Search Results (20)

Background: Oral progestogens, including megestrol acetate (MA) and medroxyprogesterone acetate (MPA), have largely been superseded by aromatase inhibitors, tamoxifen, and selective oestrogen receptor degraders (SERDs) in oestrogen receptor-positive (ER-positive) metastatic breast cancer. However, they remain an option as late-line therapy after failure of standard treatments. Contemporary data are limited, particularly in patients previously treated with CDK4/6 inhibitors. Methods: We conducted a multi-site retrospective analysis of patients with ER-positive metastatic breast cancer treated with MA or MPA between 2014 and 2024 at four hospital sites across London, United Kingdom. Patients were identified using pharmacy dispensing records. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method and Cox regression. Subgroup analyses included prior CDK4/6 inhibitor exposure, histology and liver metastases. Results: A total of 116 patients were included. Median PFS was 2.4 months (95% CI 2.2–2.9), and median OS was 3.3 months (95% CI 2.7–4.9). Prior CDK4/6 inhibitor exposure was associated with shorter PFS (1.9 vs. 2.8 months; HR 1.59; 95% CI 1.08–2.35, p = 0.019) and a trend toward shorter OS (3.1 vs. 3.6 months; HR 1.18, 95% CI 0.80–1.75, p = 0.41). Similarly, liver metastases were associated with shorter PFS (2.3 vs. 2.8 months; HR 1.78, 95% CI 1.12–2.85, p = 0.015), with a trend toward worse OS (3.1 vs. 4.9 months; HR 1.45, 95% CI 0.93–2.25, p = 0.103). A subset of patients derived prolonged benefit, with a 6-month PFS rate of 16%. Toxicity was manageable; thromboembolic events and oedema occurred in 9% and 11% of patients respectively. Appetite improvement was reported in 10%. Conclusions: MA and MPA demonstrated modest but clinically relevant late-line activity in heavily pretreated, endocrine-refractory ER-positive metastatic breast cancer. While prior exposure to CDK4/6 inhibitors was associated with shorter PFS, patients without liver metastases appeared to derive the greatest benefit. These findings support a role for oral progestogens in selected patients who have exhausted standard therapeutic options. Full article

Cancer cachexia (CC) is a multifactorial, multi-organ syndrome characterized by systemic inflammation, metabolic dysregulation, anorexia, and progressive depletion of skeletal muscle and adipose tissue. Despite its high prevalence among patients with advanced malignancies, effective therapeutic options remain limited. Recent studies have elucidated the molecular underpinnings of CC and the therapeutic potential of natural herbs, highlighting the involvement of central nervous system regulation, adipose tissue, immune responses, gut microbiota, skeletal muscle, and disruptions in anabolic–catabolic signaling pathways such as mTOR, UPS, NF-κB, and STAT3. Persistent inflammation induces E3 ubiquitin ligases (Atrogin-1/MuRF-1) through cytokines including IL-6 and TNF-α, thereby impairing muscle homeostasis, while suppression of anabolic cascades such as IGF-1/mTOR further aggravates muscle atrophy. The limited efficacy and adverse effects of synthetic agents like megestrol acetate underscore the value of herbal therapies as safer adjunctive strategies. Botanicals such as Coicis Semen, Scutellaria baicalensis, and Astragalus demonstrate anti-inflammatory and muscle-preserving activities by modulating NF-κB, IL-6, and oxidative stress signaling. Numerous investigations indicate that these herbs downregulate MuRF-1 and Atrogin-1 expression, enhance appetite, and attenuate muscle loss, though they exhibit minimal influence on tumor suppression. While promising, current evidence remains largely preclinical and mechanistic validation is incomplete. This review consolidates contemporary insights into CC pathogenesis and the bioactivity of herbal interventions, highlighting the need for translational research to bridge preclinical findings with clinical applicability. Full article

Degradation is a key natural attenuation mechanism governing the fate of PPCPs during anaerobic digestion (AD) and subsequent soil exposure. Nevertheless, the combined impact of this sequential treatment (AD followed by land application) remains poorly understood. This study evaluated the degradation characteristics of nine PPCPs during mesophilic AD in three distinct soil types. The concentration changes in the nine PPCPs were monitored after 0, 5, 10, 15, 20, 25, and 30 days of anaerobic incubation at 38 °C, as well as after 0, 2, 5, 8, 10, 12, 15, 20, and 30 days of dark incubation at 25 °C with humidity at 75% in three soils. AD effectively removed sulfamethoxydiazine, ciprofloxacin, and oxytetracycline (>80%). The removal efficiencies for carbamazepine, progesterone, triclosan, naproxen, and megestrol acetate were relatively poor, with the removal rates ranging from 50% to 80%, while gemfibrozil exhibited minimal degradation (<50%). The degradation behavior of nine PPCPs fits well with first-order kinetic equations. Calculated half-lives (days) in the three soils were as follows: sulfamethoxydiazine (20.39 to 23.10), carbamazepine (36.48 to 77.02), megestrol acetate (11.18 to 20.39), progesterone (6.08 to 23.90), ciprofloxacin (11.75 to 63.01), oxytetracycline (13.08 to 30.14), naproxen (7.79 to 40.77), gemfibrozil (8.45 to 30.14), and triclosan (14.75 to 46.21). The corresponding R² values ranged from 0.8882 to 0.9320 for sulfamethoxydiazine, 0.8579 to 0.9248 for carbamazepine, 0.8745 to 0.9658 for megestrol acetate, 0.9026 to 0.9560 for progesterone, 0.8147 to 0.9571 for ciprofloxacin, 0.8136 to 0.9063 for oxytetracycline, 0.8961 to 0.9156 for naproxen, 0.8802 to 0.9497 for gemfibrozil, and 0.9099 to 0.9457 for triclosan. Soil physicochemical properties significantly influenced PPCP degradation rates. Gemfibrozil warrants immediate attention due to its poor degradation; the five PPCPs presenting moderate concern—namely carbamazepine, ciprofloxacin, oxytetracycline, naproxen, and triclosan—require further risk assessment, while sulfamethoxydiazine, megestrol acetate, and progesterone pose low persistence risk according to current evidence. Full article

Background/Objectives: The effects of combining chemotherapy with hormonal therapy based on hormone receptor (HR) expression in epithelial ovarian, fallopian tube, or primary peritoneal (EOC) remain unclear. This study evaluated the efficacy and safety of physician-chosen chemotherapy combined with hormonal therapy in patients with heavily pretreated advanced EOC, stratified by HR expression. Methods: This phase II, multicenter, pilot study included patients with heavily pretreated advanced EOC, allocated to estrogen receptor (ER)-dominant or progesterone receptor (PR)-dominant arms. Patients in the ER-dominant arm received tamoxifen plus physician-selected chemotherapy, while those in the PR-dominant arm received megestrol acetate (MA) plus chemotherapy. The primary outcome was the best objective response rate (ORR) for six months, assessed using an optimal two-stage Simon design. Results: Among 33 ER-dominant patients with high-grade serous carcinoma (HGSC), the six-month best ORR was 27.3% (3% complete response, 24.2% partial response). The six-month ORR and clinical benefit rate (CBR) were 18.8% and 37.5%, respectively, with 62.5% experiencing progressive disease (PD). Among three PR-dominant patients (two clear cell carcinoma and one HGSC), the six-month best ORR was 0%. The six-month ORR and CBR were also 0%, and all experienced PD within six months. No unacceptable toxicity related to tamoxifen or MA was encountered. Conclusions: In heavily pretreated advanced HGSC patients with ER-dominant expression, chemotherapy combined with tamoxifen showed encouraging clinical activity with favorable safety. While limited by the study design, these findings suggest a potential role for tailored hormonal therapy combined with chemotherapy based on HR expression in heavily pretreated advanced EOC. Clinical Trial Registration: KCT0004571 Full article

Pterostilbene (3,5-dimethoxy-40-hydroxystilbene) is a potent oral antioxidant with a promising role in anti-cancer treatment. In endometrial cancer (EC), in vitro studies demonstrated a synergistic antiproliferative effect of pterostilbene (PT) with megestrol acetate (MA), a common treatment for EC. This is a randomized phase II clinical trial (NCT03671811) of PT+MA vs. MA for three weeks prior to scheduled hysterectomy. The primary objective is to determine the antiproliferative effect of PT+MA vs. MA using Ki-67 index. The secondary objectives are toxicity, histological response, transcriptional changes, and lipid metabolism. A total of 44 patients were enrolled between January 2019 and November 2022 with 23 randomized to Arm 1 (PT+MA) and 21 to Arm 2 (MA). Toxicities included one G3 thromboembolic event (PT+MA) and one G3 hypertension event (MA). Histological responses were high in both arms (>90%). There was no difference in Ki-67 changes, although, when restricted to endometroid subtype, the relative decrease in Ki67 was 33.8% in PT+MA vs. 20.1% in MA alone (p = 0.14). Whole transcriptomic gene profiling of samples before and after PT+MA exposure demonstrated the activation of interferon alpha response pathway and suppression of mTORC1 signaling, hypoxia, oxidative phosphorylation, and IL2-STAT5 signaling. Lipid metabolism analyses did not reveal any significant changes between arms. PT is well-tolerated in the preoperative treatment of EC and demonstrated in vivo anti-cancer effects on the transcriptomic level. Full article

Endometrial cancer (EC) affects 3–14% of women under 40 who wish to preserve their fertility. The standard treatment for EC is a hysterectomy with salpingo-oophorectomy. However, for those desiring fertility preservation, oral progestogens such as medroxy-progesterone acetate (MPA) or megestrol acetate (MA) are the most common therapies in Fertility-Sparing Treatment (FST). Other treatments include gonadotropin-releasing hormone agonist (GnRHa), levonorgestrel-releasing intrauterine system (LNG-IUS), and metformin plus progestin. This comprehensive review evaluates the best FST options for women with reproductive potential. PubMed, EMBASE, and Scopus were searched in June 2023 using specific keywords. Studies included in the review focused on patients with EC undergoing FST, with outcomes such as complete response rate (CRR), recurrence rate (RR), pregnancy rate (PR), and live birth rate. Eighteen studies met the inclusion criteria, involving 23,976 patients. In only-oral progestin trials, CRR ranged from 18% to 100%; RR ranged from 0% to 81.8%; Death Rate ranged from 0% to 3.6%. In studies combining oral progestin with LNG-IUS, CRR ranged from 55% to 87.5%; RR ranged from 0% to 41.7%; Death Rate was 0%. Most patients with Stage IA EC received MPA or MA. Fertility-related outcomes were reported in 15 studies. PR ranged from 4 to 44 patients in trials involving only oral progestins. When combining oral progestin with LNG-IUS, PR ranged from 1 to 46 patients. Progestin therapy, including oral MPA and MA, is considered safe and effective, with limited evidence supporting the use of LNG-IUS. Full article

A comparative analysis of the cytostatic effects of progestins (gestobutanoyl, megestrol acetate, amol, dienogest, and medroxyprogesterone acetate), glucocorticoids (hydrocortisone, dexamethasone), and diclofenac on tumor cells was carried out in order to confirm their in silico predicted probabilities experimentally. The results showed the different sensitivity of HeLa, MCF-7, Hep-2, K-562, and Wi-38 cell lines to progestins, glucocorticoids, and diclofenac. The minimum IC₅₀ was found for progestin gestobutanoyl (GB) as 18 µM for HeLa cells, and varied from 31 to 38 µM for MCF-7, Hep-2, and K-562. Glucocorticoids and diclofenac were much less cytotoxic in the HeLa, MCF-7, and Hep-2 cell lines than progestins, with IC₅₀ values in the range of 150–3000 μM. Myelogenous leukemia K-562 cells were the least sensitive to the action of progestins and glucocorticoids but the most sensitive to diclofenac, which showed a pronounced cytotoxic effect with an IC₅₀ of 31 μM. As we have shown earlier, progestins can uniquely modulate MPTP opening via the binding of adenine nucleotide translocase. On this basis, we evaluated the expression of adenylate nucleotide translocase ANT1 (SLC25 A4) as a possible participant in cytotoxic action in these cell lines after 48 h incubation with drugs. The results showed that progestins differently regulated ANT1 expression in different cell lines. Gestobutanoyl had the opposite effect on ANT1 expression in the HeLa, K562, and Wi-38 cells compared with the other progestins. It increased the ANT1 expression more than twofold in the HeLa and K562 cells but had no influence on the Wi-38 cells. Glucocorticoids and diclofenac increased ANT1 expression in the Wi-38 cells and decreased it in the K562, MCF-7, and Hep-2 cells. The modulation of ANT1 expression discovered in our study can be a new explanation of the cytotoxic and cytoprotective effects of hormones, which can vary depending on the cell type. ANT isoforms in normal and cancerous cells could be a new target for steroid hormone and anti-inflammatory drug action. Full article

(1) Background: The standard first-line therapy for advanced adrenocortical carcinoma (ACC) is represented by EDP-M (etoposide, doxorubicin, cisplatin + mitotane). Progestins have shown cytotoxic activity both in vitro and in vivo on ACC; better EDP-M tolerability and efficacy have been hypnotized due to the association with progestins. (2) Methods: The feasibility and tolerability of EDP-M combined with oral megestrol acetate (EDP-MM) were tested in 24 patients (pts) affected by metastatic ACC with a low performance status (PS); the case group was compared with a 48 pts control group according to the propensity score. The secondary objectives were clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). (3) Results: Thirteen pts (54.2%) in the EDP-MM population experienced progestin-related toxicities; in particular, five pts experienced vaginal bleeding (20.8%); four pts experienced weight gain (16.7%); and thromboembolic events, worsening of hypertension, skin rashes, and hyperglycemia were registered in one patient each (4.2%). This led to the discontinuation of megestrol acetate in four pts (16.7%). EDP-M-related toxicities were similar in both groups. No differences in PFS and OS curves were observed; the CBR was 75.0% and 60.4%, respectively. (4) Conclusions: The association of EDP-M + megestrol acetate in ACC pts with a low PS is feasible and well tolerated; its efficacy appeared to be non-inferior to EDP-M administered to pts with a good PS. Full article

Background: Adrenocortical cancer (ACC) is a rare malignancy with a dismal prognosis. The treatment includes mitotane and EDP chemotherapy (etoposide, doxorubicin, and cisplatin). However, new therapeutic approaches for advanced ACC are needed, particularly targeting the metastatic process. Here, we deepen the role of progesterone as a new potential drug for ACC, in line with its antitumoral effect in other cancers. Methods: NCI-H295R, MUC-1, and TVBF-7 cell lines were used and xenografted in zebrafish embryos. Migration and invasion were studied using transwell assays, and MMP2 activity was studied using zymography. Apoptosis and cell cycle were analyzed by flow cytometry. Results: Progesterone significantly reduced xenograft tumor area and metastases formation in embryos injected with metastatic lines, MUC-1 and TVBF-7. These results were confirmed in vitro, where the reduction of invasion was mediated, at least in part, by the decrease in MMP2 levels. Progesterone exerted a long-lasting effect in metastatic cells. Progesterone caused apoptosis in NCI-H295R and MUC-1, inducing changes in the cell-cycle distribution, while autophagy was predominantly activated in TVBF-7 cells. Conclusion: Our results give support to the role of progesterone in ACC. The involvement of its analog (megestrol acetate) in reducing ACC progression in ACC patients undergoing EDP-M therapy is now under investigation in the PESETA phase II clinical study. Full article

Hormonal therapy has long been a treatment modality for recurrent endometrial cancer. It is appealing for patients with low-grade, slow-growing tumors or in patients for which other treatment types may be too toxic. Hormonal therapy is well tolerated and has response rates ranging from 9 to 33%. Hormonal treatment options take advantage of the estrogen-dependent molecular pathways in endometrial cancers. Current options for hormonal therapies include progesterone therapy (medroxyprogesterone acetate and megestrol acetate) as a single agent or in combination and agents that target the estrogen pathway. Aromatase inhibitors have had modest single-agent activity, but synergistic effects have been found when used in combination with targeted therapy including mTOR inhibitors and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Molecular profiling of endometrial cancers has begun to help individualize treatments. This review will report on existing data and ongoing trials investigating novel hormonal therapy agents. Full article

Cancer-related anorexia/cachexia is known to be associated with worsened quality of life and survival; however, limited treatment options exist. Although megestrol acetate (MA) is often used off-label to stimulate appetite and improve anorexia/cachexia in patients with advanced cancers, the benefits are controversial. The present meta-analysis aimed to better elucidate the clinical benefits of MA in patients with cancer-related anorexia/cachexia. A systematic search of PubMed, EMBASE, OVID Medline, Clinicaltrials.gov, and Google Scholar databases found 23 clinical trials examining the use of MA in cancer-related anorexia. The available randomized, controlled trials were appraised using Version 2 of the Cochrane risk-of-bias tool (RoB 2) and they had moderate-to-high risk of bias. A total of eight studies provided sufficient data on weight change for meta-analysis. The studies were divided into high-dose treatment (>320 mg/day) and low-dose treatment (≤320 mg/day). The overall pooled mean change in weight among cancer patients treated with MA, regardless of dosage was 0.75 kg (95% CI = −1.64 to 3.15, τ² = 9.35, I² = 96%). Patients who received high-dose MA tended to have weight loss rather than weight gain. There were insufficient studies to perform a meta-analysis for the change in tricep skinfold, midarm circumference, or quality of life measures. MA was generally well-tolerated, except for a clear thromboembolic risk, especially with higher doses. On balance, MA did not appear to be effective in providing the symptomatic improvement of anorexia/cachexia in patients with advanced cancer. Full article

Endometrial cancer (EC) rarely develops in young women. Most cases are associated with known risk factors: BMI > 30, history of Polycystic Ovary Syndrome (PCOs), and race differentiation. The molecular EC classification based on The Cancer Genome Atlas Research Network divides these heterogeneous cancers into four types: Polymerase Epsilon Mutation (POLE), Microsatellite Instability (MSI), Copy Number Low (CNL), and Copy Number High (CNH). This division was introduced to allow for early assessment of neoplastic changes and clinical management, including targeted therapies. The basic technique for imaging endometrium changes is transvaginal sonography. Hysteroscopy is the standard for obtaining endometrial material for histological evaluation. The MRI result permits assessment of the extent of EC cancer infiltration. In young women who want to preserve fertility, apart from surgery, conservative management is often implemented after strict selection based on clinical and pathological data. This pharmacological treatment involves the administration of progestogens MPA (medroxyprogesterone acetate) and MA (megestrol acetate). The use of metformin may increase the effectiveness of such treatment. An alternative option is to apply progestogens locally—via the levonorgestrel-releasing intrauterine device. In addition to pharmacological treatment, hysteroscopic resection may be used—part of the uterine muscle adjacent to the pathologically changed endometrium may also undergo resection. An alternative is the administration of estrogen receptor modulators (e.g., SERMs) or aromatase inhibitors, or GnRH agonists. Full article

Cachexia may be caused by congestive heart failure, and it is then called cardiac cachexia, which leads to increased morbidity and mortality. Cardiac cachexia also worsens skeletal muscle degradation. Cardiac cachexia is the loss of edema-free muscle mass with or without affecting fat tissue. It is mainly caused by a loss of balance between protein synthesis and degradation, or it may result from intestinal malabsorption. The loss of balance in protein synthesis and degradation may be the consequence of altered endocrine mediators such as insulin, insulin-like growth factor 1, leptin, ghrelin, melanocortin, growth hormone and neuropeptide Y. In contrast to many other health problems, fat accumulation in the heart is protective in this condition. Fat in the heart can be divided into epicardial, myocardial and cardiac steatosis. In this review, we describe and discuss these topics, pointing out the interconnection between heart failure and cardiac cachexia and the protective role of cardiac obesity. We also set the basis for possible screening methods that may allow for a timely diagnosis of cardiac cachexia, since there is still no cure for this condition. Several therapeutic procedures are discussed including exercise, nutritional proposals, myostatin antibodies, ghrelin, anabolic steroids, anti-inflammatory substances, beta-adrenergic agonists, medroxyprogesterone acetate, megestrol acetate, cannabinoids, statins, thalidomide, proteasome inhibitors and pentoxifylline. However, to this date, there is no cure for cachexia. Full article

Cisplatin is a well-known chemotherapeutic agent used to treat various types of cancers; however, it can also induce anorexia, which results in reduced food intake, loss of body weight, and lower quality of life. Although drugs such as megestrol acetate and cyproheptadine are used to decrease this severe feeding disorder, they can also induce side effects, such as diarrhea and somnolence, which limit their widespread use. Various types of herbal medicines have long been used to prevent and treat numerous gastrointestinal tract diseases; however, to date, no study has been conducted to analyze and summarize their effects on cisplatin-induced anorexia. In this paper, we analyze 12 animal studies that used either a single herbal medicine extract or mixtures thereof to decrease cisplatin-induced anorexia. Among the herbal medicines, Ginseng Radix was the most used, as it was included in seven studies, whereas both Glycyrrhizae Radix et Rhizoma and Angelicae Gigantis Radix were used in four studies. As for the mechanisms of action, the roles of serotonin and its receptors, cytokines, white blood cells, ghrelin, and leptin were investigated. Based on these results, we suggest that herbal medicines could be considered a useful treatment method for cisplatin-induced anorexia. Full article