Comparative effectiveness and cost-effectiveness of natalizumab and fingolimod in rapidly evolving severe relapsing-remitting multiple sclerosis in the United Kingdom.

AIM: To evaluate the real-world comparative effectiveness and the cost-effectiveness, from a UK National Health Service perspective, of natalizumab versus fingolimod in patients with rapidly evolving severe relapsing-remitting multiple sclerosis (RES-RRMS). METHODS: Real-world data from the MSBase Registry were obtained for patients with RES-RRMS who were previously either naive to disease-modifying therapies or had been treated with interferon-based therapies, glatiramer acetate, dimethyl fumarate, or teriflunomide (collectively known as BRACETD). Matched cohorts were selected by 3-way multinomial propensity score matching, and the annualized relapse rate (ARR) and 6-month-confirmed disability worsening (CDW6M) and improvement (CDI6M) were compared between treatment groups. Comparative effectiveness results were used in a cost-effectiveness model comparing natalizumab and fingolimod, using an established Markov structure over a lifetime horizon with health states based on the Expanded Disability Status Scale. Additional model data sources included the UK MS Survey 2015, published literature, and publicly available sources. RESULTS: In the comparative effectiveness analysis, we found a significantly lower ARR for patients starting natalizumab compared with fingolimod (rate ratio [RR] = 0.65; 95% confidence interval [CI], 0.57-0.73) or BRACETD (RR = 0.46; 95% CI, 0.42-0.53). Similarly, CDI6M was higher for patients starting natalizumab compared with fingolimod (hazard ratio [HR] = 1.25; 95% CI, 1.01-1.55) and BRACETD (HR = 1.46; 95% CI, 1.16-1.85). In patients starting fingolimod, we found a lower ARR (RR = 0.72; 95% CI, 0.65-0.80) compared with starting BRACETD, but no difference in CDI6M (HR = 1.17; 95% CI, 0.91-1.50). Differences in CDW6M were not found between the treatment groups. In the base-case cost-effectiveness analysis, natalizumab dominated fingolimod (0.302 higher quality-adjusted life-years [QALYs] and £17,141 lower predicted lifetime costs). Similar cost-effectiveness results were observed across sensitivity analyses. CONCLUSIONS: This MSBase Registry analysis suggests that natalizumab improves clinical outcomes when compared with fingolimod, which translates to higher QALYs and lower costs in UK patients with RES-RRMS.

There are several medications used to treat people with relapsing remitting multiple sclerosis, such as interferon-based therapies (Betaferon/Betaseron (US), Rebif, Avonex, Extavia), glatiramer acetate (Copaxone), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera), collectively named BRACETD. Other treatments for multiple sclerosis (MS) have a narrower use, such as natalizumab (Tysabri) or fingolimod (Gilenya), among others.This study objective was to assess how well natalizumab and fingolimod helped treating MS (clinical effectiveness) and subsequently estimate what the cost of these treatments is in comparison to the benefit they bring to people with rapidly evolving severe MS that use them in the United Kingdom (UK) (cost-effectiveness).We used an international disease registry (MSBase), which collects clinical data from people with MS in various centers around the world to compare the effectiveness of natalizumab, fingolimod and BRACETD treatments. We used a technique called propensity score matching to obtain results from comparable patient groups. People treated with natalizumab had better disease control, namely with fewer relapses and higher improvement on their disability level, than patients on fingolimod or BRACETD. Conversely, there were no differences between each group of people on a measure called disability worsening.Based on these clinical results, we built an economic model that simulates the lifetime costs and consequences of treating people with MS with natalizumab in comparison with fingolimod. We found that using natalizumab was less costly and was more effective compared to using fingolimod in UK patients.

Genetic susceptibility for breast cancer--risk assessment and counseling.

The incorporation of genetic information into clinical oncology practice is a process in evolution, necessitating consideration of cancer risk assessment, ethical and social implications of testing and efficacy of treatment, and prevention interventions. Although most cancers do have a hereditary component, recognizing individuals who are at unusually high risk is important for planning their surveillance practices and considering options for risk management over a lifetime, and because of implications for their family members. Genetic information has enormous potential to inform and transform cancer risk identification, risk reduction, and treatment practices. In this review, we summarize basic information about breast cancer genetics, examine accumulating data about the prevalence and penetrance of deleterious mutations and management options for BRCA1 and BRCA2 mutation carriers, and discuss some of the counseling issues that may occur as physicians and patients explore this exploding area of oncology. The rapid incorporation of careful genetic testing into oncology practice is an important step toward more precise risk management. Currently, the time necessary for careful discussion of the complex issues raised by genetic testing for inherited breast/ovarian cancer susceptibility may necessitate referral to geneticists or genetic counselors for truly informed consent to be obtained. However, identification of women for whom testing is appropriate and management of cancer risk with women after testing, are critical new functions for oncologists. They are only the beginning of exciting new opportunities in cancer risk and prevention.

Life expectancy gains from cancer prevention strategies for women with breast cancer and BRCA1 or BRCA2 mutations.

CONTEXT: Women with BRCA1- or BRCA2-associated breast cancer are at increased risk for contralateral breast cancer and ovarian cancer and therefore may consider secondary cancer prevention strategies, such as prophylactic surgery and tamoxifen therapy. It is not proven to what extent these strategies reduce risk of second cancers in such patients. OBJECTIVE: To examine the effect of tamoxifen therapy, bilateral prophylactic oophorectomy (PO), prophylactic contralateral mastectomy (PCM), and combinations of these strategies on life expectancy for women with unilateral breast cancer and a BRCA1 or BRCA2 gene mutation. DESIGN AND SETTING: Decision analysis using a Markov model. Probabilities for developing contralateral breast cancer and ovarian cancer, dying from these cancers, dying from primary breast cancer, and the reduction in cancer incidence and mortality due to prophylactic surgeries and/or tamoxifen were estimated from published studies. PARTICIPANTS: Hypothetical breast cancer patients with BRCA1 or BRCA2 mutations facing decisions about secondary cancer prevention strategies. INTERVENTIONS: Seven strategies, including 5 years of tamoxifen use, PO, PCM, and combinations of these strategies, compared with careful surveillance. MAIN OUTCOME MEASURES: Total and incremental life expectancy (LE) with each intervention strategy. RESULTS: Depending on the assumed penetrance of the BRCA mutation, compared with surveillance alone, 30-year-old early-stage breast cancer patients with BRCA mutations gain in LE 0.4 to 1.3 years from tamoxifen therapy, 0.2 to 1.8 years from PO, and 0.6 to 2.1 years from PCM. The magnitude of these gains is least for women with low-penetrance mutations (assumed contralateral breast cancer risk of 24% and ovarian cancer risk of 6%) and greatest for those with high-penetrance mutations (assumed contralateral breast cancer risk of 65% and ovarian cancer risk of 40%.) Older age and poorer prognosis from primary breast cancer further attenuate these gains. CONCLUSIONS: Interventions to prevent second cancers, particularly PCM, may offer substantial LE gain for young women with BRCA-associated early-stage breast cancer. Estimates of LE gain may help women and their physicians consider the uncertainties, risks, and advantages of these interventions and lead to more informed choices about cancer prevention strategies.

Benefits of colonoscopic surveillance and prophylactic colectomy in patients with hereditary nonpolyposis colorectal cancer mutations.

BACKGROUND: Predisposition genetic testing is now possible for many hereditary cancer syndromes, including hereditary nonpolyposis colorectal cancer. The optimal management of the elevated risk for cancer in carriers of mutations for hereditary nonpolyposis colorectal cancer is unclear. OBJECTIVE: To assess the life expectancy and quality-adjusted life expectancy benefits derived from endoscopic surveillance and prophylactic colectomy for persons who carry a mutation associated with hereditary nonpolyposis colorectal cancer. DESIGN: Decision analysis model. Lifetime risk for colorectal cancer, efficacy of surveillance and colectomy, stage-specific colorectal cancer mortality, and quality of life were included in the model. SETTING: Decision about a cancer prevention strategy at the time of a positive result on genetic testing. PATIENTS: Carriers of a mutation for hereditary nonpolyposis colorectal cancer who were 25 years of age. INTERVENTIONS: Immediate prophylactic colectomy; delayed colectomy on the basis of age, adenoma, or diagnosis of colorectal cancer; and endoscopic surveillance. Prophylactic surgical options were proctocolectomy with ileoanal anastomosis and subtotal colectomy with ileorectal anastomosis. MEASUREMENTS: Life expectancy and quality-adjusted life expectancy. RESULTS: All risk-reduction strategies led to large gains in life expectancy for carriers of a mutation for hereditary nonpolyposis colorectal cancer, with benefits ranging from 13.5 years for surveillance to 15.6 years for prophylactic proctocolectomy at 25 years of age compared with no intervention. The benefits of colectomy compared with surveillance decreased with increasing age and were minimal if colectomy was performed at the time of colorectal cancer diagnosis. When health-related quality of life was considered, surveillance led to the greatest quality-adjusted life expectancy benefit (3.1 years compared with proctocolectomy and 0.3 years compared with subtotal colectomy). CONCLUSIONS: Colonoscopic surveillance is an effective method of reducing risk for cancer in carriers of a mutation for hereditary nonpolyposis colorectal cancer. The individual patient's choice between prophylactic surgery and surveillance is a complex decision in which personal preferences weigh heavily.

Decision analysis--effects of prophylactic mastectomy and oophorectomy on life expectancy among women with BRCA1 or BRCA2 mutations.

BACKGROUND: Women with BRCA1 or BRCA2 mutations have an increased risk of breast cancer and ovarian cancer. Prophylactic mastectomy and oophorectomy are often considered as ways of reducing these risks, but the effect of the procedures on life expectancy has not been established. METHODS: In a decision analysis, we compared prophylactic mastectomy and prophylactic oophorectomy with no prophylactic surgery among women who carry mutations in the BRCA1 or BRCA2 gene. We used available data about the incidence of cancer, the prognosis for women with cancer, and the efficacy of prophylactic mastectomy and oophorectomy in preventing breast and ovarian cancer to estimate the effects of these interventions on life expectancy among women with different levels of risk of cancer. RESULTS: We calculated that, on average, 30-year-old women who carry BRCA1 or BRCA2 mutations gain from 2.9 to 5.3 years of life expectancy from prophylactic mastectomy and from 0.3 to 1.7 years of life expectancy from prophylactic oophorectomy, depending on their cumulative risk of cancer. Gains in life expectancy decline with age at the time of prophylactic surgery and are minimal for 60-year-old women. Among 30-year-old women, oophorectomy may be delayed 10 years with little loss of life expectancy. CONCLUSIONS: On the basis of a range of estimates of the incidence of cancer, prognosis, and efficacy of prophylactic surgery, our model suggests that prophylactic mastectomy provides substantial gains in life expectancy and prophylactic oophorectomy more limited gains for young women with BRCA1 or BRCA2 mutations.

Assessment and counseling for women with a family history of breast cancer. A guide for clinicians.

More women in all risk categories are seeking information regarding their individual breast cancer risk, and there is a need for their primary care clinicians to be able to assess familial risk factors for breast cancer, provide individualized risk information, and offer surveillance recommendations. Estimates of the number of women with a family history of breast cancer range from approximately 5% to 20%, depending on the population surveyed. Many of these women will not have a family history that suggests the presence of a highly penetrant breast cancer susceptibility gene. However, a small subset of such women will come from families with a striking incidence of breast and other cancers often associated with inherited mutations. The development and refinement of risk prediction models provide an epidemiologic basis for counseling women with a family history that does not appear related to a dominant susceptibility gene. contrast, the recent isolation of BRCA1, the localization of BRCA2, and the acknowledgement that additional breast cancer susceptibility genes must exist provide a molecular basis for counseling some high-risk women. We present a guide for primary care clinicians that may be helpful in defining families as moderate or high risk, in determining individual risk in women with a family history of breast cancer based on this distinction, and for counseling women in a setting where the data necessary to design surveillance and prevention strategies are lacking. We include criteria for selecting women who may be candidates for detection of inherited mutations in breast cancer susceptibility genes.

Ethical, social and counselling issues in hereditary cancer susceptibility.

Genetic testing for hereditary susceptibility to disease is new. Much has been learned from experience with Huntington's disease and other non-malignant conditions. There are some differences in the case of predisposition testing for cancer: there is often the perception that cancer is preventable and sometimes curable, in contrast to other hereditary conditions. Testing raises many issues new to the medical community and to the public as well. There is great concern that the explosive technology be used responsibly, so that the potential benefits of genetic knowledge are not eclipsed by the risks to autonomy, privacy and justice. Practical concerns about insurability and discrimination may inhibit some at risk individuals from taking advantage of this powerful technology. There has been considerable effort already in the UK, Europe and the USA at the research and social levels to create protection for individuals found to carry genetic susceptibility to disease.

The impact of the prospective payment system on the treatment of hip fractures in the elderly.

A review of 386 Medicare patients with hip fractures admitted to a private, suburban, teaching hospital from 1981 through 1987 revealed that since the implementation of the prospective payment system in 1984, average hospital stays declined from 17.0 days to 12.9 days (24.1%). Although the mean number of physical therapy sessions declined from 11.1 to 9.8 (11.7%), the average number of treatments per day during the physical therapy phase actually increased from 1.2 before to 1.4 after the prospective payment system. The proportion of patients discharged to nursing homes remained the same (52.9% vs 53.6%); the proportion of patients remaining in a nursing home 6 months after hospital discharge did not differ significantly (22.6% vs 19.9%). Furthermore, there were no differences in the 6-month ambulation status. Total adjusted average hospital charges for the pre- and post-prospective payment system groups did not increase significantly ($7295 vs $7565). These findings do not support the contention that the quality of care provided Medicare patients with hip fractures has deteriorated in this hospital environment.