STUDY

Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer

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Abstract

Background

The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor palbociclib, in combination with fulvestrant therapy, prolongs progression-free survival among patients with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer. We report the results of a prespecified analysis of overall survival.

Methods

We randomly assigned patients with hormone-receptor–positive, HER2-negative advanced breast cancer who had progression or relapse during previous endocrine therapy to receive palbociclib plus fulvestrant or placebo plus fulvestrant. We analyzed overall survival; the effect of palbociclib according to the prespecified stratification factors of presence or absence of sensitivity to endocrine therapy, presence or absence of visceral metastatic disease, and menopausal status; the efficacy of subsequent therapies after disease progression; and safety.

Results

Among 521 patients who underwent randomization, the median overall survival was 34.9 months (95% confidence interval [CI], 28.8 to 40.0) in the palbociclib–fulvestrant group and 28.0 months (95% CI, 23.6 to 34.6) in the placebo–fulvestrant group (hazard ratio for death, 0.81; 95% CI, 0.64 to 1.03; P=0.09; absolute difference, 6.9 months). CDK4/6 inhibitor treatment after the completion of the trial regimen occurred in 16% of the patients in the placebo–fulvestrant group. Among 410 patients with sensitivity to previous endocrine therapy, the median overall survival was 39.7 months (95% CI, 34.8 to 45.7) in the palbociclib–fulvestrant group and 29.7 months (95% CI, 23.8 to 37.9) in the placebo–fulvestrant group (hazard ratio, 0.72; 95% CI, 0.55 to 0.94; absolute difference, 10.0 months). The median duration of subsequent therapy was similar in the two groups, and the median time to the receipt of chemotherapy was 17.6 months in the palbociclib–fulvestrant group, as compared with 8.8 months in the placebo–fulvestrant group (hazard ratio, 0.58; 95% CI, 0.47 to 0.73; P<0.001). No new safety signals were observed with 44.8 months of follow-up.

Conclusions

Among patients with hormone-receptor–positive, HER2-negative advanced breast cancer who had sensitivity to previous endocrine therapy, treatment with palbociclib–fulvestrant resulted in longer overall survival than treatment with placebo–fulvestrant. The differences in overall survival in the entire trial group were not significant.

n 2018, approximately 266,000 new cases of breast cancer are estimated to occur in women in the United States, with 41,000 deaths.1 Of these, hormone-receptor–positive breast cancer is the most common disease subtype.2 The cyclin-dependent kinases 4 and 6 (CDK4/6) are key promoters of tumor growth in hormone-receptor–positive breast cancer, cooperating with estrogen-receptor pathway activation.3,4 Preclinical models of hormone-receptor–positive breast cancer were highly sensitive to the CDK4/6 inhibitor palbociclib (Ibrance, Pfizer),4 and in a subsequent phase 2 study (Palbociclib: Ongoing Trials in the Management of Breast Cancer [PALOMA]–1), palbociclib resulted in a progression-free survival benefit in patients with previously untreated, estrogen-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer.5 Subsequently, the randomized, phase 3 trial PALOMA-2 confirmed that palbociclib substantially prolonged progression-free survival, in combination with letrozole, as first-line therapy for estrogen-receptor–positive, HER2-negative advanced breast cancer (hazard ratio for disease progression or death, 0.58; 95% confidence interval [CI], 0.46 to 0.72).6

In the phase 3 trial PALOMA-3, we assessed whether treatment with palbociclib, in combination with fulvestrant, prolonged progression-free survival among patients with hormone-receptor–positive, HER2-negative advanced breast cancer who had disease progression after previous endocrine therapy. The primary aim of the trial was met, with the trial showing significantly longer progression-free survival with combination palbociclib–fulvestrant therapy than with placebo–fulvestrant (median, 11.2 months [95% CI, 9.5 to 12.9] vs. 4.6 months [95% CI, 3.5 to 5.6]; hazard ratio for disease progression or death, 0.50; 95% CI, 0.40 to 0.62; absolute difference, 6.6 months).7-9

Palbociclib and other CDK4/6 inhibitors in combination with endocrine therapy have become a standard of care on the basis of prolonged progression-free survival.5,10,11 However, long-term data regarding the effect of palbociclib on overall survival and the efficacy of subsequent therapy have been limited. Here, we report the results of a prespecified analysis of the PALOMA-3 trial in which we assessed the effect of palbociclib on overall survival and the efficacy of therapies administered after disease progression.

Methods

Trial Design and Patients

We conducted this prospective, international, randomized, double-blind, placebo-controlled, phase 3 trial to compare treatment with palbociclib–fulvestrant with placebo–fulvestrant in women with hormone-receptor–positive, HER2-negative advanced breast cancer who had disease progression after previous endocrine therapy. Patients were randomly assigned, in a 2:1 ratio, to receive either palbociclib (at a dose of 125 mg, administered orally, once daily for 21 consecutive days, followed by 7 days off, to comprise a complete cycle of 28 days) plus fulvestrant (at a dose of 500 mg, administered as an intramuscular injection according to standard of care, every 14 days for the first three injections and then every 28 days) or placebo plus fulvestrant. Crossover between the two groups was not permitted.

Women were enrolled regardless of menopausal status; postmenopausal women were at least 60 years of age, had undergone bilateral oophorectomy, or were younger than 60 years of age and had had a cessation of regular menses for at least 12 consecutive months. Premenopausal or perimenopausal patients were required to receive concurrent goserelin for at least 4 weeks before the start of the trial intervention and to continue receiving it every 28 days for the duration of the trial intervention.

Randomization was stratified according to the presence or absence of documented sensitivity to previous endocrine therapy, the presence or absence of visceral metastatic disease, and menopausal status at trial entry. Sensitivity to previous endocrine therapy was defined as either a documented clinical benefit (complete response, partial response, or stable disease for ≥24 weeks) from at least one previous endocrine therapy regimen in the context of metastatic disease or the receipt of at least 24 months of adjuvant endocrine therapy before recurrence. Detailed methods of this trial have been reported previously.7,8 The protocol, with the statistical analysis plan, is available with the full text of this article at NEJM.org.

End Points

The primary end point, investigator-assessed progression-free survival, was reported previously.7,8 Overall survival, a prespecified key secondary end point, was defined as the time from randomization to death from any cause. Exploratory analyses included the investigator-assessed time receiving subsequent therapy (i.e., the time from randomization to the end of the immediate subsequent line of therapy after disease progression) and time from randomization to the receipt of chemotherapy. Safety data were updated with additional follow-up time.

Oversight

The trial was designed by an academic steering committee that included representatives of the sponsor (Pfizer). Data were gathered by representatives of the sponsor. All the authors confirm that the trial conformed to the protocol and attest to the accuracy and completeness of the data. All the authors and participating institutions have agreements with the sponsor regarding confidentiality of the data. The first author wrote the first draft of the manuscript. All the authors had full access to the data and were involved in interpreting the data, in writing and reviewing subsequent drafts of the manuscript, and in making the decision to submit the manuscript for publication. A professional medical writer provided editorial assistance and was paid by the sponsor. AstraZeneca provided fulvestrant and had no involvement with the data collection or analysis or with any aspect of the manuscript preparation.

The trial was approved by the institutional review board at each site, and all the patients provided written informed consent before enrollment. The trial was conducted according to the principles of Good Clinical Practice and the Declaration of Helsinki. The conduct of the trial was monitored by an academic steering committee.

Statistical Analysis

The median overall survival among women with advanced or metastatic breast cancer who are treated with fulvestrant monotherapy was assumed to be 24 months. The trial was powered for its primary end point, progression-free survival. The planned final analysis of overall survival was performed after approximately 60% data maturity (i.e., when death had occurred in 60% of the 521 patients who had undergone randomization), with one interim analysis of overall survival conducted at the time of the interim analysis of progression-free survival, when 28 deaths had occurred, and one interim analysis conducted when 112 deaths had occurred. The family-wise error rate was protected at the one-sided 0.025 level, with a hierarchical testing strategy between progression-free survival and overall survival.12,13 The median overall survival was estimated with the use of the Kaplan–Meier method, and the significance was determined with the use of a one-sided log-rank test with stratification according to presence or absence of sensitivity to previous endocrine therapy and the presence or absence of visceral metastases at randomization in the intention-to-treat population. All the P values reported herein are two-sided. The prespecified significance threshold was a two-sided P value of 0.047, which was adjusted for the planned interim analyses. The rank-preserving structural-failure time method was used as a sensitivity analysis to evaluate the effect of crossover to receive a CDK4/6 inhibitor in the placebo–fulvestrant group after the completion of the trial intervention. The rank-preserving structural-failure time analysis is based on the intention-to-treat population and can provide a more accurate estimation of the treatment effect by correcting for crossover between groups.14,15

Results

Patients

A total of 521 patients were enrolled between October 7, 2013, and August 26, 2014 (Fig. S1 in the Supplementary Appendix, available at NEJM.org). A total of 347 patients were randomly assigned to the palbociclib–fulvestrant group and 174 to the placebo–fulvestrant group (intention-to-treat population). A total of 345 patients in the palbociclib–fulvestrant group and 172 in the placebo–fulvestrant group received at least one dose of the assigned intervention (safety population).

Double-blinding was maintained after both the primary analysis and the interim analysis. After a request from the investigator, unblinding occurred in 12 patients (3%) who received palbociclib and in 18 (10%) who received placebo. Most of these unblinding events (in 7 patients in the palbociclib–fulvestrant group and in 17 in the placebo–fulvestrant group) occurred after disease progression.

Overall Survival

Figure 1. Overall Survival in the Overall Population and According to Subgroup.

The data regarding overall survival were analyzed at a cutoff date of April 13, 2018, with a median follow-up of 44.8 months and 60% data maturity (310 deaths among 521 patients). A total of 201 deaths occurred in the palbociclib–fulvestrant group, and 109 deaths in the placebo–fulvestrant group. The median overall survival was 34.9 months (95% CI, 28.8 to 40.0) in the palbociclib–fulvestrant group and 28.0 months (95% CI, 23.6 to 34.6) in the placebo–fulvestrant group. The stratified hazard ratio for death was 0.81 (95% CI, 0.64 to 1.03; P=0.09) (Figure 1A). The unstratified hazard ratio was 0.79 (95% CI, 0.63 to 1.00). The estimated rate of overall survival at 3 years in the Kaplan–Meier analysis was 50% (95% CI, 44 to 55) in the palbociclib–fulvestrant group and 41% (95% CI, 33 to 48) in the placebo–fulvestrant group.Figure 2. Overall Survival According to Patients’ Sensitivity to Previous Endocrine Therapy.

Subgroup analyses of overall survival were performed in prespecified subgroups (Figure 1B). The three prespecified stratification factors were the presence or absence of sensitivity to previous endocrine therapy, the presence or absence of visceral metastatic disease, and menopausal status. Among 410 patients with documented sensitivity to previous endocrine therapy, the median overall survival was 39.7 months (95% CI, 34.8 to 45.7) in the palbociclib–fulvestrant group and 29.7 months (95% CI, 23.8 to 37.9) in the placebo–fulvestrant group (hazard ratio for death, 0.72; 95% CI, 0.55 to 0.94) (Figure 1B and Figure 2A). Among 111 patients without documented sensitivity to previous endocrine therapy (also referred to as intrinsic endocrine resistance), the median overall survival was 20.2 months (95% CI, 17.2 to 26.4) in the palbociclib–fulvestrant group and 26.2 months (95% CI, 17.5 to 31.8) in the placebo–fulvestrant group (hazard ratio, 1.14; 95% CI, 0.71 to 1.84; P=0.12 for interaction) (Figure 1B and Figure 2B). In the updated analysis of PALOMA-3, which was conducted at a data cutoff of October 23, 2015, patients with sensitivity to previous endocrine therapy had progression-free survival that was 7.8 months longer in the palbociclib–fulvestrant group than in the placebo–fulvestrant group (hazard ratio for disease progression or death, 0.46; 95% CI, 0.36 to 0.59), whereas patients with intrinsic endocrine resistance had progression-free survival that was 2.3 months longer (hazard ratio, 0.69; 95% CI, 0.43 to 1.09) (Fig. S2 in the Supplementary Appendix).

Among 311 patients with visceral metastatic disease, the median overall survival was 27.6 months (95% CI, 24.4 to 31.2) in the palbociclib–fulvestrant group and 24.7 months (95% CI, 20.8 to 31.8) in the placebo–fulvestrant group (hazard ratio for death, 0.85; 95% CI, 0.64 to 1.13) (Figure 1B). Among 210 patients without visceral metastatic disease, the median overall survival was 46.9 months (95% CI, 39.3 to could not be estimated) in the palbociclib–fulvestrant group and 35.4 months (95% CI, 24.6 to could not be estimated) in the placebo–fulvestrant group (hazard ratio, 0.69; 95% CI, 0.46 to 1.04; P=0.44 for interaction) (Figure 1B).

Among 413 postmenopausal patients, the median overall survival was 34.8 months (95% CI, 28.8 to 40.1) in the palbociclib–fulvestrant group and 27.1 months (95% CI, 22.8 to 32.1) in the placebo–fulvestrant group (hazard ratio for death, 0.73; 95% CI, 0.57 to 0.95) (Figure 1B, and Fig. S3A in the Supplementary Appendix). Among 108 premenopausal or perimenopausal patients, the median overall survival was 38.0 months (95% CI, 24.4 to could not be estimated) in the palbociclib–fulvestrant group and 38.0 months (95% CI, 22.2 to could not be estimated) in the placebo–fulvestrant group (hazard ratio, 1.07; 95% CI, 0.61 to 1.86; P=0.25 for interaction) (Figure 1B, and Fig. S3B in the Supplementary Appendix).

An exploratory subgroup analysis evaluated overall survival according to ESR1 and PIK3CA mutation status, as assessed in baseline circulating tumor DNA. The median overall survival was longer with palbociclib–fulvestrant than with placebo–fulvestrant among patients with baseline ESR1 mutations than among those without such mutations (absolute difference, 11.0 months among patients with ESR1 mutations and 4.7 months among those without such mutations; P=0.60 for interaction) (Figure 1B). The absolute between-group differences in overall survival were similar among patients with baseline PIK3CA mutations and those without such mutations (6.4 months and 5.8 months, respectively; P=0.64 for interaction) (Figure 1B).

Exposure to Trial Intervention

Figure 3. Time from Randomization to the End of the Trial Intervention.

The median number of cycles of therapy received was 12 (interquartile range, 4 to 21) in the palbociclib–fulvestrant group and 5 (interquartile range, 2 to 12) in the placebo–fulvestrant group. The Kaplan–Meier estimate of the rate of patients continuing the trial intervention at 24 months was 23% (95% CI, 19 to 28) in the palbociclib–fulvestrant group and 10% (95% CI, 6 to 15) in the placebo–fulvestrant group, and the rate at 36 months was 14% (95% CI, 11 to 18) and 5% (95% CI, 3 to 9), respectively (Figure 3). At the time of the analysis, 35 patients (10%) were continuing to receive the trial intervention in the palbociclib–fulvestrant group (median duration, 45.4 months; range, 44.2 to 51.4), as compared with 6 patients (3%) in the placebo–fulvestrant group (median duration, 44.7 months; range, 44.2 to 45.6).

Disease Progression after Trial Intervention

Table 1. Systemic Anticancer Therapies Received as First, Second, and Third or Greater Lines of Subsequent Treatment by More Than 10% of the Patients in Either Trial Group Who Discontinued the Intervention.

In the intention-to-treat population, 389 patients (75%) received therapy after the end of trial intervention. The median number of lines of treatment received after disease progression was 2 (range, 1 to 10) in the palbociclib–fulvestrant group and 3 (range, 1 to 10) in the placebo–fulvestrant group. The type of subsequent treatment was similar in the two trial groups, except for subsequent CDK4/6 inhibitor treatment (Table 1). Approximately 40% of the patients in each group received endocrine-based therapy as the immediate subsequent line of treatment.

Although the protocol did not allow patients to cross over to receive palbociclib, treatment with a CDK4/6 inhibitor in the subsequent or following lines of treatment after the trial intervention occurred in 4% of patients in the palbociclib–fulvestrant group and 16% of those in the placebo–fulvestrant group (Table 1). We performed a sensitivity analysis to explore the effect of this crossover on overall survival. The rank-preserving structural-failure time analysis suggested a small decrease in overall survival in the placebo–fulvestrant group after correction for the crossover effect of 27 patients (median overall survival, 27.4 months [95% CI, 23.8 to 35.4]; stratified hazard ratio for death in the palbociclib–fulvestrant group vs. the crossover-corrected placebo–fulvestrant group, 0.78 [bootstrapped 95% CI, 0.61 to 1.04]; unstratified hazard ratio, 0.77 [bootstrapped 95% CI, 0.60 to 1.00]), as compared with a median overall survival of 28.0 months before adjustment.

Time Receiving Subsequent Line of Therapy

In exploratory analyses, we analyzed the time from randomization to the end of the immediate subsequent line of therapy after disease progression, which was 18.8 months (95% CI, 16.4 to 20.5) in the palbociclib–fulvestrant group and 14.1 months (95% CI, 12.0 to 16.7) in the placebo–fulvestrant group (hazard ratio, 0.68; 95% CI, 0.56 to 0.84; P<0.001). The time from randomization to the first use of chemotherapy after disease progression was 17.6 months (95% CI, 15.2 to 19.7) in the palbociclib–fulvestrant group, as compared with 8.8 months (95% CI, 7.3 to 12.7) in the placebo–fulvestrant group (hazard ratio, 0.58; 95% CI, 0.47 to 0.73; P<0.001). The duration of the immediate subsequent line of therapy, according to type of treatment, was similar in the palbociclib–fulvestrant group and the placebo–fulvestrant group. Details are provided in Figures S4 and S5 in the Supplementary Appendix.

Adverse Events

The adverse-event profile of palbociclib–fulvestrant remained consistent with that in the primary analysis (Table S1 in the Supplementary Appendix).7 Neutropenia of grade 3 or 4 occurred in 70% of the patients receiving palbociclib–fulvestrant and in none of the patients receiving placebo–fulvestrant, anemia of grade 3 or 4 occurred in 4% and 2% of the patients, respectively, and thrombocytopenia of grade 3 or 4 occurred in 3% and none of the patients, respectively. Febrile neutropenia remained uncommon, occurring in 1% of the patients (3 of 345 patients) who received palbociclib–fulvestrant and in none of those who received placebo–fulvestrant. Nonhematologic adverse events of grade 3 or 4 were also uncommon. Events of grade 3 or 4 that occurred at a frequency of more than 2% of the patients in the palbociclib–fulvestrant group were infections (in 5% of the patients in the palbociclib–fulvestrant group and in 3% of those in the placebo–fulvestrant group), fatigue (in 3% and 1%, respectively), and elevation in the aspartate aminotransferase level (in 3% and 2%).

Discussion

Although the results of the analysis of overall survival did not meet the prespecified threshold for statistical significance, the addition of palbociclib to fulvestrant resulted in an absolute prolongation of overall survival of 6.9 months among patients with hormone-receptor–positive, HER2-negative advanced breast cancer who had disease progression after previous endocrine therapy. This result is consistent with the significant prolongation in progression-free survival that was observed with the addition of palbociclib to fulvestrant (Fig. S6 in the Supplementary Appendix). Among patients with previous sensitivity to endocrine therapy, one of the largest subpopulations enrolled in the trial, overall survival was prolonged by 10.0 months.

Multiple studies have shown that the addition of CDK4/6 inhibitors to endocrine therapy results in substantially prolonged progression-free survival. Improvement has been observed in combination with aromatase inhibitors6,16-18 and fulvestrant7,19,20 for palbociclib, ribociclib, and abemaciclib therapy. A key issue has been the extent to which this benefit in progression-free survival translates to a prolongation of overall survival. In the PALOMA-3 trial, we found that the magnitude of improvement in progression-free survival (6.6 months longer with the addition of palbociclib to fulvestrant)9 translates directly to an improvement in overall survival of similar magnitude in the overall group of trial patients (6.9 months longer), but the difference did not reach statistical significance. This improvement was associated with a longer time from randomization to the end of the immediate subsequent line of therapy after disease progression and a longer time from randomization to the first use of chemotherapy after disease progression among patients treated with palbociclib–fulvestrant than among those who received placebo–fulvestrant. Furthermore, with this longer follow-up, a subgroup of patients who were treated with palbociclib–fulvestrant had a very long duration of disease control, with 14% of the patients continuing in the trial after 3 years of treatment with palbociclib–fulvestrant, as compared with 5% of those receiving placebo–fulvestrant.

Final data regarding overall survival from phase 3 trials of letrozole and CDK4/6 inhibitors are limited. These trials all have lower power for the statistical analysis of overall survival than for the statistical analysis of progression-free survival, and therefore the data presented in this article should be interpreted cautiously when deciding on the timing of CDK4/6 inhibitor therapy. Our data support the use of palbociclib–fulvestrant in patients with disease recurrence during endocrine therapy after at least 2 years of adjuvant therapy or in patients who received endocrine therapy alone for metastatic disease with clinical benefit. For patients for whom first-line aromatase inhibitor–based therapy is a standard of care or those who do not have a relapse while they are receiving an aromatase inhibitor, our findings do not inform the timing of palbociclib therapy.

The results regarding overall survival in the PALOMA-3 trial show the substantial challenges of finding a significant prolongation of overall survival in the context of a disease in which survival after disease progression is substantially longer than the time in the trial.21 To design a trial in this context that would detect a significant improvement in overall survival to result in a hazard ratio for death of 0.80 would have required a much larger trial. Accordingly, an 80% power calculation would involve more than 700 events, as compared with the approximate 46% power that results from the 310 deaths among the 521 patients who were enrolled in this trial. Future meta-analyses of CDK4/6 inhibitor studies may provide a more robust assessment of the effect of this class of drugs on overall survival, including in subgroups of patients. This trial also shows a further challenge of finding a significant benefit, because 16% of the patients in the placebo–fulvestrant group crossed over to receive a CDK4/6 inhibitor as subsequent therapy because of the commercial availability of this class of agents. Crossover to receive an investigational drug after disease progression may attenuate the observed advantage in overall survival22 and probably resulted in a modest prolongation of overall survival in the control group, thereby further reducing the power of the trial to show a significant benefit.

A planned subgroup analysis of overall survival regarding the three prespecified stratification factors identified the patients who derived the most benefit from palbociclib. In particular, patients with sensitivity to previous endocrine therapy had a substantial benefit, whereas those with intrinsic endocrine resistance had a limited benefit. This differential benefit in terms of overall survival closely mirrors the absolute prolongation of progression-free survival that was observed with palbociclib in these two populations. These data confirm that palbociclib was highly effective in augmenting responses in endocrine-sensitive cancers, but the effect may be more limited in tumors with intrinsic endocrine resistance. However, relatively few patients with intrinsic endocrine resistance were recruited in the trial, which limits the assessment of palbociclib in these patients.

Although palbociclib–fulvestrant resulted in a longer median overall survival than placebo–fulvestrant among postmenopausal patients but not among premenopausal or perimenopausal patients, this disparity can be attributed in part to the small size of the subgroup of premenopausal or perimenopausal patients and may also reflect variance in the proportion of patients with intrinsic endocrine resistance in the two subgroups. In the subgroup of premenopausal or perimenopausal patients, the percentage of patients with intrinsic endocrine resistance was higher than in the postmenopausal subgroup (30% vs. 19%).23 Because patients with intrinsic endocrine resistance may have limited benefit from endocrine therapy in combination with palbociclib, the overall survival benefit is difficult to ascertain. Furthermore, an imbalance in certain prognostic factors between the palbociclib–fulvestrant group and the placebo–fulvestrant group in the subgroup of premenopausal or perimenopausal patients favored the control group. Premenopausal or perimenopausal patients who had been randomly assigned to the placebo–fulvestrant group had received fewer lines of previous therapy than those who had been randomly assigned to the palbociclib–fulvestrant group (lines of previous therapy, 0 or 1: 72% of the patients in the placebo–fulvestrant group vs. 58% of those in the palbociclib–fulvestrant group), and fewer patients were 40 years of age or younger (22% of patients in the placebo–fulvestrant group vs. 35% of those in the palbociclib–fulvestrant group).23

The duration of the immediate subsequent line of therapy after disease progression after the completion of trial intervention was similar in the palbociclib–fulvestrant group and the placebo–fulvestrant group, which shows that standard treatments had similar efficacy after progression while patients were receiving palbociclib or placebo (Fig. S5 in the Supplementary Appendix). Research on the mechanisms of resistance to CDK4/6 inhibitors in the PALOMA-3 trial indicated that disease progression during palbociclib–fulvestrant treatment was due predominantly to endocrine resistance.24,25 Analysis of circulating tumor DNA in plasma samples obtained at the end of the trial intervention revealed that the genetic profile at the end of the trial intervention was largely similar in patients treated with palbociclib and those who received placebo, with the exception of retinoblastoma (RB1) mutations that were selected in 5% of the patients who had progression during palbociclib treatment.24 The data regarding overall survival in this trial suggest that the low rate of RB1 mutations selected by palbociclib has no overall detectable effect on either overall survival or sensitivity to subsequent therapies after progression during trial treatment.

Taken together, the data from the PALOMA-3 trial showed that palbociclib in combination with fulvestrant led to a 6.9-month prolongation of overall survival, although the finding did not reach significance in the intention-to-treat population. In the subgroup of patients with sensitivity to previous endocrine therapy, overall survival was 10 months longer with palbociclib–fulvestrant than with placebo–fulvestrant.

Source: NEJM

Adjuvant Intravesical Chemohyperthermia Versus Passive Chemotherapy in Patients with Intermediate-risk Non-muscle-invasive Bladder Cancer (HIVEC-II): A Phase 2, Open-label, Randomised Controlled Trial.

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BACKGROUND: Adjuvant intravesical chemotherapy following tumour resection is recommended for intermediate-risk non-muscle-invasive bladder cancer (NMIBC).

OBJECTIVE: To assess the efficacy and safety of adjuvant intravesical chemohyperthermia (CHT) for intermediate-risk NMIBC.

DESIGN, SETTING, AND PARTICIPANTS: HIVEC-II is an open-label, phase 2 randomised controlled trial of CHT versus chemotherapy alone in patients with intermediate-risk NMIBC recruited at 15 centres between May 2014 and December 2017 (ISRCTN 23639415). Randomisation was stratified by treating hospital.

INTERVENTIONS: Patients were randomly assigned (1:1) to adjuvant CHT with mitomycin C at 43°C or to room-temperature mitomycin C (control). Both treatment arms received six weekly instillations of 40 mg of mitomycin C lasting for 60 min.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was 24-mo disease-free survival as determined via cystoscopy and urinary cytology. Analysis was by intention to treat.

RESULTS: A total of 259 patients (131 CHT vs 128 control) were randomised. At 24 mo, 42 patients (32%) in the CHT group and 49 (38%) in the control group had experienced recurrence. Disease-free survival at 24 mo was 61% (95% confidence interval [CI] 51-69%) in the CHT arm and 60% (95% CI 50-68%) in the control arm (hazard ratio [HR] 0.92, 95% CI 0.62-1.37; log-rank p = 0.8). Progression-free survival was higher in the control arm (HR 3.44, 95% CI 1.09-10.82; log-rank p = 0.02) on intention-to-treat analysis but was not significantly higher on per-protocol analysis (HR 2.87, 95% CI 0.83-9.98; log-rank p = 0.06). Overall survival was similar (HR 2.55, 95% CI 0.77-8.40; log-rank p = 0.09). Patients undergoing CHT were less likely to complete their treatment (n =75, 59% vs n = 111, 89%). Adverse events were reported by 164 patients (87 CHT vs 77 control). Major (grade III) adverse events were rare (13 CHT vs 7 control).

CONCLUSIONS: CHT cannot be recommended over chemotherapy alone for intermediate-risk NMIBC. Adverse events following CHT were of low grade and short-lived, although patients were less likely to complete their treatment.

PATIENT SUMMARY: The HIVEC-II trial investigated the role of heated chemotherapy instillations in the bladder for treatment of intermediate-risk non-muscle-invasive bladder cancer. We found no cancer control benefit from heated chemotherapy instillations over room-temperature chemotherapy. Adverse events following heated chemotherapy were low grade and short-lived, although these patients were less likely to complete their treatment.

Androgen Receptor Signaling Inhibitors in Addition to Docetaxel with Androgen Deprivation Therapy for Metastatic Hormone-sensitive Prostate Cancer: A Systematic Review and Meta-analysis.

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CONTEXT: Recent randomized controlled trials (RCTs) examined the role of adding androgen receptor signaling inhibitors (ARSIs), including abiraterone acetate (ABI), apalutamide, darolutamide (DAR), and enzalutamide (ENZ), to docetaxel (DOC) and androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC).

OBJECTIVE: To analyze the oncologic benefit of triplet combination therapies using ARSI + DOC + ADT, and comparing them with available treatment regimens in patients with mHSPC.

EVIDENCE ACQUISITION: Three databases and meetings abstracts were queried in April 2022 for RCTs analyzing patients treated with first-line combination systemic therapy for mHSPC. The primary interests of measure were overall survival (OS) and progression-free survival (PFS). Subgroup analyses were conducted to assess the differential outcomes in patients with low- and high-volume disease as well as de novo and metachronous metastasis.

EVIDENCE SYNTHESIS: Overall, 11 RCTs were included for meta-analyses and network meta-analyses (NMAs). We found that the triplet combinations outperformed DOC + ADT in terms of OS (pooled hazard ratio [HR]: 0.74, 95% confidence interval [CI]: 0.65-0.84) and PFS (pooled HR: 0.49, 95% CI: 0.42-0.58). There was no statistically significant difference between patients with low- and high-volume disease in terms of an OS benefit from adding an ARSI to DOC +ADT (both HR: 0.79; p = 1). Based on NMAs, triplet therapy also outperformed ARSI + ADT in terms of OS (DAR + DOC + ADT: pooled HR: 0.74, 95% CI: 0.55-0.99) and PFS (ABI + DOC + ADT: HR: 0.68, 95% CI: 0.51-0.91, and ENZ + DOC + ADT: HR: 0.70, 95% CI: 0.53-0.93). An analysis of treatment ranking among de novo mHSPC patients showed that triplet therapy had the highest likelihood of improved OS in patients with high-volume disease; however, doublet therapy using ARSI + ADT had the highest likelihood of improved OS in patients with low-volume disease.

CONCLUSIONS: We found that the triplet combination therapy improves survival endpoints in mHSPC patients compared with currently available doublet treatment regimens. Our findings need to be confirmed in further head-to-head trials with longer follow-up and among various patient populations.

PATIENT SUMMARY: Our study suggests that triplet therapy with androgen receptor signaling inhibitor, docetaxel, androgen deprivation therapy prolongs survival in patients with metastatic hormone-sensitive prostate cancer compared with the current standard doublet therapy.

Study reveals impact of home confinement, distance learning on incident myopia

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Home confinement and distance learning significantly increased the number of hospital visits for myopia at a university hospital in Istanbul, although no correlation was found with myopia progression.

The increasing prevalence of myopia is a major public health issue worldwide. Global estimates suggest a burden of 5 billion people affected by 2050. Home confinement and implementation of long-lasting remote learning techniques due to the pandemic have increased digital screen time while substantially decreasing time spent outdoors.

Empty Classroom
“Our results showed a significant increase in hospital admission rates for myopia during the COVID-19 pandemic compared to admission rates in the period before the pandemic,” Sebnem Egriboyun, MD, said. 

“In Turkey, in-person education was suspended in all schools on the 22nd of March 2020. Additionally, home quarantine became mandatory for all citizens under the age of 20 after April 3,” Sebnem Egriboyun, MD, said at the virtual European Society of Cataract and Refractive Surgeons winter meeting. “These facts led us to the research question: Could the lockdown measures for the COVID-19 pandemic have aggravated the rate of clinical admission or progression of myopia in school-aged children in Turkey?”

The data of patients aged between 7 and 18 years examined between Jan. 1, 2014, and May 1, 2021, were analyzed. Visits were divided into before and during the COVID-19 pandemic, and the percentage of myopia diagnosis in each subgroup was determined. In addition, myopia prescriptions in both eyes were documented, and differences in subsequent visits were used to evaluate progression.

“Our results showed a significant increase in hospital admission rates for myopia during the COVID-19 pandemic compared to admission rates in the period before the pandemic. A similar statistically significant difference could not be determined for the rate of progression,” Egriboyun said.

This study, she said, highlights the importance of preventive measures to avoid the increase of myopia cases due to distance learning methods. These may include limiting digital screen time, advocating for increased outdoor activities and implementing frequent nationwide myopia screening programs for school-aged children.

“We acknowledge that several other factors such as decreased outdoor sunlight exposure during this period might have been relevant, and the respective role of each of these factors should be further investigated,” she said.

Girl, 10, Dies After Genital Cutting in Sierra Leone

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A 10-year-old girl has died after undergoing  female genital mutilation (FGM) during an initiation into a secret women’s society in Sierra Leone, police said on Wednesday, sparking renewed calls for the practice to be banned.

Authorities have arrested the woman in charge of initiations as investigations continue, said Amadu Turay, unit commander of the Mile 91 police division, in Sierra Leone’s northern Tonkolili district about 240 km (145 miles) east of Freetown.

“She died of blood loss,” Turay told the Thomson Reuters Foundation, adding that it was assumed FGM was the cause.

A local activist said 67 other girls were reported to have been initiated and were awaiting medical examination.

Female genital cutting is widely practiced in the West African nation as part of girls’ initiation into secret societies which wield significant political clout.

Nine in 10 women have been cut in Sierra Leone which has one of the highest rates of FGM in Africa, according to United Nations data. It is one of only a handful of African countries which has not outlawed the internationally condemned practice.

The ritual typically involves the partial or total removal of the female genitalia and can cause serious health problems. The last reported death in Sierra Leone was two years ago, and the victim was 19.

Activists have helped develop a national strategy for FGM reduction but are waiting for the government to adopt it, said campaigner Rugiatu Turay, formerly the deputy minister of social welfare, gender and children’s affairs.

Just last week discussions on the strategy were held with religious leaders, doctors and chiefs in the district where the girl died, she said. One of the things they were told was to warn parents of the risk of death.

“Now that we have this situation, we want to just set the law,” said Turay, founder of Amazonian Initiative Movement, a grassroots anti-FGM group in Sierra Leone.

“FGM is killing our women and girls. We need to get enough publicity on this incident to draw the attention of government.”

A government spokesman could not immediately be reached for comment.

President Julius Maada Bio this month launched a campaign led by the First Lady called “Hands Off Our Girls,” focused on ending rape and child marriage, according to a statement.

Though it aims to eliminate “all forms of abuses against woman and girls,” the campaign does not mention FGM.

Effectiveness of a text-messaging-based smoking cessation intervention (“Happy Quit”) for smoking cessation in China: A randomized controlled trial

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Abstract

Background

China has the highest global prevalence of cigarette smokers, accounting for more than 40% of the total cigarette consumption in the world. Considering the shortage of smoking cessation services in China, and the acceptability, feasibility, and efficacy of mobile-phone-based text messaging interventions for quitting smoking in other countries, we conducted a mobile-phone-based smoking cessation study in China.

Methods and findings

We conducted a randomized controlled trial in China across 30 cities and provinces from August 17, 2016, to May 27, 2017. Adult smokers aged 18 years and older with the intention to quit smoking were recruited and randomized to a 12-week high-frequency messaging (HFM) or low-frequency messaging (LFM) intervention (“Happy Quit”) or to a control group in a 5:2:3 ratio. The control group received only text messages unrelated to quitting. The primary outcome was biochemically verified continuous smoking abstinence at 24 weeks. Secondary outcomes included (1) self-reported 7-day point prevalence of abstinence (i.e., not even a puff of smoke, for the last 7 days) at 1, 4, 8, 12, 16, 20, and 24 weeks; (2) self-reported continuous abstinence at 4, 12, and 24 weeks; and (3) self-reported average number of cigarettes smoked per day. A total of 1,369 participants received 12 weeks of intervention or control text messages with continued follow-up for 12 weeks. The baseline characteristics of participants among the HFM (n = 674), LFM (n = 284), and control (n = 411) groups were similar. The study sample included 1,295 (94.6%) men; participants had a mean age of 38.1 (SD 9.79) years and smoked an average of 20.1 (SD 9.19) cigarettes per day. We included the participants in an intention-to-treat analysis. Biochemically verified continuous smoking abstinence at 24 weeks occurred in 44/674 participants in the HFM group (6.5%), 17/284 participants in the LFM group (6.0%), and 8/411 participants (1.9%) in the control group; participants in both the HFM (odds ratio [OR] = 3.51, 95% CI 1.64–7.55, p < 0.001) and the LFM (OR = 3.21, 95% CI 1.36–7.54], p = 0.002) intervention groups were more likely to quit smoking than those in the control group. However, there was no difference in quit rate between the HFM and LFM interventions. We also found that the 7-day point quit rate from week 1 to week 24 ranged from approximately 10% to more than 26% with the intervention and from less than 4% to nearly 12% without the intervention. Those who continued as smokers in the HFM group smoked 1 to 3 fewer cigarettes per day than those in the LFM group over the 24 weeks of trial. Among study limitations, the participants were able to use other smoking cessation services (although very few participants reported using them), cotinine tests can only detect smoking status for a few days, and the proportion of quitters was small.

Conclusions

Our findings demonstrate that a mobile-phone-based text messaging intervention (Happy Quit), with either high- or low-frequency messaging, led to smoking cessation in the present study, albeit in a low proportion of smokers, and can therefore be considered for use in large-scale intervention efforts in China. Mobile-phone-based interventions could be paired with other smoking cessation services for treatment-seeking smokers in China.

High CRP: a marker for depression in metastatic lung cancer

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Takeaway

  • C-reactive protein (CRP), a measure of inflammation, is a strong predictor of clinically significant depression in patients with lung cancer.
  • Patients with moderate or high inflammation are more likely to have depression.

Why this matters

  • Lung cancer has 1 of the highest rates of comorbid depression among all types of cancer, ranging from 16% to 29%.
  • Inflammation is elevated in both lung cancer and depression.

Study design

  • 109 patients undergoing treatment for stage IV lung cancer.
  • Funding: National Cancer Institute.

Key results

  • 71.8% had NSCLC adenocarcinoma, 6.4% squamous cell carcinoma NSCLC, and 16.5% SCLC; the remaining were unspecified.
  • 23.9% overall had clinically significant depression symptoms.
  • After multiregression analysis, only CRP (log-transformed) was significantly associated with depression (aR2, 0.23; P=.001).
  • After linear regression, CRP was a predictor for approximately 20% of depression variability (aR2, 0.2; P=.001), and patients with clinically significant depression scores had higher median CRP levels (3.4 vs 1.3 mg/mL; P=.003) and were more likely to be receiving advanced lines of treatment (P=.24).
  • Among those with depression, 76.9% had a CRP level ≥1 mg/mL, and 50% had a CRP level ≥3 mg/mL.
  • Only 7 of the patients with clinically significant depression were receiving antidepressants.

Limitations

  • Retrospective study.

Zolpidem increased cancer risk in patients with sleep disorder: A 3-year follow-up study

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  Abstract

Background: Zolpidem has been increasingly used in patients with sleep disorder due to its minimal respiratory depressor effects and short half-life. Materials and Methods: Recent case reports indicate that zolpidem usage may be associated with increased cancer mortality. This study aimed to determine the impact of zolpidem usage on the risk of incident cancer events in sleep disorder patients over a 3-year follow-up. Of the 6924 subjects diagnosed with sleep disorder in 2004, 1728 had used zolpidem. A Cox proportional hazard model was performed to estimate 3-year cancer event-free survival rates for patients using zolpidem and those not using it, after adjusting for confounding and risk factors. Results: At the end of follow-up, 56 patients had incident cancers, 26 (1.5%) who used zolpidem, and 30 (0.6%) who did not. After adjustments for gender, age, comorbidities, and other medications, patients using zolpidem had a 1.75 times (95% confidence interval [CI], 1.02–3) greater risk of cancer events than those not using zolpidem during the 3-year follow-up. Greater mean daily dose and longer use were associated with increased risk. Among patients with sleep disorder, mean daily dose >10 mg and length of drug use >2 months was associated with 3.74 times greater risk (95% CI, 1.42–9.83; P = 0.008) of incident cancer events. Conclusions: In this study, zolpidem use increased cancer events risk in sleep disorder patients. Risks and benefits of chronic zolpidem usage should be explained to sleep disorder patients, and long-term use should be monitored.

Keywords: Cancer, hazard ratios, mean daily dose, sleep disorder, zolpidem

 

How to cite this article:
Lin SC, Su YC, Huang YS, Lee CC. Zolpidem increased cancer risk in patients with sleep disorder: A 3-year follow-up study. J Med Sci 2016;36:68-74

 

How to cite this URL:
Lin SC, Su YC, Huang YS, Lee CC. Zolpidem increased cancer risk in patients with sleep disorder: A 3-year follow-up study. J Med Sci [serial online] 2016 [cited 2018 Dec 15];36:68-74. Available from: http://www.jmedscindmc.com/text.asp?2016/36/2/68/181522

 

  Introduction Top

The clinical use of sedatives or hypnotics has increased gradually so that a 53% growth in prescriptions over 5 years was reported in 2006.[1] Some 6–10% of US adults have used hypnotics, and the percentage is higher in Europe.[2] The most commonly prescribed medications are benzodiazepines, nonbenzodiazepines, gamma-aminobutyric acid (GABA) agonists, melatonin receptor agonists, sedating antidepressants, antihistamines, and wake-promoting drugs.[3] However, the potential side effects of hypnotics, such as cancer risk, may be overlooked.

Zolpidem, an imidazopyridine in use since 1980, has been increasingly used in patients with sleep disorder due to its very few respiratory depressor effects and short half-life of 2.5 h.[4],[5] Of the 8607 patients who reported side effects of zolpidem on the eHealthMe website, which continuously monitor drug adverse effects, 71 (i.e. 0.82%) reported incident cancer.[6] Previous studies reported an association of hypnotics and cancer death.[7],[8],[9] However, in these studies, neither the specific hypnotic drug nor the quantity was provided. Furthermore, zolpidem was not included in these series. Recently, Kripke et al. conducted a matched cohort study and found that taking hypnotics, either zolpidem or temazepam, was associated with increased cancer risk in rural US patients.[10] The main limitation of this study was its stratification of hypnotic drug dosage in three equivalent groups to validate the dose-response relationship; however, such stratification is not practical in terms of clinical use.

The critical dosage and length of use at which zolpidem will affect the development of incident cancer events in patients with sleep disorder have not clearly explored. The goals of the current study are (1) to determine the relative risk of incident cancer events associated with zolpidem use in sleep disorder patients using a population-based dataset and (2) to provide the critical dosage and length of zolpidem usage associated with increased cancer risk.

  Materials and Methods Top

Ethics statement

This study was initiated after approval by the Institutional Review Board of Buddhist Dalin Tzu Chi General Hospital, Taiwan. Since all identifying personal information was stripped from the secondary files before analysis, the review board waived the requirement for written informed consent from the patients involved.

Database

The National Health Insurance Program, which provides compulsory universal health insurance, was implemented in Taiwan in 1995. It enrolls up to 99% of the Taiwanese population and contracts with 97% of all medical providers. The resulting database contains comprehensive information on insured subjects including dates of clinical visits, diagnostic codes, details of prescriptions, and expenditure amounts. This study used the Longitudinal Health Insurance Dataset for 2004–2006 released by the Taiwan Nation Health Research Institute. The patients studied did not differ statistically significantly from the general population in age, gender, or health care costs, as reported by the Taiwan National Health Research Institute (www. nhri.org.tw).

Study population

All patient records in the dataset between January 1, 2002, and December 31, 2002, with sleep disorder diagnostic codes (International Classification of Diseases, 9th revision-Clinical Modification [ICD-9-CM] 780.5x) from an urban area were included in the study.[11],[12] Excluded were those with any type of cancer (ICD-9-CM codes 140-208) diagnosed before or during the index ambulatory visit.

Identification of study cohort

A total of 6924 sleep disorder patients were identified. Each patient was tracked for 3 years from his or her index ambulatory visit in 2002 to identify outcomes, including any type of incident cancer (ICD-9-CM 140-208). To maximize case ascertainment, only patients verified by also being in cancer and catastrophic illness patient database were included in the study. These patients were then linked to the administrative data for the period 2002–2004 to calculate cancer disease-free survival time, with cases censored for patients who withdrew coverage from the National Health Insurance Program or were still robust without defined events at the end of follow-up.

Definition of exposure and covariate adjustment

The main exposure of interest was zolpidem. The dosage, date of prescription, supply days, and a total number of pills dispensed were obtained from the outpatient pharmacy prescription database. The mean daily dose was estimated by dividing the cumulative number of pills prescribed by the follow-up time from the date of initiating zolpidem treatment to the date of incident cancer, date of stopping medicine, or end of this follow-up study. The defined daily dose (DDD) was 10 mg for zolpidem. Other medications included in analysis were antihypertensives (i.e. propranolol, terazosin, doxazosin, prazosin, atenolol, furosemide, nifedipine, verapamil, diltiazem, isosorbide dinitrate, lisinopril, amitriptyline, chlorpromazine, or prochlorperazine), psychotropic agents (i.e. diazepam, alprazolam, or haloperidol), oral hypoglycemic agents, and insulin. Information on patients’ age, gender, comorbidities, and monthly income level as a proxy of socioeconomic status (SES) were collected. The comorbidities for each patient was based on the modified Charlson comorbidity index score, a widely used measure for risk adjustment in administrative claims data sets.[13]

Statistical analysis

The SAS statistical package, version 9.2 (SAS Institute, Inc., Cary, NC), and SPSS version 15 (SPSS Inc., Chicago, IL, USA) were used for data analysis. Pearson’s Chi-square test was used for categorical variables, demographic characteristics (age group and gender), comorbidities, and medications.

The 3-year cancer event-free survival rate was estimated using the Kaplan–Meier method. The cumulative risk of incident cancer event was estimated as a function of time from initial treatment. A Cox proportional hazard regression model was used to calculate the risk of cancer event in sleep disorder patients who used zolpidem versus those who did not, after adjustments for age, gender, comorbidities, SES and other medication usage. A P < 0.05 was considered statistically significant in the regression models.

  Results Top

The distribution of demographic characteristics for the two cohorts is shown in [Table 1]. Those taking zolpidem were significantly older and more likely to be female than those who did not take it. They were also more likely to have more comorbidities, low SES, and more frequently used antiglycemic drugs, psychotropic agents, and antihypertensive medications.

Table 1: Baseline characteristics (n=6924)

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At the end of follow-up, 56 patients had incident cancers, 26 (1.5%) in those using zolpidem, and 30 (0.6%) in those not using it. Patients using zolpidem had an increased risk of cancer events. [Table 2] shows the types of cancer events for the two cohorts stratified by gender. Increased mean daily dose and longer use were associated with increased cumulative risk of cancer events [Figure 1] and [Figure 2]. After adjustments for gender, age, comorbidities, and other medications, patients using zolpidem had a 1.75-times (95% CI, 1.02–3.02) higher risk of cancer events than those who did not use zolpidem during the 3-year follow-up period. [Figure 3] shows the combined effect of mean daily dose and length of zolpidem use on increased cancer risk. [Table 3] shows the adjusted ratios of cancer incidence with zolpidem usage after adjusting for gender, comorbidities, and other medications. Mean daily dose >1 DDD and usage >2 months was associated with 3.74 times (95% CI, 1.42–9.83; P = 0.008) higher risk of incident cancer events in a Cox regression model.

Table 2: Incident tumors in individuals with zolpidem usage and those without by stratification for gender

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Figure 1: Effect of zolpidem dose on cancer risk

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Figure 2: Effect of zolpidem duration on cancer risk

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Figure 3: Combined effect of zolpidem dose and duration on cancer risk

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Table 3: Adjusted hazard ratios for zolpidem in patients with sleep disturbance

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  Discussion Top

Our data showed that zolpidem usage was associated with increased incident cancer risk in patients with sleep disorder. Zolpidem usage >1 DDD for a period >2 months incurred a 3.7-fold higher risk of cancer events. Although zolpidem, the newer nonbenzodiazepine, has been shown to be safe and effective in patients with insomnia,[14] its chronic usage should be carefully restricted and monitored.

Our results suggest that zolpidem usage for more than 2 months increases cancer risk significantly in patients with sleep disorder. Comparing with previous studies, this series further provided a critical period (>2 months) and mean daily dose (>1 DDD) for elevated risk of incident cancer for clinical physicians and the general population.

Due to its short half-life and selective Type I GABAA receptor agonist, zolpidem is a widely used, standard treatment for patients with sleep disorder or insomnia.[3],[15] Of the 8607 patients who reported side effects with zolpidem use on the eHealthMe website, which continuously monitors drug adverse effects, 71 (i.e., 0.82%) reported an incident cancer.[6] In our study, 1.5% persons with zolpidem usage developed incident cancer within 3 years. Zolpidem use was associated with a 1.8-times higher risk of cancer events after adjusting for other medications and confounding factors. Our findings are consistent with Iqbal et al. that zolpidem usage was associated with a 1.13-times higher risk of cancer (95% CI, 1.09–1.17).[16] Higher doses and longer use were positively associated with cancer risk. This series revealed that a mean daily dose >1 DDD and drug usage >2 months was associated with 3.7 times risk (95% CI, 1.4–10) of incident cancer events in patients with sleep disorder.

The exact relationship between zolpidem and infection events remains unknown although several mechanisms are plausible. Benzodiazepines have been found to affect polymorphonuclear cell chemotaxis and phagocytosis.[17] Benzodiazepines in general suppress the immune response through peripheral and central benzodiazepine receptors.[18] The impairment of macrophage spreading could be attributed to the anti-inflammatory effect of the peripheral benzodiazepine receptor on blood cells through inhibition of the release of pro-inflammatory cytokines such as interleukin-6 and interleukin-13.[19] An uncontrolled small case series described carcinogenicity following the prescription of zopiclone or eszopiclone to HIV Type 1 infected individuals.[20] Eszopiclone and zolpidem use have been reported associated with increased risk of infection, raising the speculation that hypnotics impair immune surveillance.[21] A suppression of immune function may partly explain the increased risk of incident cancers. Sparse data on the new hypnotics (eszopiclone, zaleplon, zolpidem, and ramelteon) suggest an increased risk of cancer, which is supported by studies demonstrating a carcinogenic effect in rodents.[22]

Furthermore, hypnotics such as zolpidem can increase the incidence of sleep apnea and may suppress the respiratory drive. Zolpidem increased the apnea index and provoked greater oxygen desaturation than flurazepam and placebo in a controlled, double–blind, cross-over study. Such that 20 mg zolpidem failed to overcome the existing contraindications to administration of hypnotic drugs in patients with heavy snoring and obstructive sleep apnea syndrome.[23] Sleep apnea induced by medication may in turn induce early apoptosis of large granular lymphocytes which further compromises immunity and reduces immune surveillance.[24]

A greater incidence of depression with zolpidem use has been reported.[25] A decrease in the number of natural killer T-cells has also been reported in patients with major depressive disorder.[26] Depressed immunity to varicella zoster in older adults with major depressive disorder has been observed.[27] Compromised immunity may contribute to tumor formation.

Benzodiazepines can decrease lower esophageal sphincter tone, independently of the awareness or drowsiness of patients.[28] Zolpidem reduced the arousal response to nocturnal acid exposure and increased the duration of each esophageal acid reflux event.[29] Gastroesophageal reflux can lead to chronic sinusitis, recurrent croup, and laryngitis.[30] A recent meta-analysis reported an increased risk of infection with zolpidem use.[21] Infection may result from increased gastroesophageal regurgitation or from zolpidem usage and subsequent increased cancer development.[31] However, the exact relationship between zolpidem and cancer event remains unknown, and further research is needed to explore the possible mechanism.

This study has several limitations. First, the diagnosis of sleep disorder, incident cancer, and any other comorbid conditions are completely dependent on accurate recording of ICD-9-CM codes. However, the cancer events were further verified by their appearance in the registry for cancer and catastrophic illness patient database. Furthermore, the National Health Insurance Bureau of Taiwan randomly reviews charts and interviews patients to verify diagnosis accuracy. Hospitals with outlier charges or practice may undergo an audit, with subsequent heavy penalties for malpractice or discrepancies. Second, the database did not include detailed information on body mass index, smoking, or alcohol drinking. Further studies linking administrative data and primary surveys of health behaviors are warranted. Third, we did not control for depression, anxiety, and other emotional factors, which may have influenced these results. Fourth, the number of cases was small, warranting caution in interpreting the data. Finally, associations derived from epidemiological studies do not prove causality. It is hard to discern the correlation between the zolpidem usage and the sleep disorder in time sequence. We cannot exclude the possibility that zolpidem usage is a marker for other risk factors or cancer-related illness and acts a confounder in its association with cancer.

In summary, this study found that zolpidem use was associated with increased risk of cancer events in sleep disorder patients. For patients with sleep disorder who chronically use zolpidem, the likelihood of developing cancer events within 3 years is 1.7 times that of those who do not use zolpidem. Risks and benefits of chronic zolpidem usage should be explained to sleep disorder patients. Cognitive-behavioral therapy for patients with chronic insomnia may be more beneficial than use of hypnotics.[32]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

  References Top

 

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Mallon L, Broman JE, Hetta J. Is usage of hypnotics associated with mortality? Sleep Med 2009;10:279-86.  Back to cited text no. 8
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Belleville G. Mortality hazard associated with anxiolytic and hypnotic drug use in the national population health survey. Can J Psychiatry 2010;55:558-67.  Back to cited text no. 9
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Kripke DF, Langer RD, Kline LE. Hypnotics’ association with mortality or cancer: A matched cohort study. BMJ Open 2012;2:e000850.  Back to cited text no. 10
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Iqbal U, Nguyen PA, Syed-Abdul S, Yang HC, Huang CW, Jian WS, et al. Is long-term use of benzodiazepine a risk for cancer? Medicine (Baltimore) 2015;94:e483.  Back to cited text no. 16
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Zavala F. Benzodiazepines, anxiety and immunity. Pharmacol Ther 1997;75:199-216.  Back to cited text no. 18
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Stebbing J, Waters L, Davies L, Mandalia S, Nelson M, Gazzard B, et al. Incidence of cancer in individuals receiving chronic zopiclone or eszopiclone requires prospective study. J Clin Oncol 2005;23:8134-6.  Back to cited text no. 20
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Joya FL, Kripke DF, Loving RT, Dawson A, Kline LE. Meta-analyses of hypnotics and infections: Eszopiclone, ramelteon, zaleplon, and zolpidem. J Clin Sleep Med 2009;5:377-83.  Back to cited text no. 21
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Steiropoulos P, Lourou N, Nakou E, Bouchliou E, Tzouvelekis A, Nena E, et al. Lymphocyte subsets and early apoptosis in the peripheral blood of patients with obstructive sleep apnoea syndrome (Preliminary Results). Pneumon 2009;22:42-5.  Back to cited text no. 24
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Kripke DF. Greater incidence of depression with hypnotic use than with placebo. BMC Psychiatry 2007;7:42.  Back to cited text no. 25
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A randomised trial of the effect of omega-3 polyunsaturated fatty acid supplements on the human intestinal microbiota

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Abstract

Objective Omega-3 polyunsaturated fatty acids (PUFAs) have anticolorectal cancer (CRC) activity. The intestinal microbiota has been implicated in colorectal carcinogenesis. Dietary omega-3 PUFAs alter the mouse intestinal microbiome compatible with antineoplastic activity. Therefore, we investigated the effect of omega-3 PUFA supplements on the faecal microbiome in middle-aged, healthy volunteers (n=22).

Design A randomised, open-label, cross-over trial of 8 weeks’ treatment with 4 g mixed eicosapentaenoic acid/docosahexaenoic acid in two formulations (soft-gel capsules and Smartfish drinks), separated by a 12-week ‘washout’ period. Faecal samples were collected at five time-points for microbiome analysis by 16S ribosomal RNA PCR and Illumina MiSeq sequencing. Red blood cell (RBC) fatty acid analysis was performed by liquid chromatography tandem mass spectrometry.

 

Results Both omega-3 PUFA formulations induced similar changes in RBC fatty acid content, except that drinks were associated with a larger, and more prolonged, decrease in omega-6 PUFA arachidonic acid than the capsule intervention (p=0.02). There were no significant changes in α or β diversity, or phyla composition, associated with omega-3 PUFA supplementation. However, a reversible increased abundance of several genera, including Bifidobacterium, Roseburia and Lactobacillus was observed with one or both omega-3 PUFA interventions. Microbiome changes did not correlate with RBC omega-3 PUFA incorporation or development of omega-3 PUFA-induced diarrhoea. There were no treatment order effects.

 

Conclusion Omega-3 PUFA supplementation induces a reversible increase in several short-chain fatty acid-producing bacteria, independently of the method of administration. There is no simple relationship between the intestinal microbiome and systemic omega-3 PUFA exposure.

Efficacy and Safety of GIAPREZA™ (angiotensin II) in ATHOS-3 Trial

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Distributive shock, characterized by low mean arterial pressure (MAP) and decreased tissue perfusion due to microcirculatory dysfunction, is associated with high morbidity and mortality.1 The Surviving Sepsis Campaign recommends an initial MAP of ≥65 mmHg.2 About 30% of patients in the intensive care unit who receive standard of care vasopressors (catecholamines) require high doses.3

GIAPREZA™ (angiotensin II) injection for IV infusion: A novel vasopressor to increase BP in adults with septic or other distributive shock

GIAPREZA™ (angiotensin II) is a vasoconstrictor that increases blood pressure in adults with septic or other distributive shock. It is the first and only FDA-approved synthetic human angiotensin II treatment that activates the renin-angiotensin-aldosterone system (RAAS) to increase MAP.4,5 GIAPREZA leverages a system that is currently not targeted by other therapies for hypotension in distributive shock.4-6

ATHOS-3 Trial Design

The Angiotensin II for the Treatment of High-Output Shock (ATHOS‑3) trial was an international, multicenter, randomized, double-blind, placebo-controlled study in which 344 adults with septic or other distributive shock who remained hypotensive despite fluid and vasopressor therapy were randomized 1:1 to GIAPREZA or placebo, and 321 of them received GIAPREZA or placebo.4,6,7

aGIAPREZA and placebo were studied in conjunction with norepinephrine, epinephrine, dopamine, phenylephrine, and vasopressin.4
bTreatment allowed up to day 7. Day 28 (+/- 2 days) follow-up determined safety events that occurred between day 7 and day 28.6,8

  • Doses of GIAPREZA or placebo were titrated to a target MAP of ≥75 mmHg during the first 3 hours of treatment while doses of other vasopressors were maintained4
  • From hour 3 to hour 48, GIAPREZA or placebo was titrated to maintain MAP between 65 and 70 mmHg, while reducing doses of other vasopressors4
  • The primary endpoint was the percentage of subjects who achieved either a MAP ≥75 mmHg or a ≥10 mmHg increase from baseline in MAP without an increase in baseline vasopressor therapy at 3 hours4

Efficacy in ATHOS-3

GIAPREZA increased MAP in critically ill, hypotensive patients with septic or other distributive shock4,6

At hour 3, significantly more patients treated with GIAPREZA achieved target MAP vs patients treated with placebo4

IMPORTANT SAFETY INFORMATION

Indication
GIAPREZA™ (angiotensin II) increases blood pressure in adults with septic or other distributive shock.

Contraindications
None.

Warnings and Precautions
The safety of GIAPREZA was evaluated in 321 adults with septic or other distributive shock in the randomized, double-blind, placebo-controlled ATHOS-3 study. There was a higher incidence of arterial and venous thrombotic and thromboembolic events in patients who received GIAPREZA compared to placebo treated patients in the ATHOS-3 study [13% (21/163 patients) vs. 5% (8/158 patients)]. The major imbalance was in deep venous thromboses. Use concurrent venous thromboembolism prophylaxis.

Adverse Reactions
The most common adverse reactions reported in greater than 10% of GIAPREZA-treated patients were thromboembolic events. Adverse reactions occurring in ≥4% of patients treated with GIAPREZA and ≥1.5% more often than placebo-treated patients in the ATHOS‑3 study were thromboembolic events (including deep vein thrombosis), thrombocytopenia, tachycardia, fungal infection, delirium, acidosis, hyperglycemia, and peripheral ischemia.

Drug Interactions
Angiotensin converting enzyme inhibitors may increase response to GIAPREZA.

Angiotensin II receptor blockers may reduce response to GIAPREZA.

To report SUSPECTED ADVERSE REACTIONS, contact La Jolla Pharmaceutical at 1-800-651-3861 or the FDA at 1- 800- FDA -1088 or www.fda.gov/medwatch.

Please see the full Prescribing Information at www.giapreza.com.

cModified intent-to-treat (mITT) population; patients randomized and treated with study drug in any quantity were included in the primary efficacy analysis.6

  • Target MAP defined as ≥75 mmHg or an increase from baseline of ≥10 mmHg without an increase in baseline vasopressor therapy4
  • In addition, GIAPREZA rapidly increased MAP, with a median response time of approximately 5 minutes for GIAPREZA responders, while some patients took longer.4,d The plasma half-life of GIAPREZA is less than 1 minute, which allows for individualized dose adjustment with titration every 5 to 15 minutes by increments up to 15 ng/kg/min4
  • Mortality through day 28 was 46% on GIAPREZA and 54% on placebo (hazard ratio 0.78; 95% confidence interval 0.57-1.07)4

dResponse was defined as achievement of target MAP ≥75 mmHg or an increase from baseline of ≥10 mmHg without an increase in baseline vasopressor therapy.4

Safety in ATHOS-3

87% of patients treated with GIAPREZA experienced at least one adverse event (AE) versus 92% of patients treated with placebo6,e

  • The most common adverse reactions reported in greater than 10% of GIAPREZA-treated patients were thromboembolic events: 12.9% for GIAPREZA versus 5.1% for placebo. Use concurrent venous thromboembolism prophylaxis in patients treated with GIAPREZA4
  • Adverse reactions occurring in ≥4% of patients treated with GIAPREZA and ≥1.5% more often than placebo-treated patients in the ATHOS‑3 study were thromboembolic events (including deep vein thrombosis), thrombocytopenia, tachycardia, fungal infection, delirium, acidosis, hyperglycemia, and peripheral ischemia4
  • 14.1% of patients discontinued GIAPREZA due to AEs versus 21.5% of patients who discontinued placebo due to AEs6,e

eNot statistically significant.6

fIncluded arterial and venous thrombotic events.4

In summary,

  • GIAPREZA is the first and only FDA-approved synthetic human angiotensin II treatment that activates RAAS to increase MAP4,6
  • 70% of patients treated with GIAPREZA achieved target MAP at hour 3 versus 23% of patients treated with placebo4,g,h,i
  • GIAPREZA also rapidly increased MAP, with a median response time of approximately 5 minutes for GIAPREZA responders, while some patients took longer4,d,i
  • Mortality through day 28 was 46% on GIAPREZA and 54% on placebo (hazard ratio 0.78; 95% CI, 0.57-1.07)4,i,j
  • More patients treated with GIAPREZA experienced thrombotic events compared with patients treated with placebo (12.9% versus 5.1%).4,j Use concurrent venous thromboembolism prophylaxis6

dResponse was defined as achievement of target MAP ≥75 mmHg or an increase from baseline of ≥10 mmHg without an increase in baseline vasopressor therapy.4
gTarget MAP defined as ≥75 mmHg or an increase from baseline of ≥10 mmHg without an increase in baseline vasopressor therapy.4
hGIAPREZA and placebo were studied in conjunction with norepinephrine, epinephrine, dopamine, phenylephrine, and vasopressin.4
iResults from ATHOS-3 trial.4
jNo significant difference.6

For additional Important Safety Information, please see the full Prescribing Information.

References:

  1. Vincent JL, De Backer D. Circulatory shock. N Engl J Med. 2013;369(18):1726-1734.
  2. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. March 2017;43(3): pp 304-377.
  3. Sviri S, Hashoul J, Stav I, van Heerden PV. Does high-dose vasopressor therapy in medical intensive care patients indicate what we already suspect? J Crit Care. 2014;29(1):157-160.
  4. GIAPREZA™ (angiotensin II) [package insert]. San Diego, CA: La Jolla Pharmaceutical Company; 2017.
  5. Trotter J. Catecholamine-resistant hypotension following induction for spinal exploration. AANA J. 2012;80(1):55-60.
  6. Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017;377(5):419-430. doi:10.1056/NEJMoa1704154.
  7. Chawla LS, Russell JA, Bagshaw SM, et al. Angiotensin II for the Treatment of High-Output Shock 3 (ATHOS‑3): protocol for a phase III, double-blind, randomized controlled trial. Crit Care Resusc. 2017;19(1):43-49.
  8. Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of vasodilatory shock [trial protocol]. N Engl J Med. 2017;377(5):1-95. doi:10.1056/NEJMoa1704154.

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