Ribociclib plus Endocrine Therapy in Early Breast Cancer.

BACKGROUND: Ribociclib has been shown to have a significant overall survival benefit in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether this benefit in advanced breast cancer extends to early breast cancer is unclear. METHODS: In this international, open-label, randomized, phase 3 trial, we randomly assigned patients with HR-positive, HER2-negative early breast cancer in a 1:1 ratio to receive ribociclib (at a dose of 400 mg per day for 3 weeks, followed by 1 week off, for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI; letrozole at a dose of 2.5 mg per day or anastrozole at a dose of 1 mg per day for ≥5 years) or an NSAI alone. Premenopausal women and men also received goserelin every 28 days. Eligible patients had anatomical stage II or III breast cancer. Here we report the results of a prespecified interim analysis of invasive disease-free survival, the primary end point; other efficacy and safety results are also reported. Invasive disease-free survival was evaluated with the use of the Kaplan-Meier method. The statistical comparison was made with the use of a stratified log-rank test, with a protocol-specified stopping boundary of a one-sided P-value threshold of 0.0128 for superior efficacy. RESULTS: As of the data-cutoff date for this prespecified interim analysis (January 11, 2023), a total of 426 patients had had invasive disease, recurrence, or death. A significant invasive disease-free survival benefit was seen with ribociclib plus an NSAI as compared with an NSAI alone. At 3 years, invasive disease-free survival was 90.4% with ribociclib plus an NSAI and 87.1% with an NSAI alone (hazard ratio for invasive disease, recurrence, or death, 0.75; 95% confidence interval, 0.62 to 0.91; P = 0.003). Secondary end points - distant disease-free survival and recurrence-free survival - also favored ribociclib plus an NSAI. The 3-year regimen of ribociclib at a 400-mg starting dose plus an NSAI was not associated with any new safety signals. CONCLUSIONS: Ribociclib plus an NSAI significantly improved invasive disease-free survival among patients with HR-positive, HER2-negative stage II or III early breast cancer. (Funded by Novartis; NATALEE ClinicalTrials.gov number, NCT03701334.).

Real-world effectiveness and safety of goserelin 10.8-mg depot in Chinese patients with localized or locally advanced prostate cancer.

OBJECTIVE: Real-word data on long-acting luteinizing hormone-releasing hormone (LHRH) agonists in Chinese patients with prostate cancer are limited. This study aimed to determine the real-world effectiveness and safety of the LHRH agonist, goserelin, particularly the long-acting 10.8-mg depot formulation, and the follow-up patterns among Chinese prostate cancer patients. METHODS: This was a multicenter, prospective, observational study in hormone treatment-naïve patients with localized or locally advanced prostate cancer who were prescribed goserelin 10.8-mg depot every 12 weeks or 3.6-mg depot every 4 weeks with or without an anti-androgen. The patients had follow-up evaluations for 26 weeks. The primary outcome was the effectiveness of goserelin in reducing serum testosterone and prostate-specific antigen (PSA) levels. The secondary outcomes included testosterone and PSA levels, attainment of chemical castration (serum testosterone <50 ng/dL), and goserelin safety. The exploratory outcome was the monitoring pattern for serum testosterone and PSA. All analyses were descriptive. RESULTS: Between September 2017 and December 2019, a total of 294 eligible patients received ≥ 1 dose of goserelin; 287 patients (97.6%) were treated with goserelin 10.8-mg depot. At week 24 ± 2, the changes from baseline [standard deviation (95% confidence interval)] in serum testosterone (n = 99) and PSA (n = 131) were -401.0 ng/dL [308.4 ng/dL (-462.5, -339.5 ng/dL)] and -35.4 ng/mL [104.4 ng/mL (-53.5, -17.4 ng/mL)], respectively. Of 112 evaluable patients, 100 (90.2%) achieved a serum testosterone level < 50 ng/dL. Treatment-emergent adverse events (TEAEs) and severe TEAEs occurred in 37.1% and 10.2% of patients, respectively. The mean testing frequency (standard deviation) was 1.6 (1.5) for testosterone and 2.2 (1.6) for PSA. CONCLUSIONS: Goserelin 10.8-mg depot effectively achieved and maintained castration and was well-tolerated in Chinese patients with localized and locally advanced prostate cancer.

Erythema nodosum caused by goserelin acetate sustained-release: Case report and literature review.

Goserelin acetate is a gonadotropin-releasing hormone analog that is commonly used in patients with prostate cancer, endometriosis, and precocious puberty. The side effects of the drug include allergic rash, flushing, excessive sweating, skin swelling at the injection site, sexual dysfunction, erectile dysfunction, and menopausal symptoms. However, erythema nodosum has so far not been reported. In this paper, we have presented the case of erythema nodosum caused by goserelin acetate and a review of the literature on its adverse effects, thus providing useful insights into clinical management and medication safety.

Comparison of goserelin and leuprorelin for ovarian protection during chemotherapy in young patients with breast cancer.

PURPOSE: Although different gonadotropin-releasing hormone (GnRH) agonists may have different effects, their effect of ovarian protection during chemotherapy for breast cancer has not been compared. This study aimed to compare the effects of goserelin and leuprorelin for ovarian protection during chemotherapy in young patients with breast cancer. METHODS: This prospective study analyzed 193 patients with breast cancer aged ≤ 40 years who had regular menstruation and serum anti-Müllerian hormone (AMH) levels ≥ 1 ng/mL before treatment. Patients received either goserelin or leuprorelin for ovarian protection during doxorubicin/cyclophosphamide-based chemotherapy. Resumption of menstruation and changes in serum levels of AMH were compared between the two groups at 12 months after completion of chemotherapy. RESULTS: The mean age and the pretreatment serum AMH level were 33.2 years and 4.4 ng/mL in goserelin group and 34.2 years and 4.0 ng/mL in leuprorelin group. The proportion of patients who resumed menstruation was not different between the goserelin (94.4%) and leuprorelin (95.3%) groups at 12 months after chemotherapy completion. Serum AMH levels decreased significantly in both the goserelin (from 4.4 to 1.2 ng/mL) and leuprorelin (from 4.0 to 1.2 ng/mL) groups, with no statistical significance. In addition, no difference was found in the proportion of patients with serum AMH levels ≥ 1 ng/mL between the goserelin (49.5%) and leuprorelin (44.2%) groups at 12 months after chemotherapy. CONCLUSION: Goserelin and leuprorelin were comparable in terms of ovarian protection during doxorubicin/cyclophosphamide-based chemotherapy in young patients with breast cancer.

Clinical efficacy and safety of trimonthly administration of goserelin acetate 10.8 mg in premenopausal Chinese females with symptomatic adenomyosis: a prospective cohort study.

OBJECTIVE: This prospective cohort study aimed to compare the clinical efficacy and safety of goserelin 10.8 mg administered trimonthly with goserelin 3.6 mg administered monthly in premenopausal females with symptomatic adenomyosis. METHODS: We recruited 139 premenopausal females with adenomyosis who complained of dysmenorrhea and/or menorrhagia. The first group (n = 70) received a single subcutaneous injection of goserelin 10.8 mg, and the second group (n = 69) received monthly subcutaneous goserelin 3.6 mg administered for 3 months. Follow-up was performed at the outpatient department after 12 weeks. RESULTS: Ultimately, 130 patients completed the study, including 68 and 62 patients in the goserelin 10.8 mg (n = 70) and 3.6 mg (n = 69) groups, respectively. We observed a significant decrease in the dysmenorrhea (NRS) score, uterine volume, and cancer antigen 125 (CA125) levels, and a significant increase in hemoglobin (HGB) levels in both treatment groups. There was no significant difference between the two groups. The sum of the adverse event scores was slightly higher in the goserelin 3.6 mg than in the 10.8 mg group. CONCLUSIONS: The clinical efficacy of trimonthly administration of goserelin 10.8 mg was equivalent to monthly 3.6 mg dosing and was non-inferior regarding safety and tolerability. Hence, it can be a more cost-effective and convenient alternative treatment option in premenopausal females with symptomatic adenomyosis. TRIAL REGISTRATION: ChiCTR2200059548.

Analysis of adverse event of interstitial lung disease in men with prostate cancer receiving hormone therapy using the Food and Drug Administration Adverse Event Reporting System.

AIMS: To investigate interstitial lung disease (ILD) in men with prostate cancer receiving hormone therapy. METHODS: We gathered cases diagnosed with prostate cancer based on the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database from 2004 to 2020. We divided the included cases into 3 groups based on the primary suspected drugs: a hormone therapy group, a positive control group (taxanes), and a negative control group. We employed reporting odds ratio, a disproportionality method, to detect the association between ILD events and target drugs. RESULTS: We finally included a total of 85 403 cases, 69 894 cases (628 ILD event cases) in the hormone therapy group, 2302 cases (158 ILD event cases) in the positive control group and 13 207 cases (72 ILD event cases) in the negative control group. There were 394 ILD event cases (62.74%) in the hormone therapy group in Japan; 78.68% of the ILD events occurred within the first year after hormone treatment. Disproportionality analysis indicated that ILD events were significantly associated with nilutamide, flutamide, bicalutamide, goserelin, degarelix and apalutamide; the reporting odds ratios (95% confidence interval) were 32.14 (11.03-93.63), 9.93 (3.62-27.21), 8.19 (6.01-11.16), 3.74 (2.61-5.37), 2.41 (1.55-3.75) and 1.94 (1.01-3.75), respectively. CONCLUSION: Based on this FAERS pharmacovigilance analysis, the association between ILD events and hormone therapy drugs, including bicalutamide, flutamide, nilutamide, goserelin, degarelix and apalutamide, should not be ignored, especially in the Japanese population. Lung function of prostate cancer patients should be monitored when receiving the hormone therapy drugs mentioned above, especially for the first year post medication.

Gonadotropin-releasing hormone agonists in prostate cancer: A comparative review of efficacy and safety.

Androgen deprivation therapy (ADT) using gonadotropin-releasing hormone agonist (s) (GnRH-A) remains the backbone of advanced prostate cancer treatment. In this review, we assessed the efficacy, safety, and convenience of administration of various GnRH-A. All GnRH-A (goserelin, triptorelin, buserelin, histrelin, and leuprorelin) have comparable potential to suppress testosterone (T) levels (≤50 ng/dL in a month and ≤20 ng/dL in 3 months). However, goserelin has shown better efficacy in maintaining T levels ≤50 ng/dL compared with leuprolide. The incidences of T escape are lower with goserelin and leuprolide than buserelin. Goserelin also has maximum benefit in prostate-specific antigen suppression. In neoadjuvant setting, when only goserelin was used, the 10-year overall survival (OS) rate was 42.6% to 86%. When either goserelin or leuprolide was used, the 10-year OS rate was 62%. As an adjuvant to radical prostatectomy, goserelin had a 10-year survival rate of 87%, and triptorelin had an 8-year survival rate of 84.6%. Goserelin further showed an absolute survival rate of 49% when used as an adjuvant to radiotherapy. The survival rates further improved when GnRH-A are used as combined androgen blockade compared with monotherapy. The frequency and severity of adverse events (hot flushes, fatigue, sexual dysfunction) are comparable among the GnRH-A. Goserelin appears to be the most convenient of all the GnRH-A for administration. Lack of conclusive comparative evidence makes it imperative to have a holistic approach of considering the patient profile and the disease characteristics to select the appropriate GnRH-A for ADT in prostate cancer.

Patient preferences and adherence to adjuvant GnRH analogs among premenopausal women with hormone receptor positive breast cancer.

PURPOSE: Adjuvant ovarian function suppression (OFS) in premenopausal hormone receptor (HR) positive breast cancer (BC) improves survival. Adherence to adjuvant gonadotropin-releasing hormone analogs (GnRHa) remains a challenge and is associated with toxicities and inconvenient parenteral administration. The goal of this study was to describe real-world adherence patterns and patient preferences surrounding adjuvant GnRHa. METHODS: We analyzed the medical records of premenopausal women with non-metastatic HR positive BC from January 2000 to December 2017; participants received adjuvant monthly goserelin or leuprolide at The Ohio State University. Data collected included demographics, clinicopathologic characteristics, and OFS adherence/side effects. We defined non-adherence as discontinuation of GnRHa within 3 years for a reason other than switching to an alternate OFS, delay > 7 days from a dose, or a missed dose. Chi-square tests assessed associations between clinical characteristics and outcomes. RESULTS: A total of 325 patients met eligibility. Of these, 119 (37%) patients were non-adherent to GnRHa; 137 (42%) underwent elective bilateral salpingo-oophorectomy after initial GnRHa. Those opting for surgery reported significantly more hot flashes (74% vs 48%, p < 0.001), arthralgias (46% vs 30%, p = 0.003), and vaginal dryness (37% vs 21%, p = 0.001) compared with patients remaining on GnRHa. CONCLUSION: Non-adherence to adjuvant GnRHa occurred in over a third of patients and almost half the patients initiating GnRHa underwent subsequent surgical ablation. These high frequencies highlight real-world patterns of OFS. Additionally, treatment toxicities may impact personal preference of OFS modality. Personalized practices to target predictors of adjuvant GnRHa non-adherence are critical to optimize symptoms, adherence, and survivorship.

Protective effect of goserelin on ovarian reserve during (neo)adjuvant chemotherapy in young breast cancer patients: a prospective cohort study in China.

STUDY QUESTION: Does goserelin, a GnRH agonist, have a protective effect in young breast cancer patients in terms of ovarian reserve markers anti-Müllerian hormone (AMH) and antral follicle count (AFC) during chemotherapy? SUMMARY ANSWER: Compared with chemotherapy alone, concurrent goserelin is associated with a higher probability of ovarian reserve recovery at 1 year after chemotherapy. WHAT IS KNOWN ALREADY: Previous studies on the administration of goserelin to protect ovarian function during chemotherapy have produced conflicting results because of the endpoint used, namely, chemotherapy-induced amenorrhoea. Reproductive medicine specialists consider AMH and AFC as the most sensitive ovarian reserve markers; however, they have never been used as biomarkers to assess the potential protective effects on ovarian reserve of goserelin during chemotherapy. STUDY DESIGN, SIZE, DURATION: This was a prospective cohort study in which patients were assigned to receive (neo)adjuvant chemotherapy with goserelin (the goserelin group) or without goserelin (the control group) according to each patient's preference. Of 242 breast cancer patients enrolled between December 2015 and November 2019, 76 in control group and 73 in goserelin group were able to be assessed at 1 year after chemotherapy. PARTICIPANTS/MATERIALS, SETTING, METHODS: Premenopausal patients with a regular menstrual cycle and aged 18-45 years were eligible for enrolment if they were newly diagnosed with stages I-III breast cancer for which treatment with adjuvant or neoadjuvant chemotherapy was planned. Each patient in the goserelin group was given a subcutaneous dose of 3.6 mg at least 1 week before the first cycle of chemotherapy and then every 4 weeks for the duration of chemotherapy. Ovarian reserve markers and menstrual status were evaluated before and after chemotherapy in the two treatment groups. The primary endpoint was the AMH recovery rate, the secondary endpoints were the recovery rates of AFC, estradiol (E2), follicle-stimulating hormone (FSH) and menstruation. MAIN RESULTS AND THE ROLE OF CHANCE: Among 149 patients (76 in the control group and 73 in the goserelin group) with complete data at 1 year after chemotherapy, the adjusted recovery rate of AMH was 46.5% and 21.8% in the goserelin group and control group, respectively (odds ratio: 3.08; P = 0.002). The trends in AFC and FSH recovery rates were consistent with that in AMH recovery rate. Notably, AMH levels remained low in 41.3% of patients whose menstrual activity had resumed. LIMITATIONS, REASONS FOR CAUTION: Randomisation was not performed because of ethical considerations, so selection bias was inevitable, although propensity score weighting was done. The study was also underpowered because 21.5% (52/242) of enrolled patients received GnRH agonist-containing endocrine therapy and could not be analysed at 1 and 2 years after chemotherapy. WIDER IMPLICATIONS OF THE FINDINGS: Our results indicate that co-administration of goserelin with chemotherapy provides obvious ovarian reserve protection in these young breast cancer patients. We expect that these results will be applicable in clinical practice for young breast cancer patients. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the National Key R&D Program of China No. 2016YFC0901302, by the Research and Development Fund of Peking University People's Hospital No. RD2014-13, RDY2017-19 and by AstraZeneca. The authors have no disclosures. TRIAL REGISTRATION NUMBER: NCT02430103.

A Phase Ib Study of Alpelisib or Buparlisib Combined with Tamoxifen Plus Goserelin in Premenopausal Women with HR-Positive HER2-Negative Advanced Breast Cancer.

PURPOSE: This study reports the MTD, recommended phase 2 dose (RP2D), and preliminary efficacy of alpelisib or buparlisib used in combination with tamoxifen plus goserelin in premenopausal patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). PATIENTS AND METHODS: This study enrolled premenopausal women with HR+, HER2- ABC. Patients received tamoxifen (20 mg once daily) and goserelin acetate (3.6 mg every 28 days) with either alpelisib (350 mg once daily; n = 16) or buparlisib (100 mg once daily; n = 13) in 28-day cycles until MTD was observed. RESULTS: The criteria for MTD were not met for both alpelisib and buparlisib. The RP2D of alpelisib and buparlisib in combination with tamoxifen and goserelin were 350 mg and 100 mg, respectively. Both combinations met protocol-specified criteria for tolerability. The most common grade 3/4 treatment-emergent adverse events (TEAE) were hypokalemia (12.5%), hyperglycemia (6.3%), and rash (6.3%) for alpelisib and alanine aminotransferase increase (30.8%), aspartate aminotransferase increase (23.1%), and anxiety (15.4%) for buparlisib. TEAEs led to treatment discontinuation in 18.8% and 53.8% of alpelisib- and buparlisib-treated patients, respectively. Progression-free survival was 25.2 months in the alpelisib group and 20.6 months in the buparlisib group. CONCLUSIONS: The RP2Ds of alpelisib and buparlisib were 350 mg and 100 mg, respectively. No unexpected safety findings were reported. Although an early-phase study, data suggest that alpelisib plus endocrine therapy may be a potentially efficacious treatment that warrants further evaluation for premenopausal patients with HR+, HER2- ABC.See related commentary by Clark et al., p. 371.

Predictive Value of Molecular Subtypes in Premenopausal Women with Hormone Receptor-positive Early Breast Cancer: Results from the ABCSG Trial 5.

PURPOSE: To assess the predictive value of molecular breast cancer subtypes in premenopausal patients with hormone receptor-positive early breast cancer who received adjuvant endocrine treatment or chemotherapy. EXPERIMENTAL DESIGN: Molecular breast cancer subtypes were centrally assessed on whole tumor sections by IHC in patients of the Austrian Breast and Colorectal Cancer Study Group Trial 5 who had received either 5 years of tamoxifen/3 years of goserelin or six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Luminal A disease was defined as Ki67 <20% and luminal B as Ki67 ≥20%. The luminal B/HER2-positive subtype displayed 3+ HER2-IHC or amplification by ISH. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Cox models adjusted for clinical and pathologic factors. RESULTS: 185 (38%), 244 (50%), and 59 (12%) of 488 tumors were classified as luminal A, luminal B/HER2-negative and luminal B/HER2-positive, respectively. Luminal B subtypes were associated with poor outcome. Patients with luminal B tumors had a significantly shorter RFS [adjusted HR for recurrence: 2.22; 95% confidence interval (CI), 1.41-3.49; P = 0.001] and OS (adjusted HR for death: 3.51; 95% CI, 1.80-6.87; P < 0.001). No interaction between molecular subtypes and treatment was observed (test for interaction: P = 0.84 for RFS; P = 0.69 for OS). CONCLUSIONS: Determination of molecular subtypes by IHC is an independent prognostic factor for recurrence and death in premenopausal women with early-stage, hormone receptor-positive breast cancer but is not predictive for outcome of adjuvant treatment with tamoxifen/goserelin or CMF.See related commentary by Hunter et al., p. 5543.

Evaluation of goserelin effectiveness based on assessment of inflammatory cytokines and symptoms in uterine leiomyoma.

Background Uterine leiomyoma is a benign tumour of the uterine smooth muscles associated with an elevated level of inflammatory cytokines. Goserelin, a synthetic gonadotropin-releasing hormone analogue, suppresses the production of sex hormones and release of inflammatory cytokines in uterine leiomyoma cells. Objective The primary objective of this study was to find out the effectiveness of subcutaneous goserelin therapy on lowering serum levels of inflammatory cytokines and improving uterine leiomyoma-related symptoms in female patients diagnosed with uterine leiomyoma. The secondary objective was to assess the tolerability to goserelin therapy used in the management of this tumour. Setting Outpatient gynaecological clinic of the medical consultation department of Baghdad Teaching Hospital, Baghdad province, Iraq. Methods A single centre, prospective, longitudinal, cohort study was carried out on female patients diagnosed with uterine leiomyoma. Goserelin 3.6 mg subcutaneous injection was given in a consecutive monthly dose for the total time duration of three months. Serum levels of inflammatory cytokines, tumour necrosis factor-α and monocyte chemotactic protein-1 were detected before and after goserelin therapy in a consecutive monthly assessment. The study also assessed the improvement in uterine leiomyoma-related symptoms, including pelvic pain alongside the incidence of goserelin-related side effects during therapy schedules. Main Outcome Measures Assessment of serum levels of tumour necrosis factor-α and monocyte chemotactic protein-1 alongside uterine leiomyoma-related symptoms, including pelvic pain and goserelin-related side effects. Results There was a significant decrease in serum levels of tumour necrosis factor-α and monocyte chemotactic protein-1 compared to the baseline level over the 3-month duration of goserelin therapy (0.11 ± 0.02 vs. 0.74 ± 0.19) pg/mL; (0.07 ± 0.00 vs. 0.44 ± 0.18) pg/mL respectively. Patients showed a clinical improvement regarding uterine leiomyoma-related symptoms following each of the consecutive monthly doses of goserelin therapy (n = 11, 55%, P < 0.0001; n = 15, 75%, P < 0.0001; n = 18, 90%, P < 0.0001) respectively. This also includes a significant decrease in the intensity of leiomyoma-related pelvic pain before and after goserelin therapy (7.2 ± 1.43 vs. 3.05 ± 1.14, P < 0.0001). The majority of patients reported vaginal dryness (60%) as the main goserelin-related side effect. Conclusion Goserelin therapy reduces serum levels of inflammatory cytokines, tumour necrosis factor- α and monocyte chemotactic protein-1, improving leiomyoma-related symptoms with good tolerability in patients with uterine leiomyoma.

Recurrence of uterine adenomyosis after administration of gonadotropin-releasing hormone agonist and the efficacy of dienogest.

This study elucidated the degree of adenomyosis recurrence following gonadotropin-releasing hormone agonist (GnRHa) discontinuation and dienogest efficiency for recurrent adenomyosis. This retrospective cohort study included 30 patients, divided into a group of patients whose progress was observed without providing additional therapy following GnRHa administration for six months (Group G) and a group of patients administered dienogest for six months following six months of GnRHa administration (Group D). Menorrhagia, dysmenorrhea, chronic pelvic pain, abdominal fullness, and uterine volume were recorded prior to treatment, six months after the start of therapy (6 M), and 12 months after the start of therapy (12 M). In Group G (n = 15), although all subjective symptoms disappeared at 6 M, nearly all symptoms recurred at 12 M. Uterine volume significantly decreased from 341.0 cm3 to 156.0 cm3 at 6 M (p = .001) and significantly increased again to 282.3 cm3 at 12 M (p = .003). In Group D (n = 15), all subjective symptoms disappeared at 6 M, and only abdominal fullness returned in a significant number of patients (5 of 5; p = .021) at 12 M. Uterine volume decreased significantly at 6 M (p = .003) and significantly increased again from 162.5 cm3 to 205.6 cm3 at 12 M (p = .006). Subjective symptoms, except for abdominal fullness, did not recur when dienogest was administered after GnRHa.

[Anti-Müllerian hormone as a new marker of the ovarian reserve function preservation by goserelin during (neo)adjuvant chemotherapy for young breast cancer patients].

OBJECTIVE: To observe the dynamic change of anti-Müllerian hormone (AMH) in 1 year after chemotherapy which is the best biochemical marker of ovarian reserve in reproductive medicine setting and to evaluate the effect of gonadotropin-releasing hormone agonist (GnRHa)goserelin to prevent ovarian reserve function during (neo)adjuvant chemotherapy for young breast cancer patients. METHODS: Between December 2015 and June 2017, 101 breast cancer patients of age ≤ 45 years with stages I to III had been enrolled. The patients were assigned without interference to receive either (neo) adjuvant chemotherapy with goserelin (goserelin group) or without goserelin (chemotherapy group) as their own selection. AMH and menstrual status were evaluated before, during and 0.5 year, 1 year after chemotherapy. Primary end point was the incidence of low AMH value (<0.4 µg/L) at the end of 1 year. Secondary end point was the incidence of amenorrhea (the absence of menses in the preceding 12 months after assignment). RESULTS: In the study, 51 patients chose to join the chemotherapy group, while the other 50 patients selected goserelin to preserve their ovarian reserve function. More unmarried or childless, hormone receptors negative,receiving breast conservation therapy patients with earlier stage selected goserelin before chemotherapy. The incidence of low AMH value was significantly higher in chemotherapy group than in goserelin group (74.5% vs. 38.0%, P<0.001) in 1 year after chemotherapy. The incidence of amenorrhea was consistent with AMH (56.9% vs. 24.0%, P=0.001). And more patients' menstruation (78.9% vs. 54.5%) and AMH value (71.0% vs. 53.8%) recovered in goserelin group within 6 months after chemotherapy. In subgroup analysis, AMH and menstruation seemingly recovered more in goserelin group independent of age, chemotherapy regimen and use of tamoxifen. Especially, AMH value of 36.4% (8/22) patients in chemotherapy group and 18.4% (7/38) patients in goserelin group still maintained low level (<0.4 µg /L) although their menstruation had recovered 1 year after chemotherapy. In addition, 41 patients (20 patients in chemotherapy group, 21 patients in goserelin group) could be evaluated for the dynamic change of AMH and menstrual status during chemotherapy. The mean level of AMH in chemotherapy group declined rapidly to very low level before the 3rd cycle, while 70% of the patients kept presence of menstruation. At the same time, the mean level of AMH in goserelin group was still above 0.4 µg /L, but all of the patients had menopause. CONCLUSION: Our study has offered evidence that Goserelin with chemotherapy could protect against ovarian reserve failure for young breast cancer patients, now that more patients' AMH value recovered earlier who had selected co-treatment. AMH may be a more precise marker than menstrual status to clinically evaluate ovarian reserve function pre-, during and post- chemotherapy.

Anti-Müllerian hormone as a new marker of the ovarian reserve function preservation by goserelin during (neo)adjuvant chemotherapy for young breast cancer patients / 北京大学学报(医学版)

OBJECTIVE@#To observe the dynamic change of anti-Müllerian hormone (AMH) in 1 year after chemotherapy which is the best biochemical marker of ovarian reserve in reproductive medicine setting and to evaluate the effect of gonadotropin-releasing hormone agonist (GnRHa)goserelin to prevent ovarian reserve function during (neo)adjuvant chemotherapy for young breast cancer patients.@*METHODS@#Between December 2015 and June 2017, 101 breast cancer patients of age ≤ 45 years with stages I to III had been enrolled. The patients were assigned without interference to receive either (neo) adjuvant chemotherapy with goserelin (goserelin group) or without goserelin (chemotherapy group) as their own selection. AMH and menstrual status were evaluated before, during and 0.5 year, 1 year after chemotherapy. Primary end point was the incidence of low AMH value (<0.4 μg/L) at the end of 1 year. Secondary end point was the incidence of amenorrhea (the absence of menses in the preceding 12 months after assignment).@*RESULTS@#In the study, 51 patients chose to join the chemotherapy group, while the other 50 patients selected goserelin to preserve their ovarian reserve function. More unmarried or childless, hormone receptors negative,receiving breast conservation therapy patients with earlier stage selected goserelin before chemotherapy. The incidence of low AMH value was significantly higher in chemotherapy group than in goserelin group (74.5% vs. 38.0%, P<0.001) in 1 year after chemotherapy. The incidence of amenorrhea was consistent with AMH (56.9% vs. 24.0%, P=0.001). And more patients' menstruation (78.9% vs. 54.5%) and AMH value (71.0% vs. 53.8%) recovered in goserelin group within 6 months after chemotherapy. In subgroup analysis, AMH and menstruation seemingly recovered more in goserelin group independent of age, chemotherapy regimen and use of tamoxifen. Especially, AMH value of 36.4% (8/22) patients in chemotherapy group and 18.4% (7/38) patients in goserelin group still maintained low level (<0.4 μg /L) although their menstruation had recovered 1 year after chemotherapy. In addition, 41 patients (20 patients in chemotherapy group, 21 patients in goserelin group) could be evaluated for the dynamic change of AMH and menstrual status during chemotherapy. The mean level of AMH in chemotherapy group declined rapidly to very low level before the 3rd cycle, while 70% of the patients kept presence of menstruation. At the same time, the mean level of AMH in goserelin group was still above 0.4 μg /L, but all of the patients had menopause.@*CONCLUSION@#Our study has offered evidence that Goserelin with chemotherapy could protect against ovarian reserve failure for young breast cancer patients, now that more patients' AMH value recovered earlier who had selected co-treatment. AMH may be a more precise marker than menstrual status to clinically evaluate ovarian reserve function pre-, during and post- chemotherapy.

Impact of Patient- and Clinician-Reported Cumulative Toxicity on Quality of Life in Patients With Metastatic Castration-Naïve Prostate Cancer.

Background: Current toxicity evaluation is primarily focused on high-grade adverse events (AEs) reported by clinicians. However, the cumulative effect of multiple lower-grade AEs may also impact patients' quality of life (QoL). Further, patient-reported toxicity may be more representative of patients' treatment experiences. This study aimed to determine whether cumulative toxicity comprising all-grade AEs is more associated with QoL than cumulative toxicity comprising high-grade AEs only, and whether patient-reported cumulative toxicity is more associated with QoL than clinician-reported cumulative toxicity. Methods: Patients with metastatic castration-naïve prostate cancer participating in the phase III GETUG-AFU 15 trial completed questionnaires on AEs (at 3 and 6 months) and QoL (at baseline and 3 and 6 months). Clinicians reported AEs during clinical visits. Cumulative toxicity scores were calculated for clinicians and patients in 3 ways: total number of high-grade AEs, total number of all-grade AEs, and total number of all AEs multiplied by their grade (severity score). Relationships between cumulative toxicity scores and QoL were studied using longitudinal regression analyses; unstandardized (B) and standardized regression coefficients (ß) are reported. Results: Of 385 patients, 184 with complete QoL and toxicity data were included. Clinician-reported all-grade AEs (B, -2.2; 95% CI, -3.3 to -1.1; P<.01) and severity score (B, -1.4; 95% CI, -2.2 to -0.7; P<.01) were associated with deteriorated physical QoL, whereas the total number of high-grade AEs was not. All patient-reported scores were significantly (P<.01 for all) associated with deteriorated physical and global QoL. Standardized regression coefficients indicated that patient-reported toxicity scores were more associated with QoL outcomes than clinician-reported scores, with the strongest association found for the all-grade AEs and severity cumulative toxicity scores. Conclusions: Patient- and clinician-based cumulative toxicity scores comprising all-grade AEs better reflect impact on patient QoL than toxicity scores comprising high-grade AEs only. To assess the effect of toxicity on QoL, patient-reported cumulative toxicity scores are preferred.

Sequence of hormonal therapy and radiotherapy field size in unfavourable, localised prostate cancer (NRG/RTOG 9413): long-term results of a randomised, phase 3 trial.

BACKGROUND: The NRG/RTOG 9413 study showed that whole pelvic radiotherapy (WPRT) plus neoadjuvant hormonal therapy (NHT) improved progression-free survival in patients with intermediate-risk or high-risk localised prostate cancer compared with prostate only radiotherapy (PORT) plus NHT, WPRT plus adjuvant hormonal therapy (AHT), and PORT plus AHT. We provide a long-term update after 10 years of follow-up of the primary endpoint (progression-free survival) and report on the late toxicities of treatment. METHODS: The trial was designed as a 2 × 2 factorial study with hormonal sequencing as one stratification factor and radiation field as the other factor and tested whether NHT improved progression-free survival versus AHT, and NHT plus WPRT versus NHT plus PORT. Eligible patients had histologically confirmed, clinically localised adenocarcinoma of the prostate, an estimated risk of lymph node involvement of more than 15% and a Karnofsky performance status of more than 70, with no age limitations. Patients were randomly assigned (1:1:1:1) by permuted block randomisation to receive either NHT 2 months before and during WPRT followed by a prostate boost to 70 Gy (NHT plus WPRT group), NHT 2 months before and during PORT to 70 Gy (NHT plus PORT group), WPRT followed by 4 months of AHT (WPRT plus AHT group), or PORT followed by 4 months of AHT (PORT plus AHT group). Hormonal therapy was combined androgen suppression, consisting of goserelin acetate 3·6 mg once a month subcutaneously or leuprolide acetate 7·5 mg once a month intramuscularly, and flutamide 250 mg twice a day orally for 4 months. Randomisation was stratified by T stage, Gleason Score, and prostate-specific antigen concentration. NHT was given 2 months before radiotherapy and was continued until radiotherapy completion; AHT was given at the completion of radiotherapy for 4 months. The primary endpoint progression-free survival was analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00769548. The trial has been terminated to additional follow-up collection and this is the final analysis for this trial. FINDINGS: Between April 1, 1995, and June 1, 1999, 1322 patients were enrolled from 53 centres and randomly assigned to the four treatment groups. With a median follow-up of 8·8 years (IQR 5·07-13·84) for all patients and 14·8 years (7·18-17·4) for living patients (n=346), progression-free survival across all timepoints continued to differ significantly across the four treatment groups (p=0·002). The 10-year estimates of progression-free survival were 28·4% (95% CI 23·3-33·6) in the NHT plus WPRT group, 23·5% (18·7-28·3) in the NHT plus PORT group, 19·4% (14·9-24·0) in the WPRT plus AHT group, and 30·2% (25·0-35·4) in the PORT plus AHT group. Bladder toxicity was the most common grade 3 or worse late toxicity, affecting 18 (6%) of 316 patients in the NHT plus WPRT group, 17 (5%) of 313 in the NHT plus PORT group, 22 (7%) of 317 in the WPRT plus AHT group, and 14 (4%) of 315 in the PORT plus AHT group. Late grade 3 or worse gastrointestinal adverse events occurred in 22 (7%) of 316 patients in the NHT plus WPRT group, five (2%) of 313 in the NHT plus PORT group, ten (3%) of 317 in the WPRT plus AHT group, and seven (2%) of 315 in the PORT plus AHT group. INTERPRETATION: In this cohort of patients with intermediate-risk and high-risk localised prostate cancer, NHT plus WPRT improved progression-free survival compared with NHT plus PORT and WPRT plus AHT at long-term follow-up albeit increased risk of grade 3 or worse intestinal toxicity. Interactions between radiotherapy and hormonal therapy suggests that WPRT should be avoided without NHT. FUNDING: National Cancer Institute.

Efficacy and safety of 3-month dosing regimen of degarelix in Japanese subjects with prostate cancer: A phase III study.

Non-inferiority in the cumulative castration rate of the 3-month formulation of degarelix compared with the 3-month formulation of goserelin was evaluated in subjects with prostate cancer. A phase III, open-label, parallel-arm study was carried out. An initial dose of 240 mg degarelix or 3.6 mg goserelin was given s.c.; after day 28, a maintenance dose of 480 mg degarelix or 10.8 mg goserelin was given once every 84 days. Non-inferiority in castration rate and safety of degarelix to goserelin were evaluated. The primary end-point was the cumulative castration rate from day 28 to day 364 and the non-inferiority margin was set to be 10%. A total of 234 subjects with prostate cancer were randomized to the degarelix group (n = 117) and the goserelin group (n = 117). The cumulative castration rate was 95.1% in the degarelix group and 100.0% in the goserelin group. As there were no events in the goserelin group, an additional analysis was carried out using 95% confidence intervals of the difference in the proportion of subjects with castration. Analyses indicated the non-inferiority of the 3-month formulation of degarelix to goserelin. Degarelix showed more rapid decreases in testosterone, luteinizing hormone, follicle stimulating hormone, and prostate-specific antigen levels compared with goserelin. The most common adverse events in the degarelix group were injection site reactions. Non-inferiority of the 3-month formulation of degarelix to goserelin was shown for testosterone suppression. The 3-month formulation of degarelix was also found to be tolerated as an androgen deprivation therapy for patients with prostate cancer. This trial was registered with ClinicalTrials.gov (identifier NCT01964170).

Occurrence of pneumonitis following radiotherapy of breast cancer - A prospective study.

AIM: of this study is to determine the temporal resolution of therapy-induced pneumonitis, and to assess promoting factors in adjuvant treated patients with unilateral mammacarcinoma. PATIENTS AND METHODS: A total of 100 post-surgery patients were recruited. The cohort was treated by 2 field radiotherapy (2FRT; breast and chest wall, N = 75), 3 field radiotherapy (3FRT; + supraclavicular lymphatic region, N = 8), or with 4 field radiotherapy (4FRT; + parasternal lymphatic region, N = 17). Ninety-one patients received various systemic treatments prior to irradiation. Following an initial screening visit post-RT, two additional visits after 12 and 25 weeks were conducted including radiographic examination. In addition, general anamnesis and the co-medication were recorded. The endpoint was reached as soon as a pneumonitis was developed or at maximum of six months post-treatment. RESULTS: A pneumonitis incidence of 13% was determined. Of 91 patients with prior systemic therapy, 11 patients developed pneumonitis. Smoking history and chronic obstructive pulmonary disease (COPD) appeared to be positive predictors, whereas past pneumonia clearly promoted pneumonitis. Further pneumonitis-promoting predictors are represented by the applied field extensions (2 field radiotherapy [2FRT] < 3 field radiotherapy [3FRT] < 4 field radiotherapy [4FRT]) and the type of combined initial systemic therapies. As a consequence, all of the three patients in the study cohort treated with 4FRT and initial chemotherapy combined with anti-hormone and antibody protocols developed pneumonitis. A combination of the hormone antagonists tamoxifen and goserelin might enhance the risk for pneumonitis. Remarkably, none of the 11 patients co-medicated with statins suffered from pneumonitis. CONCLUSIONS: The rapidly increasing use of novel systemic therapy schedules combined with radiotherapy (RT) needs more prospective studies with larger cohorts. Our results indicate that contribution to pneumonitis occurrence of various (neo)adjuvant therapy approaches followed by RT is of minor relevance, whereas mean total lung doses of >10 Gy escalate the risk of lung tissue complications. The validity of potential inhibitors of therapy-induced pneumonitis as observed for statin co-medication should further be investigated in future trials.

Are all gonadotrophin-releasing hormone agonists equivalent for the treatment of prostate cancer? A systematic review.

To review direct comparative studies of the gonadotrophin-releasing hormone (GnRH) agonists goserelin, triptorelin, and leuprorelin for the treatment of prostate cancer, and identify whether there are meaningful clinical differences between these agents. In June 2017, the following searches were performed independently by two reviewers in PubMed: (i) 'prostate cancer' and 'triptorelin' and 'leuprorelin', (ii) 'prostate cancer' and 'triptorelin' and 'goserelin', and (iii) 'prostate cancer' and 'goserelin' and 'leuprorelin', without time restriction. Duplicates were deleted. Relevant conference abstracts were also screened. A total of 16 direct comparative trials were identified: 12 reported on efficacy outcomes, four on safety/tolerability, and five on the convenience of administration/user perceptions. These studies are restricted in terms of patient numbers, formulations assessed, and endpoints measured; none were adequately powered for survival outcome measures. Studies reporting on efficacy endpoints did not show major differences in the ability of these GnRH agonists to reduce levels of testosterone or prostate-specific antigen. Some studies suggest differences in short- or long-term testosterone control, the rate of injection site adverse events, and patient/healthcare professional perceptions, but definitive conclusions cannot be drawn from the existing evidence. Few direct comparative trials of GnRH agonists have been conducted. Whilst GnRH agonists provide a similar castration effect, there is not enough evidence to show that GnRH agonists are equivalent.