A. Perler.

To help practitioners differentiate the hype from reality, the “Progress in the Medical Treatments of Vascular Disease; Vascular Diseases and Risk Prediction” session on Friday will bring together internationally respected experts in the field. These faculty will present “the latest and most important advances in the perioperative and long-term medical management of our patients in a succinct and easily digestible fashion,” said Dr. Perler of Johns Hopkins University School of Medicine, who will co-moderate the session with Dr. Caron B. Rockman of New York University School of Medicine.

Today we are witnessing unprecedented rapid development and dissemination of new scientific information regarding vascular diseases, and it is becoming increasingly difficult for busy practitioners to keep up with the avalanche of information, according to Dr. Bruce A. Perler.

To help practitioners differentiate the hype from reality, the “Progress in the Medical Treatments of Vascular Disease; Vascular Diseases and Risk Prediction” session on Friday will bring together internationally respected experts in the field. These faculty will present “the latest and most important advances in the perioperative and long-term medical management of our patients in a succinct and easily digestible fashion,” said Dr. Perler of Johns Hopkins University School of Medicine, who will co-moderate the session with Dr. Caron B. Rockman of New York University School of Medicine.

SAN DIEGO—Masitinib may provide meaningful clinical benefits for patients with amyotrophic lateral sclerosis (ALS), according to research presented at the 142nd Annual Meeting of the American Neurological Association. Early initiation of masitinib may be more beneficial than delayed initiation.

The worldwide prevalence of ALS is approximately 235,000. By 2040, the prevalence is expected to increase by 69%. Riluzole, the only widely available drug for the treatment of ALS, has been associated with little improvement in quality of life and modest increase in survival. IV edaravone demonstrated efficacy only in patients in good clinical condition, which is estimated to be less than 7% of patients with ALS.

Masitinib, an oral tyrosine kinase inhibitor with activity against CSF1/CSF1R signaling and mast cell function, is under investigation as a therapeutic option for patients with ALS. Masitinib provides neuroprotection in the CNS and peripheral nervous system by targeting microglia and macrophage and mast cell activity. The drug has been associated with significantly slower progression of paralysis in post paralytic rats. To test this therapy in patients with ALS, Angela Genge, MD, Director of the ALS Clinic at the Montreal Neurological Institute and Hospital, and colleagues conducted a double blind, placebo-controlled, randomized trial.

A total of 394 people from nine countries were included in the study. Patients with ALS were randomized to riluzole (100 mg/kg) plus either 4.5 mg/kg/day of oral masitinib, 3.0 mg/kg/day of oral masitinib, or placebo over 48 weeks.

The primary end point was absolute change in ALS Functional Rating Scale-Revised (ALSFRS-R) at 48 weeks in patients with baseline ALSFRS-R progression of less than 1.1 points per month. Secondary end points included the 40-item ALS Assessment Questionnaire (ALSAQ-40), forced vital capacity, and survival to event (defined as ALSFRS-R deterioration of 9 points from baseline or death). Researchers categorized participants as normal progressors (ie, those with a rate of change in ALSFRS-R score < 1.1 points per month) or faster progressors (ie, those with a rate of change in ALSFRS-R score ≥ 1.1 points per month).

Masitinib showed significant benefit over placebo in ALSFRS-R. At week 48, the score had decreased by 12.6 points among controls, compared with 9.2 points in the masitinib groups. Masitinib was associated with 27% slowing of ALSFRS-R deterioration, 29% slowing of deterioration in quality of life, 22% slowing of deterioration in respiratory function, and 25% delay in disease progression.

Secondary analyses also indicated masitinib’s superiority to placebo. A post hoc analysis indicated that early treatment (ie, at less than 24 months duration of illness) conferred greater benefits than delayed treatment. Patients who had milder symptoms or shorter duration of illness showed enhanced masitinib treatment effect.Adverse events with greatest positive difference between masitinib and placebo treatment arms were maculopapular rash and peripheral edema. The rate of adverse events was 78.9% for placebo, 88.4% for the 4.5-mg/kg/day dose of masitinib, and 84.7% for the 3.0-mg/kg/day dose of masitinib. No deaths related to study treatment were reported in either masitinib or placebo groups.

—Erica Tricarico

SAN DIEGO—Masitinib may provide meaningful clinical benefits for patients with amyotrophic lateral sclerosis (ALS), according to research presented at the 142nd Annual Meeting of the American Neurological Association. Early initiation of masitinib may be more beneficial than delayed initiation.

The worldwide prevalence of ALS is approximately 235,000. By 2040, the prevalence is expected to increase by 69%. Riluzole, the only widely available drug for the treatment of ALS, has been associated with little improvement in quality of life and modest increase in survival. IV edaravone demonstrated efficacy only in patients in good clinical condition, which is estimated to be less than 7% of patients with ALS.

Masitinib, an oral tyrosine kinase inhibitor with activity against CSF1/CSF1R signaling and mast cell function, is under investigation as a therapeutic option for patients with ALS. Masitinib provides neuroprotection in the CNS and peripheral nervous system by targeting microglia and macrophage and mast cell activity. The drug has been associated with significantly slower progression of paralysis in post paralytic rats. To test this therapy in patients with ALS, Angela Genge, MD, Director of the ALS Clinic at the Montreal Neurological Institute and Hospital, and colleagues conducted a double blind, placebo-controlled, randomized trial.

A total of 394 people from nine countries were included in the study. Patients with ALS were randomized to riluzole (100 mg/kg) plus either 4.5 mg/kg/day of oral masitinib, 3.0 mg/kg/day of oral masitinib, or placebo over 48 weeks.

The primary end point was absolute change in ALS Functional Rating Scale-Revised (ALSFRS-R) at 48 weeks in patients with baseline ALSFRS-R progression of less than 1.1 points per month. Secondary end points included the 40-item ALS Assessment Questionnaire (ALSAQ-40), forced vital capacity, and survival to event (defined as ALSFRS-R deterioration of 9 points from baseline or death). Researchers categorized participants as normal progressors (ie, those with a rate of change in ALSFRS-R score < 1.1 points per month) or faster progressors (ie, those with a rate of change in ALSFRS-R score ≥ 1.1 points per month).

Masitinib showed significant benefit over placebo in ALSFRS-R. At week 48, the score had decreased by 12.6 points among controls, compared with 9.2 points in the masitinib groups. Masitinib was associated with 27% slowing of ALSFRS-R deterioration, 29% slowing of deterioration in quality of life, 22% slowing of deterioration in respiratory function, and 25% delay in disease progression.

Secondary analyses also indicated masitinib’s superiority to placebo. A post hoc analysis indicated that early treatment (ie, at less than 24 months duration of illness) conferred greater benefits than delayed treatment. Patients who had milder symptoms or shorter duration of illness showed enhanced masitinib treatment effect.Adverse events with greatest positive difference between masitinib and placebo treatment arms were maculopapular rash and peripheral edema. The rate of adverse events was 78.9% for placebo, 88.4% for the 4.5-mg/kg/day dose of masitinib, and 84.7% for the 3.0-mg/kg/day dose of masitinib. No deaths related to study treatment were reported in either masitinib or placebo groups.

—Erica Tricarico

SAN DIEGO—Masitinib may provide meaningful clinical benefits for patients with amyotrophic lateral sclerosis (ALS), according to research presented at the 142nd Annual Meeting of the American Neurological Association. Early initiation of masitinib may be more beneficial than delayed initiation.

The worldwide prevalence of ALS is approximately 235,000. By 2040, the prevalence is expected to increase by 69%. Riluzole, the only widely available drug for the treatment of ALS, has been associated with little improvement in quality of life and modest increase in survival. IV edaravone demonstrated efficacy only in patients in good clinical condition, which is estimated to be less than 7% of patients with ALS.

Masitinib, an oral tyrosine kinase inhibitor with activity against CSF1/CSF1R signaling and mast cell function, is under investigation as a therapeutic option for patients with ALS. Masitinib provides neuroprotection in the CNS and peripheral nervous system by targeting microglia and macrophage and mast cell activity. The drug has been associated with significantly slower progression of paralysis in post paralytic rats. To test this therapy in patients with ALS, Angela Genge, MD, Director of the ALS Clinic at the Montreal Neurological Institute and Hospital, and colleagues conducted a double blind, placebo-controlled, randomized trial.

A total of 394 people from nine countries were included in the study. Patients with ALS were randomized to riluzole (100 mg/kg) plus either 4.5 mg/kg/day of oral masitinib, 3.0 mg/kg/day of oral masitinib, or placebo over 48 weeks.

The primary end point was absolute change in ALS Functional Rating Scale-Revised (ALSFRS-R) at 48 weeks in patients with baseline ALSFRS-R progression of less than 1.1 points per month. Secondary end points included the 40-item ALS Assessment Questionnaire (ALSAQ-40), forced vital capacity, and survival to event (defined as ALSFRS-R deterioration of 9 points from baseline or death). Researchers categorized participants as normal progressors (ie, those with a rate of change in ALSFRS-R score < 1.1 points per month) or faster progressors (ie, those with a rate of change in ALSFRS-R score ≥ 1.1 points per month).

Masitinib showed significant benefit over placebo in ALSFRS-R. At week 48, the score had decreased by 12.6 points among controls, compared with 9.2 points in the masitinib groups. Masitinib was associated with 27% slowing of ALSFRS-R deterioration, 29% slowing of deterioration in quality of life, 22% slowing of deterioration in respiratory function, and 25% delay in disease progression.

Secondary analyses also indicated masitinib’s superiority to placebo. A post hoc analysis indicated that early treatment (ie, at less than 24 months duration of illness) conferred greater benefits than delayed treatment. Patients who had milder symptoms or shorter duration of illness showed enhanced masitinib treatment effect.Adverse events with greatest positive difference between masitinib and placebo treatment arms were maculopapular rash and peripheral edema. The rate of adverse events was 78.9% for placebo, 88.4% for the 4.5-mg/kg/day dose of masitinib, and 84.7% for the 3.0-mg/kg/day dose of masitinib. No deaths related to study treatment were reported in either masitinib or placebo groups.

—Erica Tricarico

SAN DIEGO – Among patients with mild to moderate patellofemoral osteoarthritis, intra-articular administration of the novel agent TPX-100 was safe and associated with functional benefits up to 1 year, a proof-of-concept study showed.

“We don’t yet have a disease-modifying drug for osteoarthritis [OA]; that’s sort of the holy grail for researchers,” lead study author Dawn McGuire, MD, said in an interview at the annual meeting of the American College of Rheumatology. “All of the patient-reported outcome and patient function indices that we studied moved in the same direction, showing a benefit of TPX-100. I think this is very promising.”

Doug Brunk/Frontline Medical News

[email protected]

SAN DIEGO – Among patients with mild to moderate patellofemoral osteoarthritis, intra-articular administration of the novel agent TPX-100 was safe and associated with functional benefits up to 1 year, a proof-of-concept study showed.

“We don’t yet have a disease-modifying drug for osteoarthritis [OA]; that’s sort of the holy grail for researchers,” lead study author Dawn McGuire, MD, said in an interview at the annual meeting of the American College of Rheumatology. “All of the patient-reported outcome and patient function indices that we studied moved in the same direction, showing a benefit of TPX-100. I think this is very promising.”

Doug Brunk/Frontline Medical News

[email protected]

SAN DIEGO – Among patients with mild to moderate patellofemoral osteoarthritis, intra-articular administration of the novel agent TPX-100 was safe and associated with functional benefits up to 1 year, a proof-of-concept study showed.

“We don’t yet have a disease-modifying drug for osteoarthritis [OA]; that’s sort of the holy grail for researchers,” lead study author Dawn McGuire, MD, said in an interview at the annual meeting of the American College of Rheumatology. “All of the patient-reported outcome and patient function indices that we studied moved in the same direction, showing a benefit of TPX-100. I think this is very promising.”

Doug Brunk/Frontline Medical News

[email protected]

“There is a ‘one size fits all’ strategy by a lot of people who simply read a paper or a guideline and say that’s how patients must be treated,” said co-moderator Dr. Ross Naylor, professor of vascular surgery at the University of Leicester and a consultant vascular surgeon at the Leicester Royal Infirmary. “This session will question how you actually treat your patients, so I think it will open people’s eyes toward the benefits of modern medical therapy. It also questions the role of carotid stenting in asymptomatic patients and how to reduce the risks; unless we reduce the risks, it’s going to be less likely to be adopted.”

The session has several themes, he explained. One is the benefit of optimizing best medical therapy: “There are a couple of papers on the role of starting statins before carotid surgery or carotid stenting. There’s now good evidence that if you do this, you will reduce the perioperative risk of stroke, and this needs to be emphasized more in guidelines.”

In addition, Dr. Naylor said, there is increasing evidence that patients who have asymptomatic carotid stenosis, and who are started on good quality medical therapy, have much lower annual risks of stroke than they would 15 to 20 years ago. Presentations by Dr. J. David Spence of Western University and University Hospital in London, Canada, and by Dr. Henrik Sillesen of the University of Copenhagen and Rigshospitalet, will question current attitudes toward intervening in asymptomatic patients. “Their big plea is that the majority can be treated medically,” Dr. Naylor said. “Only a small proportion actually will benefit from stenting and surgery.” Dr. Spence will address the value of Mediterranean and Nordic diets in patients with carotid stenosis, while Dr. Sillesen will examine if stenosis or plaque progression are reasons to treat asymptomatic patients with carotid artery stenting (CAS) versus carotid artery endarterectomy (CEA).

“There is a ‘one size fits all’ strategy by a lot of people who simply read a paper or a guideline and say that’s how patients must be treated,” said co-moderator Dr. Ross Naylor, professor of vascular surgery at the University of Leicester and a consultant vascular surgeon at the Leicester Royal Infirmary. “This session will question how you actually treat your patients, so I think it will open people’s eyes toward the benefits of modern medical therapy. It also questions the role of carotid stenting in asymptomatic patients and how to reduce the risks; unless we reduce the risks, it’s going to be less likely to be adopted.”

The session has several themes, he explained. One is the benefit of optimizing best medical therapy: “There are a couple of papers on the role of starting statins before carotid surgery or carotid stenting. There’s now good evidence that if you do this, you will reduce the perioperative risk of stroke, and this needs to be emphasized more in guidelines.”

In addition, Dr. Naylor said, there is increasing evidence that patients who have asymptomatic carotid stenosis, and who are started on good quality medical therapy, have much lower annual risks of stroke than they would 15 to 20 years ago. Presentations by Dr. J. David Spence of Western University and University Hospital in London, Canada, and by Dr. Henrik Sillesen of the University of Copenhagen and Rigshospitalet, will question current attitudes toward intervening in asymptomatic patients. “Their big plea is that the majority can be treated medically,” Dr. Naylor said. “Only a small proportion actually will benefit from stenting and surgery.” Dr. Spence will address the value of Mediterranean and Nordic diets in patients with carotid stenosis, while Dr. Sillesen will examine if stenosis or plaque progression are reasons to treat asymptomatic patients with carotid artery stenting (CAS) versus carotid artery endarterectomy (CEA).

“There is a ‘one size fits all’ strategy by a lot of people who simply read a paper or a guideline and say that’s how patients must be treated,” said co-moderator Dr. Ross Naylor, professor of vascular surgery at the University of Leicester and a consultant vascular surgeon at the Leicester Royal Infirmary. “This session will question how you actually treat your patients, so I think it will open people’s eyes toward the benefits of modern medical therapy. It also questions the role of carotid stenting in asymptomatic patients and how to reduce the risks; unless we reduce the risks, it’s going to be less likely to be adopted.”

The session has several themes, he explained. One is the benefit of optimizing best medical therapy: “There are a couple of papers on the role of starting statins before carotid surgery or carotid stenting. There’s now good evidence that if you do this, you will reduce the perioperative risk of stroke, and this needs to be emphasized more in guidelines.”

In addition, Dr. Naylor said, there is increasing evidence that patients who have asymptomatic carotid stenosis, and who are started on good quality medical therapy, have much lower annual risks of stroke than they would 15 to 20 years ago. Presentations by Dr. J. David Spence of Western University and University Hospital in London, Canada, and by Dr. Henrik Sillesen of the University of Copenhagen and Rigshospitalet, will question current attitudes toward intervening in asymptomatic patients. “Their big plea is that the majority can be treated medically,” Dr. Naylor said. “Only a small proportion actually will benefit from stenting and surgery.” Dr. Spence will address the value of Mediterranean and Nordic diets in patients with carotid stenosis, while Dr. Sillesen will examine if stenosis or plaque progression are reasons to treat asymptomatic patients with carotid artery stenting (CAS) versus carotid artery endarterectomy (CEA).