Inclusion of pregnant women in COVID-19 treatment trials: a review and global call to action.

Inclusion of pregnant women in COVID-19 clinical trials would allow evaluation of effective therapies that might improve maternal health, pregnancy, and birth outcomes, and avoid the delay of developing treatment recommendations for pregnant women. We explored the inclusion of pregnant women in treatment trials of COVID-19 by reviewing ten international clinical trial registries at two timepoints in 2020. We identified 155 COVID-19 treatment studies of non-biological drugs for the April 7-10, 2020 timepoint, of which 124 (80%) specifically excluded pregnant women. The same registry search for the July 10-15, 2020 timepoint, yielded 722 treatment studies, of which 538 (75%) specifically excluded pregnant women. We then focused on studies that included at least one of six drugs (remdesivir, lopinavir-ritonavir, interferon beta, corticosteroids, chloroquine and hydroxychloroquine, and ivermectin) under evaluation for COVID-19. Of 176 such studies, 130 (74%) listed pregnancy as an exclusion criterion. Of 35 studies that evaluated high-dose vitamin treatment for COVID-19, 27 (77%) excluded pregnant women. Despite the surge in treatment studies for COVID-19, the proportion excluding pregnant women remains consistent. Exclusion was not well justified as many of the treatments being evaluated have no or low safety concerns during pregnancy. Inclusion of pregnant women in clinical treatment trials is urgently needed to identify effective COVID-19 treatment for this population.

Phase II trial evaluating the clinical efficacy of cefixime for treatment of active syphilis in non-pregnant women in Brazil (CeBra).

BACKGROUND: Syphilis is a sexually and vertically transmitted infection caused by the bacteria Treponema pallidum for which there are few proven alternatives to penicillin for treatment. For pregnant women infected with syphilis, penicillin is the only WHO-recommended treatment that will treat the mother and cross the placenta to treat the unborn infant and prevent congenital syphilis. Recent shortages, national level stockouts as well as other barriers to penicillin use call for the urgent identification of alternative therapies to treat pregnant women infected with syphilis. METHODS: This prospective, randomized, non-comparative trial will enroll non-pregnant women aged 18 years and older with active syphilis, defined as a positive rapid treponemal and a positive non-treponemal RPR test with titer ≥1:16. Women will be a, domized in a 2:1 ratio to receive the oral third generation cephalosporin cefixime at a dose of 400 mg two times per day for 10 days (n = 140) or benzathine penicillin G 2.4 million units intramuscularly based on the stage of syphilis infection (n = 70). RPR titers will be collected at enrolment, and at three, six, and nine months following treatment. Participants experiencing a 4-fold (2 titer) decline by 6 months will be considered as having an adequate or curative treatment response. DISCUSSION: Demonstration of efficacy of cefixime in the treatment of active syphilis in this Phase 2 trial among non-pregnant women will inform a proposed randomized controlled trial to evaluate cefixime as an alternative treatment for pregnant women with active syphilis to evaluate prevention of congenital syphilis. TRIAL REGISTRATION: Trial identifier: www.Clinicaltrials.gov, NCT03752112. Registration Date: November 22, 2018.

Fracture risk in older, long-term survivors of early-stage breast cancer.

OBJECTIVES: To examine the effect of breast cancer and its treatment on fracture risk in older breast cancer survivors. DESIGN: A 10-year prospective cohort study beginning 5 years after a diagnosis of breast cancer for survivors and match date for comparison women. SETTING: Six integrated healthcare systems. PARTICIPANTS: Women aged 65 and older (1,286 survivors, 1,286 comparison women, mean age 77.7 in both groups, white, non-Hispanic: survivors, 81.6%; comparison women, 85.2%) who were alive and recurrence free 5 years after a diagnosis of early-stage breast cancer and matched on age, study site, and enrollment year to a comparison cohort without breast cancer. MEASUREMENTS: Cox proportional hazards models were used to estimate the association between fracture risk and survivor-comparison status, adjusting for drugs and risk factors associated with bone health. A subanalysis was used to evaluate the association between tamoxifen exposure and fracture risk. RESULTS: No difference was observed in fracture rates between groups (hazard ratio (HR) = 1.1, 95% confidence interval (CI) = 0.9-1.3). The protective effect of tamoxifen was not statistically significant (HR = 0.9, 95% CI = 0.6-1.2). CONCLUSION: Long-term survivors of early-stage breast cancer diagnosed at age 65 and older are not at greater risk of osteoporotic fractures than age-matched women without breast cancer. There appears to be no long-term protection from fractures with tamoxifen use.

Age, comorbidity, and breast cancer severity: impact on receipt of definitive local therapy and rate of recurrence among older women with early-stage breast cancer.

BACKGROUND: The definitive local therapy options for early-stage breast cancer are mastectomy and breast-conserving surgery followed by radiation therapy. Older women and those with comorbidities frequently receive breast-conserving surgery alone. The interaction of age and comorbidity with breast cancer severity and their impact on receipt of definitive therapy have not been well-studied. STUDY DESIGN: In a cohort of 1,837 women aged 65 years and older receiving treatment for early-stage breast cancer in 6 integrated health care delivery systems in 1990-1994 and followed for 10 years, we examined predictors of receiving nondefinitive local therapy and assessed the impact on breast cancer recurrence within levels of severity, defined as level of risk for recurrence. RESULTS: Age and comorbidity were associated with receipt of nondefinitive therapy. Compared with those at low risk, women at the highest risk were less likely to receive nondefinitive therapy (odds ratio = 0.32; 95% CI, 0.22-0.47), and women at moderate risk were about half as likely (odds ratio = 0.54; 95% CI, 0.35-0.84). Nondefinitive local therapy was associated with higher rates of recurrence among women at moderate (hazard ratio = 5.1; 95% CI, 1.9-13.5) and low risk (hazard ratio = 3.2; 95% CI, 1.1-8.9). The association among women at high risk was weak (hazard ratio = 1.3; 95% CI, 0.75-2.1). CONCLUSIONS: Among these older women with early-stage breast cancer, decisions about therapy partially balanced breast cancer severity against age and comorbidity. However, even among women at low risk, omitting definitive local therapy was associated with increased recurrence.

Delayed radiotherapy for breast cancer patients in integrated delivery systems.

OBJECTIVE: To identify factors associated with delayed radiotherapy (RT) in older women with early-stage breast cancer. METHODS: We studied 541 women age >or=65 years diagnosed with early-stage breast cancer in 1990-1994 at 5 integrated healthcare delivery systems and treated with breast-conserving surgery and RT, but not chemotherapy. We examined whether demographic, tumor, or treatment characteristics were associated with RT delays of >8 weeks postsurgery using chi(2) tests and multivariable logistic regression. RESULTS: Seventy-six women (14%) had delayed RT, with a median delay of 14 weeks. Even though they had insurance and access to care, nonwhite and Hispanic women were much more likely than white women to have delayed RT (odds ratio = 3.3; 95% confidence interval = 1.7, 10) in multivariable analyses that controlled for demographic and clinical variables. CONCLUSIONS: Timely RT should be facilitated through physician and patient education, navigation, and notification programs to improve quality of care. Queues for RT appointments should be evaluated on an ongoing basis to ensure adequate access. Future research should examine modifiable barriers to RT timeliness and whether delays impact long-term outcomes.

Mortality impact of less-than-standard therapy in older breast cancer patients.

BACKGROUND: The purpose of this study was to compare the rates of all-cause and breast cancer-specific mortality after breast-conserving surgery (BCS) only, BCS plus radiation therapy (RT), mastectomy, and the receipt of adjuvant tamoxifen in a large population-based cohort of older women with early-stage disease. STUDY DESIGN: This cohort study was conducted within six US integrated health-care delivery systems. Automated administrative databases, medical records, and tumor registries were used to identify women aged 65 years or older who received BCS or mastectomy to treat stage I or II breast cancer diagnosed from January 1, 1990, through December 31, 1994. We compared cause-specific 10-year mortality rates across treatment categories by fitting Cox proportional hazards models adjusted for demographics and tumor characteristics. RESULTS: We identified 1,837 women having operations for stage I or II breast cancer. Compared with women receiving mastectomy, those receiving BCS without RT were twice as likely to die of breast cancer (adjusted hazards ratio [HR]=2.19, 95% confidence interval [CI], 1.51 to 3.18). Breast cancer mortality rates were similar between women receiving BCS plus RT and women receiving mastectomy (adjusted HR=1.08, 95% CI, 0.79 to 1.48). In the subset of 886 chemotherapy-naive women treated with tamoxifen, those treated with tamoxifen for less than 1 year had a substantially higher breast cancer mortality rate than those exposed 5 years or more (adjusted HR=6.26, 95% CI, 3.10 to 12.64). CONCLUSIONS: Our findings indicate that older women receiving BCS alone have higher rates of breast cancer death than those receiving BCS + RT or mastectomy and that the survival benefit from tamoxifen increases with increasing duration of treatment.

Breast cancer treatment of older women in integrated health care settings.

PURPOSE: A substantial literature describes age-dependent variations in breast cancer treatment, showing that older women are less likely to receive standard treatment than younger women. We sought to identify patient and tumor characteristics associated with the nonreceipt of standard primary tumor and systemic adjuvant therapies. PATIENTS AND METHODS: We studied 1,859 women age 65 years or older with stage I and II breast cancer diagnosed between 1990 and 1994 who were cared for in six geographically dispersed community-based health care systems. We collected demographic, tumor, treatment, and comorbidity data from electronic data sources, including cancer registry, administrative, and clinical databases, and from subjects' medical records. RESULTS: Women 75 years of age or older and women with higher comorbidity indices were more likely to receive nonstandard primary tumor therapy, to not receive axillary lymph node dissection, and to not receive radiation therapy after breast-conserving surgery (BCS). Asian women were less likely to receive BCS, and African American women were less likely to be prescribed tamoxifen. Although nonreceipt of most therapies was associated with a lower baseline risk of recurrence, an important minority of high-risk women (16% to 30%) did not receive guideline therapies. CONCLUSION: Age is an independent risk factor for nonreceipt of effective cancer therapies, even when comorbidity and risk of recurrence are taken into account. Information regarding treatment effectiveness in this age group and tools that allow physicians and patients to estimate the benefits versus the risks of therapies, taking into account age and comorbidity burden, are critically needed.