Pharmaceutical good manufacturing practice: Leuplin® production in Japan identifies major international shortcomings.

In Japan, the production of Leuplin®, a key drug for the treatment of prostate cancer and breast cancer, was temporarily suspended in 2020 by the manufacturer. The incident illustrated several significant failings, namely the lack of uniformity in international GMP (Good Manufacturing Practice) regulations, the lack of mechanisms to resolve disputes between PIC/S (Pharmaceutical Inspection Co-operation Scheme) member countries, and the importance of maintaining a stable supply of safe GMP-compliant essential medicines.

Molecular Assays to Determine Optimal Duration of Adjuvant Endocrine Therapy in Breast Cancer.

OPINION STATEMENT: Hormone receptor (HR) positive breast cancer has a high propensity for late recurrences that might be prevented with longer durations of endocrine therapy (ET). However, trials evaluating extended adjuvant ET have produced somewhat conflicting results. Additionally, ET is associated with not only day to day side effects that can impact quality of life, but more detrimental effects that can cause significant morbidity. Although patients with higher stage disease are at greater risk of late recurrences, even patients with stage 1 disease have a significant risk of recurrence after 5 years. Current guidelines recommend extending therapy for patients with node-positive disease, but recommendations for patients with node-negative disease are less clear. This has led to the development of various genomic tests to aid oncologists in further individualizing their approach when it comes to deciding which subpopulation of patients with HR-positive breast cancer may benefit from extending their endocrine therapy beyond 5 years. There are several assays that are prognostic of recurrences years 6 to 10 following diagnosis. Additionally, the breast cancer index has been shown to be predictive of extended ET in patients who have completed 5 years of tamoxifen. None of the available assays are, to date, predictive of recurrence after 10 years. Genomic testing is not appropriate for all patients, especially if the results will not predict the choice of further treatment. Ultimately, genomic testing should help facilitate shared decision making between the patient and oncologist.

Ductal Carcinoma in Situ: A French National Survey. Analysis of 2125 Patients.

BACKGROUND: Ductal carcinoma in situ (DCIS) represents 15% of all breast cancers in France. The first national survey was conducted in 2003. The present multi-center real-life practice survey aimed at assessing possible changes in demographic, clinical, pathologic, and treatment features. MATERIAL AND METHODS: From March 2014 to September 2015, patients diagnosed with DCIS from 71 centers with complete information about age, diagnostic features, and treatment modalities were prospectively included. RESULTS: A total of 2125 patients with a median age of 58.6 years from 71 centers were studied. DCIS was diagnosed by mammography in 87.5% of cases. Preoperative biopsy was performed in 96% of cases. The median tumor size was 15 mm. Nuclear grade was low, intermediate, and high in 12%, 36%, and 47% of cases, respectively. Margins were considered to be negative in 83% of cases. Overall mastectomy and lumpectomy rates were 25% and 75%, respectively. The immediate breast reconstruction rate was 50%. Sentinel node biopsy and axillary dissection rates were 41% and 2.6%, respectively. After lumpectomy, 97% of patients underwent radiotherapy, and 32% received a boost dose. Only 1% of patients received endocrine therapy. Compared with our previous survey, the median tumor size remained the same, and the proportion of high-grade lesions increased by 9%. The mastectomy rate decreased by 4%. CONCLUSIONS: The clinical practice identified in this survey complies with French DCIS guidelines. About 10% of patients with low-grade DCIS may be eligible to participate in treatment de-escalation trials.

Radiotherapy Utilization for Patients Over Age 60 With Early Stage Breast Cancer.

INTRODUCTION: Recent studies have questioned the relative benefit of radiotherapy (RT) for older patients with favorable breast cancer given the lack of survival benefit and marginal local control benefit. Despite the 2004 National Comprehensive Cancer Network (NCCN) guidelines advocating for the option of hormonal therapy alone, trends in utilization rates of RT in this group are not well-documented. We analyzed our institutional experience with implementation of the guidelines over time. MATERIAL AND METHODS: We identified 564 patients aged ≥ 60 years with favorable breast cancer treated with breast conserving surgery from 2000 to 2017. Patients met criteria for Cancer and Leukemia Group B (CALGB) 9343, Postoperative Radiotherapy in Minimum Risk Elderly (PRIME II), or the very-low risk cohort identified in the Toronto-British Columbia study. Multivariable logistic regression analysis was performed to assess the magnitude of association between omission status, grade, and tumor size while controlling for age and year of diagnosis. RESULTS: Overall RT omission rates were 17.6% prior to the 2004 NCCN update and 45% after the publication of the 10-year CALGB data in 2013. The overall RT omission rate was 29%. Patients with grade 1 to 2 histology (odds ratio, 3.2; 95% confidence interval, 1.3-7.7; P = .01) and tumors < 1 cm (odds ratio, 1.60; 95% confidence interval, 0.4-0.9; P = .007) were more likely to omit RT than those with higher grade or larger tumors. CONCLUSIONS: We observed a slight decrease in the use of RT over time, suggesting a move towards adoption of the NCCN guidelines. There remains a fundamental need to continue to individualize breast cancer care based on risk stratification and make evidenced-based treatment recommendations with equitable use of health care resources.

Patterns of endocrine therapy in a national cohort of early stage HER2-positive breast cancer patients.

PURPOSE: Guidelines recommend ≥5 years of endocrine therapy for hormone receptor-positive breast cancer patients, but nonadherence and treatment discontinuation are common. We examined adherence trajectories and early discontinuation of endocrine therapy over 5 years from treatment initiation. METHODS: Our retrospective cohort study used a national sample of Australian women dispensed publicly subsidised trastuzumab for early HER2-positive breast cancer. We included women initiating endocrine therapy between April 2007 and June 2011, followed until June 2016 (n = 2656). We used group-based trajectory modelling and Kaplan-Meier analysis to examine patterns of adherence and time to discontinuation and restarting. RESULTS: We identified five adherence trajectories: quick decline (10.4%), moderate decline (8.6%), quick decline then stable (10.3%), stable with late decline (23.6%), and high and stable (47.2%). Women in the high and stable trajectory group were older and more likely to initiate therapy with anastrozole than women in other groups. Time periods after first 6 months, 1.5, and 4 years from initiation seemed critical in terms of remaining adherent on endocrine therapy; 45.8% of the cohort discontinued endocrine therapy with a median time to discontinuation of 2.6 years (interquartile range 1.0-4.4), and 45.8% of the women discontinuing restarted treatment (median time 182.0, interquartile range 133.0-279.0 days). CONCLUSIONS: Our study highlights evidence-practice gaps in the use of endocrine therapy, with half of our sample experiencing suboptimal adherence or persistence. Trajectory modelling provided detailed information about patterns of nonadherence and critical time periods for adherence to endocrine therapy. This information is important for developing targeted interventions to improve adherence.

Separation and identification of acylated leuprorelin inside PLGA microspheres.

Studies have shown that the N-terminus and lysine side residue of peptides are prone to acylation in poly(d,l-lactide-co-glycolide) (PLGA) microspheres. Peptides such as leuprorelin lack a free N-terminus or lysine and only contain serine, arginine, and tyrosine as nucleophilic residues. The purpose of this study was to detect potential acylation impurities and determine their corresponding acylation sites in commercial leuprorelin-loaded PLGA microspheres. Commercial samples from three vendors were selected as targets for our study. The high-performance liquid chromatography (HPLC) conditions of the European Pharmacopoeia were used to separate and collect impurities. HPLC-tandem mass spectrometry (HPLC-MS/MS) was applied to confirm both the structure and acylation sites of the impurities. Our study demonstrated that impurities originating from both degradation of microspheres and synthesis of leuprorelin were well separated and identified using these HPLC conditions. HPLC-MS/MS analysis of acylated leuprorelin showed that diglycoyl, lactoyl-glycoyl, dilactoyl, and monolactoyl groups were conjugated to serine in leuprorelin-loaded PLGA microspheres. This is the first report showing serine to be the acylation site in peptide-loaded PLGA microspheres. Separation and identification of acylated leuprorelin derivatives will assist in minimising acylation and guiding the development of quality control for commercial leuprorelin-loaded PLGA microspheres.

Undertreatment of High-Risk Localized Prostate Cancer in the California Latino Population.

Background: The NCCN Clinical Practice Guidelines in Oncology recommend definitive therapy for all men with high-risk localized prostate cancer (PCa) who have a life expectancy >5 years or who are symptomatic. However, the application of these guidelines may vary among ethnic groups. We compared receipt of guideline-concordant treatment between Latino and non-Latino white men in California. Methods: California Cancer Registry data were used to identify 2,421 Latino and 8,636 non-Latino white men diagnosed with high-risk localized PCa from 2010 through 2014. The association of clinical and sociodemographic factors with definitive treatment was examined using logistic regression, overall and by ethnicity. Results: Latinos were less likely than non-Latino whites to receive definitive treatment before (odds ratio [OR], 0.79; 95% CI, 0.71-0.88) and after adjusting for age and tumor characteristics (OR, 0.84; 95% CI, 0.75-0.95). Additional adjustment for sociodemographic factors eliminated the disparity. However, the association with treatment differed by ethnicity for several factors. Latino men with no health insurance were considerably less likely to receive definitive treatment relative to insured Latino men (OR, 0.34; 95% CI, 0.23-0.49), an association that was more pronounced than among non-Latino whites (OR, 0.63; 95% CI, 0.47-0.83). Intermediate-versus high-grade disease was associated with lower odds of definitive treatment in Latinos (OR, 0.75; 95% CI, 0.59-0.97) but not non-Latino whites. Younger age and care at NCI-designated Cancer Centers were significantly associated with receipt of definitive treatment in non-Latino whites but not in Latinos. Conclusions: California Latino men diagnosed with localized high-risk PCa are at increased risk for undertreatment. The observed treatment disparity is largely explained by sociodemographic factors, suggesting it may be ameliorated through targeted outreach, such as that aimed at younger and underinsured Latino men.

Adjuvant endocrine therapy in premenopausal patients with hormone receptor-positive early breast cancer: Evidence evaluation and GRADE recommendations by the Italian Association of Medical Oncology (AIOM).

Premenopausal women with hormone receptor-positive early breast cancer are candidates for adjuvant endocrine therapy, as recommended by the major international guidelines. To date, adjuvant endocrine options for premenopausal women include tamoxifen with or without ovarian function suppression (OFS) or an aromatase inhibitor with OFS. Multiple strategies for endocrine treatment of premenopausal women with hormone-responsive breast cancer have been assessed, and the results of randomised clinical trials have been reported over the last years. Despite this evidence, the optimal algorithm for endocrine therapy for premenopausal women with hormone receptor-positive early stage invasive breast cancer shows open questions regarding the role of OFS in addition to tamoxifen and the optimal use of hormonal agents. The panel of the Italian Association of Medical Oncology (AIOM) Clinical Practice Guidelines on Breast Cancer applied the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology on three critical questions on the choice of the adjuvant hormonal therapy in premenopausal breast cancer patients to summarise available evidence and to create recommendations to help physicians in their clinical practice.

NCCN Guidelines Updates: Prostate Cancer and Prostate Cancer Early Detection.

Peter H. Carroll, MD, MPH, and James L. Mohler, MD, updated attendees on what is new in the 2018 NCCN Guidelines for Prostate Cancer Early Detection and for Prostate Cancer, respectively. Their presentations touched on new screening recommendations, shared decision-making, risk stratification, the role of genomic and molecular testing, active surveillance, and newer systemic treatments.

Fulvestrant in management of hormone receptor-positive metastatic breast cancer.

Fulvestrant is a steroidal selective estrogen receptor degrader that was approved by the US FDA in 2002 for treatment of ER-positive metastatic breast cancer (ER + MBC) post-progression on aromatase inhibitors. In 2017, the label was updated to include endocrine therapy naive ER + MBC. While initially fulvestrant was thought to be equivalent to aromatase inhibitors with monthly dose of 250 mg intramuscular injection, several postmarketing trials challenged this understanding. Subsequently, the recommended dose changed to 500 mg monthly plus loading dose, and this was proven to be superior to anastrozole in efficacy. Most recently the results of FALCON trial have further challenged the way fulvestrant is viewed and used. This report provides a historical perspective on this compound, its evolving role in management of ER + MBC and what the future may hold for this drug.

Clinical Impact of 21-Gene Recurrence Score Test Within the Veterans Health Administration: Utilization and Receipt of Guideline-Concordant Care.

INTRODUCTION: Ensuring guideline-concordant cancer care is a Department of Veterans Affairs (VA) priority, especially as the number of breast cancer patients at VA medical centers (VAMCs) grows. We assessed the utilization and clinical impact of the 21-gene Recurrence Score test, which predicts 10-year risk of breast cancer recurrence and the likelihood of chemotherapy benefit, on veterans newly diagnosed with breast cancer. PATIENTS AND METHODS: We conducted a retrospective cohort study using 2011-2012 VA Central Cancer Registry, chart review, and laboratory test data. Independent variables assessed included patient and site-of-care characteristics. The outcome of interest was whether newly diagnosed, eligible (node negative, hormone-receptor positive, human epidermal growth factor receptor 2 [HER2] negative) veterans underwent the 21-gene test. We performed descriptive statistics on all patients and multivariate logistic regression to determine associations. We correlated treatments received with test results. RESULTS: Among 328 eligible veterans, 82 (25%) had the 21-gene test; 100 eligible veterans (30%) sought care at a VAMC where no tests were ordered. Receiving care at a VAMC that had women's health services (odds ratio [OR], 1.84, 95% confidence interval [CI], 1.05-3.22) and having tumor characteristics meeting the National Comprehensive Cancer Network 2010 test criteria (OR, 3.06, 95% CI, 1.69-5.57) were positive predictors of testing; increasing age (OR, 0.93, 95% CI, 0.91-0.96 per year) and fee-based care (OR, 0.46, 95% CI, 0.26-0.82) were negative predictors. The majority of tested patients received guideline-concordant care. CONCLUSION: Site of care and tumor characteristics were important predictors of test uptake. Facilitating delivery of guideline-concordant cancer care requires improved laboratory informatics and clinical decision support.

A European, Observational Study of Endocrine Therapy Administration in Patients With an Initial Diagnosis of Hormone Receptor-Positive Advanced Breast Cancer.

BACKGROUND: Despite guideline recommendations, reports suggest that a proportion of patients with hormone receptor (HR)-positive locally advanced or metastatic breast cancer (LA/MBC) might not receive endocrine therapy. The aims of this study were to estimate the proportion of postmenopausal patients with an initial (primary) diagnosis of HR-positive LA/MBC in Europe, and to assess the administration of endocrine treatment in these patients. MATERIALS AND METHODS: Fourteen national and regional cancer registries across Europe were invited to participate in this observational study. Six registries each provided anonymized clinical information on > 5000 postmenopausal women with breast cancer diagnosed between January 2000 and December 2014, including age at diagnosis, estrogen and/or progesterone receptor status, disease stage, and receipt of endocrine therapy. The proportion of patients with an initial diagnosis of HR-positive LA/MBC and, of these, the proportion who received endocrine therapy, was calculated. RESULTS: Registries from Belgium, England, Ireland, Norway, The Netherlands, and Munich, Germany provided data. In total, 316,680 postmenopausal women were diagnosed with breast cancer, including 244,268 with known HR status and disease stage. Of these patients, 19,002 (7.8%) had a primary diagnosis of HR-positive LA/MBC. This proportion ranged from 5.4% (N = 4484) in England to 12.7% (N = 4085) in Germany. Most of these patients (n = 14,157; 74.5%) received endocrine treatment, ranging from 55.5% (n = 445) in Norway to 88.1% (n = 443) in Belgium. CONCLUSION: These results indicate that a sizeable proportion of postmenopausal patients in Europe received a primary diagnosis of HR-positive LA/MBC, and that almost three-quarters received subsequent endocrine therapy as per guideline recommendations.

Adjuvant endocrine therapy in hormone receptor-positive postmenopausal breast cancer: evolution of NCCN, ASCO, and St Gallen recommendations.

Endocrine therapy has a firm role in adjuvant treatment of women with hormone receptor-positive invasive breast cancer. Until recently, tamoxifen was the most commonly used adjuvant endocrine therapy in premenopausal and postmenopausal women. Several randomized clinical trials have studied the third-generation selective aromatase inhibitors (AIs) (anastrozole, letrozole, and exemestane) as adjuvant endocrine therapy in postmenopausal women. These studies compared therapy with an AI alone versus tamoxifen alone; 2 to 3 years of tamoxifen followed by switching to an AI versus continuation of tamoxifen; or extended therapy with an AI after approximately 5 years of tamoxifen therapy. No statistically significant differences in overall survival were observed. A single trial using extended treatment with an adjuvant AI suggests a small, statistically significant survival advantage in women with axillary lymph node-positive disease while showing no statistically significant decrease in survival with the use of an AI. The toxicities of the AIs are generally acceptable, with fewer endometrial cancers, gynecologic complaints, and thromboembolic events, but more bone fractures and arthralgias compared with tamoxifen alone. Three widely disseminated treatment guidelines, the National Comprehensive Cancer Network Breast Cancer Clinical Practice Guidelines in Oncology, the American Society of Clinical Oncology Technology Assessment on the Use of Aromatase Inhibitors, and the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer, now incorporate AIs in the adjuvant therapy of postmenopausal women with estrogen receptor-positive breast cancer.

State-of-the-art treatment of metastatic hormone-refractory prostate cancer.

Initial therapy for advanced prostate cancer includes androgen ablation by surgical or medical castration. Still, nearly all men with metastases will progress to hormone-refractory prostate cancer (HRPC). Current U.S. Food and Drug Administration-approved agents for the treatment of HRPC include mitoxantrone and estramustine, although the vinca alkaloids and the taxanes have shown promising activity in single-agent phase II trials. Combinations of these agents induce a biochemical response in greater than 50% of patients, but the median duration of response is approximately 6 months. Overall survival of patients treated with these combinations is approximately 18-24 months. Studies are ongoing to develop novel therapies that target specific molecular pathways or mechanisms of chemotherapy resistance. Novel agents under development include growth factor receptor inhibitors, antisense oligonucleotides, bisphosphonates, and cell differentiating agents. Evaluation and incorporation of these agents into existing treatment regimens will guide us in the development of more active regimens in the treatment of HRPC.

Prevention of menstruation with leuprorelin (GnRH agonist) in women undergoing myelosuppressive chemotherapy or radiochemotherapy for hematological malignancies: a pilot study.

Vaginal bleeding during aplasia can induce transfusion support, infection and discomfort. Oral and intramuscular hormonotherapy can be toxic and/or difficult to manage (mucositis). This single-center pilot study evaluated the efficacy and safety of leuprorelin (L) in preventing heavy vaginal bleeding in 20 nonmenopausal women with leukemia, lymphoma or myeloma and foreseable therapy-induced thrombocytopenia. Until platelet recovery, patients received subcutaneous injections of L, with concomitant nomegestrol acetate (NA) during the first 35 days to prevent flare-up. Median age was 33 years (18-48). Platelet nadir was < 20 x 10(9)/l in 17 patients; 103 L injections were performed (median per patient: 4 [1-14]). No moderate or severe adverse event was related to hormonal therapy. Seventeen patients did not experience any clinically or therapeutically relevant bleeding. Eleven spottings and 8 metrorrhagias (mean duration: 3 days) occurred in 11 patients, requiring enhanced NA in 3 cases (baseline platelet count was < 20 x 10(9)/l in 1 pt, premature termination of NA [the single platelet transfusion for metrorrhagia] in 1 pt, and endometrial hyperplasia (EH) in the third). In patients without EH, only 5 spottings were observed after the third injection, without neither clinical nor therapeutic impact (63 injections). In conclusion, leuprorelin administration is safe and effective in preventing vaginal bleeding. The sustained-release form and subcutaneous administration offer quality of life advantages.

Commentary on maximal androgen blockade in prostate cancer: a theory to put into practice?

The population at risk of prostate cancer is on the increase, and so is public awareness of this disease. There has been an unresolved controversy surrounding the benefits of maximal androgen blockade (MAB) as a valid approach to treatment of non-curative prostate cancer since it was first proposed in 1945. How are we to interpret the data on MAB in order to give each patient the best advice on treatment? Studies of MAB using medical castration (luteinizing hormone-releasing hormone [LHRH] analogue plus antiandrogen) vs. LHRH analogues alone are inconclusive when viewed collectively, although the largest showed objective benefits for MAB. The remaining studies have insufficient power to show the expected effect size. Studies of MAB using surgical castration plus antiandrogen vs. surgical castration alone also gave inconsistent results, although a meta-analysis is in favor of MAB on objective criteria of response. Among trials of MAB using an LHRH analogue vs. surgical castration alone, one is positive and the remaining two are neutral for MAB. No study shows MAB to be worse than either medical or surgical castration alone. An overall meta-analysis shows a trend for benefit with MAB but is not statistically significant. The existing data have strongly suggested that there may be a particular benefit for certain subgroups of patients (including those with minimal disease) but numbers studied have been too small to allow valid conclusions. The INT 0105 trial in progress may permit firmer conclusions to be drawn on this and other questions. In the meantime one of the drawbacks to current MAB regimens is the exchange of modest clinical advantages for the side effects of nilutamide and flutamide. Given that the disease is noncurative, improved quality of life is the main goal of therapy, and excellent tolerability of treatment is fundamental to this. In a comparative trial, bicalutamide (Casodex) was more effective than flutamide (each in combination with an LHRH analogue) in terms of time to treatment failure and produced a significantly lower incidence of diarrhoea. In conclusion, the evidence supports early use of adequate hormonal treatment, and this should mean either medical or surgical castration, ideally augmented by an antiandrogen. Tolerability of the antiandrogen is a key consideration in gaining an improvement in quality of life with MAB.