Fertility-sparing hormonal treatment in patients with stage I endometrial cancer of grade 2 without myometrial invasion and grade 1-2 with superficial myometrial invasion: Gynecologic Oncology Research Investigators coLLaborAtion study (GORILLA-2001).

OBJECTIVES: To evaluate oncologic and pregnancy outcomes of fertility-sparing treatment (FST) using progestin in patients with stage I grade 2 endometrioid endometrial cancer (EC) without myometrial invasion (MI) or grade 1-2 with superficial MI. METHODS: Multicenter data of patients with stage I grade 2 EC without MI or grade 1-2 EC with superficial MI, who received FST between 2005 and 2021, were analyzed. Cox regression analysis identified independent factors for progressive disease (PD) during the FST. RESULTS: Altogether, 54 patients received FST [medroxyprogesterone acetate (500-1000 mg) in 44, megestrol acetate (40-800 mg) in 10] with concurrent levonorgestrel-releasing intrauterine devices use in 31. With median time to achieve a complete response (CR) of 10 (3-24) months, 39 patients (72.2%) achieved CR. Of the 15 patients who attempted to conceive after achieving CR, 7 (46.7%) became pregnant (2 abortions, 5 live births). During a median FST duration of 6 (3-12) months, nine patients (16.6%) were diagnosed with PD. Fifteen (38.5%) experienced recurrence with a median recurrence-free survival of 23 (3-101) months. In the multivariable analysis, tumor size before FST ≥2 cm (HR 5.456, 95% CI 1.34 to 22.14; p = 0.018) was significantly associated with a high PD rate during FST. CONCLUSION: The overall response rate to FST was promising, however, the PD rate was significant during the first 12 months of FST. Therefore, performing thorough endometrial biopsy and imaging studies is essential to strictly evaluate the extent of the disease every 3 months from FST initiation.

Plain language summary of the HERO study comparing relugolix with leuprolide for men with advanced prostate cancer.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a research study (known as a clinical trial) called HERO. The HERO study compared how well relugolix and leuprolide worked in lowering blood testosterone to sustained castration levels in men with advanced prostate cancer. Sustained castration is a blood testosterone level below 50 ng/dl from Day 29 through 48 weeks of treatment. WHAT WERE THE RESULTS?: Researchers looked at 930 adult men with advanced prostate cancer: 622 of these men took relugolix (by mouth once daily) and 308 received leuprolide (injected every 3 months). The HERO study showed that more men taking relugolix (97%) achieved sustained castration through 48 weeks than men receiving leuprolide (89%). This decrease in testosterone also happened more quickly in men taking relugolix. In 184 men who were followed up for 90 days after completing treatment, blood levels of testosterone returned to normal in more men who took relugolix than men who received leuprolide. Side effects were similar among men taking relugolix or receiving leuprolide, and most were identified as mild or moderate in terms of how bad they were. WHAT DO THE RESULTS OF THE STUDY MEAN?: In men with advanced prostate cancer and compared with those receiving leuprolide, more men taking relugolix had lower levels of blood testosterone. ClinicalTrials.gov NCT number: NCT03085095.

Extending Treatment Intervals of R-CHOP Therapy Might Be Acceptable for Some Patients with Non-indolent Non-Hodgkin's B-cell Lymphoma.

R-CHOP therapy is generally performed every 3 weeks. We investigated the effects of extending the interval of R-CHOP therapy for > 1 week on the prognoses of patients with non-indolent non-Hodgkin's B-cell lymphoma. Among the 338 patients with non-indolent non-Hodgkin's B-cell lymphoma who received initial chemotherapy at our institution, we focused on 178 patients who received R-CHOP therapy and analyzed the outcomes of the patients stratified by the treatment intervals. The estimated 3-year overall survival (OS) for the entire population was 82.1%. Patients treated at intervals of ≥ 4 weeks were significantly older, and they had significantly longer follow-up periods and lower relative dose intensity. But the estimated 3-year OS was comparable to those treated at <4 weeks (83.3% vs. 80.5% p=0.947). In a multivariate analysis, age and the dose of anti-cancer agents had significant impacts on OS, but there was no significant relationship regarding the treatment intervals. Propensity score matching confirmed the same result. R-CHOP therapy every around 4 weeks could achieve relatively good survival in some selected patients with non-indolent non-Hodgkin's B-cell lymphoma.

Envafolimab: First Approval.

Envafolimab (®) is a subcutaneously (SC) administered single domain anti-programmed death ligand 1 (PD-L1) antibody being developed for the treatment of various solid tumours and chronic hepatitis B in China, and for soft tissue sarcomas and biliary tract cancer in the USA. Single-domain antibodies are more soluble and more rapidly penetrate tissues than full monoclonal antibodies, enabling SC administration. Based on the results of a pivotal phase II trial, SC envafolimab was recently approved in China for the treatment of adult patients with previously-treated microsatellite instability-high (MSI-H) or deficient MisMatch Repair (dMMR) advanced solid tumours. This article summarizes the milestones in the development of envafolimab leading to this first approval.

Therapeutic Drug Monitoring of Endoxifen for Tamoxifen Precision Dosing: Feasible in Patients with Hormone-Sensitive Breast Cancer.

BACKGROUND: Endoxifen is the most important active metabolite of tamoxifen. Several retrospective studies have suggested a minimal or threshold endoxifen systemic concentration of 14-16 nM is required for a lower recurrence rate. The aim of this study was to investigate the feasibility of reaching a predefined endoxifen level of ≥ 16 nM (5.97 ng/mL) over time using therapeutic drug monitoring (TDM). METHODS: This prospective open-label intervention study enrolled patients who started treatment with a standard dose of tamoxifen 20 mg once daily for early breast cancer. An outpatient visit was combined with a TDM sample at 3, 4.5, and 6 months after initiation of the tamoxifen treatment. The tamoxifen dose was escalated to a maximum of 40 mg if patients had an endoxifen concentration < 16 nM. The primary endpoint of the study was the percentage of patients with an endoxifen level ≥ 16 nM at 6 months after the start of therapy compared with historical data, in other words, 80% of patients with endoxifen levels ≥ 16 nM with standard therapy. RESULTS: In total, 145 patients were included. After 6 months, 89% of the patients had endoxifen levels ≥ 16 nM, compared with a literature-based 80% of patients with endoxifen levels ≥ 16 nM at baseline (95% confidence interval 82-94; P = 0.007). In patients with an affected CYP2D6 allele, it was not always feasible to reach the predefined endoxifen level of ≥ 16 nM. No increase in tamoxifen-related adverse events was reported after dose escalation. CONCLUSION: This study demonstrated that it is feasible to increase the percentage of patients with endoxifen levels ≥ 16 nM using TDM. TDM is a safe strategy that offers the possibility of nearly halving the number of patients with endoxifen levels < 16 nM.

External Validity of Somatostatin Analogs Trials in Advanced Neuroendocrine Neoplasms: The GETNE-TRASGU Study.

INTRODUCTION: Somatostatin analogs (SSA) prolong progression-free survival (PFS) in patients with well-differentiated gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). However, the eligibility criteria in randomized clinical trials (RCTs) have been restricted, which contrasts with the vast heterogeneity found in NENs. METHODS: We identified patients with well-differentiated (Ki-67% ≤20%), metastatic GEP-NENs treated in first line with SSA monotherapy from the Spanish R-GETNE registry. The therapeutic effect was evaluated using a Bayesian Cox model. The objective was to compare survival-based outcomes from real-world clinical practice versus RCTs. RESULTS: The dataset contained 535 patients with a median age of 62 years (range: 26-89). The median Ki-67% was 4 (range: 0-20). The most common primary tumor sites were as follows: midgut, 46%; pancreas, 34%; unknown primary, 10%; and colorectal, 10%. Half of the patients received octreotide LAR (n = 266) and half, lanreotide autogel (n = 269). The median PFS was 28.0 months (95% CI: 22.1-32.0) for octreotide versus 30.1 months (95% CI: 23.1-38.0) for lanreotide. The overall hazard ratio for lanreotide versus octreotide was 0.90 (95% credible interval: 0.71-1.12). The probability of effect sizes >30% with lanreotide versus octreotide was 2 and 6% for midgut and foregut NENs, respectively. CONCLUSION: Our study evaluated the external validity of RCTs examining SSAs in the real world, as well as the main effect-modifying factors (progression status, symptoms, tumor site, specific metastases, and analytical data). Our results indicate that both octreotide LAR and lanreotide autogel had a similar effect on PFS. Consequently, both represent valid alternatives in patients with well-differentiated, metastatic GEP-NENs.

A prospective study of carcinoid crisis with no perioperative octreotide.

BACKGROUND: Carcinoid crises, defined as the sudden onset of hemodynamic instability in patients with neuroendocrine tumors undergoing operation, are associated with significantly increased risk of postoperative complications. Octreotide has been used prophylactically to reduce crisis rates as well as therapeutically to treat crises that still occur. However, studies using octreotide still report crisis rates of 3.4% to 35%, leading to the questioning of its efficacy. METHODS: Patients with neuroendocrine tumors undergoing operation between 2017 to 2020 with no perioperative octreotide were prospectively studied. Clinicopathologic data were compared by χ2 test for discrete variables and by Mann-Whitney U test for continuous variables. RESULTS: One hundred and seventy-one patients underwent 195 operations. Crisis was documented in 49 operations (25%), with a mean duration of 3 minutes. Crisis was more likely to occur in patients with small bowel primary tumors (P = .012), older age (P = .015), and carcinoid syndrome (P < .001). Those with crises were more likely to have major postoperative complications (P = .003). CONCLUSION: Completely eliminating perioperative octreotide resulted in neither increased rate nor duration compared with previous studies using octreotide. We conclude perioperative octreotide use may be safely stopped, owing to inefficacy, though the need for an effective medication is clear given continued higher rates of complications.

Differences in sex hormone recovery profile after cessation of 12-week gonadotropin-releasing hormone antagonist versus agonist therapy.

BACKGROUND: Pharmacobiological behavior differs between gonadotropin-releasing hormone (GnRH) antagonists and GnRH agonists. However, reliable evidence clarifying the difference between them is limited. OBJECTIVES: We aimed to elucidate the difference in recovery profile between GnRH antagonist (degarelix) and GnRH agonist (leuprorelin acetate or goserelin acetate) as short-term (12 weeks) neoadjuvant androgen deprivation therapy (ADT) prior to 125I-transperineal prostate brachytherapy (TPPB) for localized prostate cancer. MATERIALS AND METHODS: This study was initially designed as a single-center, prospective, open-label, randomized controlled trial. The primary endpoint was a serum testosterone level above the castration range (>50 ng/dl) after the cessation of 12-week neoadjuvant ADT (GnRH antagonist or GnRH agonists). All patients underwent 12 weeks of neoadjuvant ADT. The recovery profiles of hormones, prostate-specific antigen, total prostate volume (TPV), bone mineral density, and quality of life scores were investigated. RESULTS: Testosterone recovery duration after the last injection was significantly longer in the GnRH antagonist arm than in the GnRH agonist arm (median, 27.3 vs. 4.8 weeks, p < 0.001). The serum levels of luteinizing hormone and follicle-stimulating hormone in the GnRH antagonist arm also remained significantly lower than those in the GnRH agonist arm between 16 and 24 weeks (p < 0.01). Meanwhile, reduction in TPV at the time of TPPB was comparable between both arms (p = 0.128). There were also no significant between-arm differences in the International Prostate Symptom Score and the International Index of Erectile Function scores. DISCUSSION AND CONCLUSION: The recovery patterns of hormonal profiles after short-term (12 weeks) neoadjuvant ADT differ between GnRH antagonists and GnRH agonists. The choice between these drugs matters and may have a clinical impact depending on the primary objective of ADT.

The Future of Somatostatin Receptor Ligands in Acromegaly.

Currently, the first-generation somatostatin receptor ligands (fg-SRLs), octreotide LAR and lanreotide autogel, are the mainstays of acromegaly treatment and achieve biochemical control in approximately 40% of patients and tumor shrinkage in over 60% of patients. Pasireotide, a second-generation SRL, shows higher efficacy with respect to both biochemical control and tumor shrinkage but has a worse safety profile. In this review, we discuss the future perspectives of currently available SRLs, focusing on the use of biomarkers of response and precision medicine, new formulations of these SRLs and new drugs, which are under development. Precision medicine, which is based on biomarkers of response to treatment, will help guide the decision-making process by allowing physicians to choose the appropriate drug for each patient and improving response rates. New formulations of available SRLs, such as oral, subcutaneous depot, and nasal octreotide, may improve patients' adherence to treatment and quality of life since there will be more options available that better suit each patient. Finally, new drugs, such as paltusotine, somatropin, ONO-5788, and ONO-ST-468, may improve treatment adherence and present higher efficacy than currently available drugs.

Cutaneous metastasis of occult breast cancer: a case report.

Occult breast cancer (OBC) is characterized by metastatic presentation of undetectable breast tumor on imaging exams. OBC is a rare disease (accounting for 0.3% to 1.0% of all breast cancers) that represents a major diagnostic challenge. The aim of this study was to report a case of OBC with primary presentation of multiple cutaneous metastases with subsequent emergence of bone metastasis. A 70-year female patient had multiple cutaneous metastatic lesions in the left cervical region, left breast, left axillary region, left subscapular region, in three chirodactylus of the right hand and three chirodactylus of the left hand. Imaging tests (mammogram, ultrasonography and magnetic resonance imaging of the breast) did not show alterations. Biopsy, histology sections and immunohistochemistry of the left cervical cutaneous lesion were compatible with OBC. After two years of anastrozole treatment (1mg/day), there was regression of all cutaneous lesions and stabilization of bone metastasis. OBC has a better prognosis. It may exhibit spontaneous regression or respond to less aggressive treatment strategies, as described in this case.

Prolactin and endocrine therapy resistance in breast cancer: The next potential hope for breast cancer treatment.

Breast cancer, a hormone-dependent tumour, generally includes four molecular subtypes (luminal A, luminal B, HER2 enriched and triple-negative) based on oestrogen receptor, progesterone receptor and human epidermal growth factor receptor-2. Multiple hormones in the body regulate the development of breast cancer. Endocrine therapy is one of the primary treatments for hormone-receptor-positive breast cancer, but endocrine resistance is the primary clinical cause of treatment failure. Prolactin (PRL) is a protein hormone secreted by the pituitary gland, mainly promoting mammary gland growth, stimulating and maintaining lactation. Previous studies suggest that high PRL levels can increase the risk of invasive breast cancer in women. The expression levels of PRL and PRLR in breast cancer cells and breast cancer tissues are elevated in most ER+ and ER- tumours. PRL activates downstream signalling pathways and affects endocrine therapy resistance by combining with prolactin receptor (PRLR). In this review, we illustrated and summarized the correlations between endocrine therapy resistance in breast cancer and PRL, as well as the pathophysiological mechanisms and clinical practices. The study on PRL and its receptor would help explore reversing endocrine therapy-resistance for breast cancer.

A combination approach of pseudotime analysis and mathematical modeling for understanding drug-resistant mechanisms.

Cancer cells acquire drug resistance through the following stages: nonresistant, pre-resistant, and resistant. Although the molecular mechanism of drug resistance is well investigated, the process of drug resistance acquisition remains largely unknown. Here we elucidate the molecular mechanisms underlying the process of drug resistance acquisition by sequential analysis of gene expression patterns in tamoxifen-treated breast cancer cells. Single-cell RNA-sequencing indicates that tamoxifen-resistant cells can be subgrouped into two, one showing altered gene expression related to metabolic regulation and another showing high expression levels of adhesion-related molecules and histone-modifying enzymes. Pseudotime analysis showed a cell transition trajectory to the two resistant subgroups that stem from a shared pre-resistant state. An ordinary differential equation model based on the trajectory fitted well with the experimental results of cell growth. Based on the established model, it was predicted and experimentally validated that inhibition of transition to both resistant subtypes would prevent the appearance of tamoxifen resistance.

Genomic Profiling of Premenopausal HR+ and HER2- Metastatic Breast Cancer by Circulating Tumor DNA and Association of Genetic Alterations With Therapeutic Response to Endocrine Therapy and Ribociclib.

PURPOSE: This analysis evaluated the genomic landscape of premenopausal patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer and the association of genetic alterations with response to ribociclib in the phase III MONALEESA-7 trial. METHODS: Premenopausal patients were randomly assigned 1:1 to receive endocrine therapy plus ribociclib or placebo. Plasma collected at baseline was sequenced using targeted next-generation sequencing for approximately 600 relevant cancer genes. The association of circulating tumor DNA alterations with progression-free survival (PFS) was evaluated to identify biomarkers of response and resistance to ribociclib. RESULTS: Baseline circulating tumor DNA was sequenced in 565 patients; 489 had evidence of ≥ 1 alteration. The most frequent alterations included PIK3CA (28%), TP53 (19%), CCND1 (10%), MYC (8%), GATA3 (8%), receptor tyrosine kinases (17%), and the Chr8p11.23 locus (12%). A treatment benefit of ribociclib was seen with wild-type (hazard ratio [HR] 0.45 [95% CI, 0.33 to 0.62]) and altered (HR 0.57 [95% CI, 0.36 to 0.9]) PIK3CA. Overall, patients with altered CCND1 had shorter PFS regardless of treatment, suggesting CCND1 as a potential prognostic biomarker. Benefit with ribociclib was seen in patients with altered (HR 0.21 [95% CI, 0.08 to 0.54]) or wild-type (HR 0.52 [95% CI, 0.39 to 0.68]) CCND1, but greater benefit was observed with altered, suggesting predictive potential of CCND1. Alterations in TP53, MYC, Chr8p11.23 locus, and receptor tyrosine kinases were associated with worse PFS, but ribociclib benefit was independent of alteration status. CONCLUSION: In this study-to our knowledge, the first large study of premenopausal patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative advanced breast cancer-multiple genomic alterations were associated with poor outcome. A PFS benefit of ribociclib was observed regardless of gene alteration status, although in this exploratory analysis, a magnitude of benefits varied by alteration.

De-escalation of Endocrine Therapy in Early Hormone Receptor-positive Breast Cancer: When Is Local Treatment Enough?

OBJECTIVE: To identify subgroups of hormone receptor-positive (HR+) breast cancer patients that might not benefit from adding endocrine therapy (ET) to their local treatment. BACKGROUND: De-escalation in breast cancer treatment has included surgery, radiation, and chemotherapy and has often focused on older patient populations. Systemic ET has yet to be de-escalated, though it carries serious side-effects, decreasing quality of life over 5 to 10 years. We hypothesize the 21-gene recurrence score (RS) could identify subgroups of younger patients whose long-term survival is unaffected by adjuvant ET. METHODS: The National Cancer Database was used to identify women aged ≥50, with HR+, HER2-negative tumors, ≤3 cm in size, N0 status, and a RS≤25, who underwent breast-conserving surgery in 2010 to 2016. Kaplan-Meier and Cox proportional hazards models were used to identify association between treatment and overall survival (OS). RESULTS: Of the 45,217 patients identified, 80.6% were 50 to 69 years old. 42,632 (94.3%) patients received ET and 2585 (5.7%) did not. The 5-year OS was 96.4% for patients receiving ET and 93.1% for those who did not (P < 0.001). After adjusting for all covariates, patients aged 50 to 69 with RS < 11 showed no statistically significant improvement in OS when adding ET to surgery, with or without radiation (P = 0.40). With RS 11 to 25, there was a significant improvement of OS with ET plus radiation (P < 0.001). CONCLUSIONS: Local treatment only, with de-escalation of long-term ET, for patients aged 50 to 69 with RS < 11, seems not to impact OS and should have an anticipated quality of life improvement. Prospective studies investigating this approach are warranted.

Evaluating Serum Thymidine Kinase 1 in Patients with Hormone Receptor-Positive Metastatic Breast Cancer Receiving First-line Endocrine Therapy in the SWOG S0226 Trial.

PURPOSE: Serum thymidine kinase 1 (sTK1) activity is associated with poor prognosis in metastatic breast cancer (MBC). We assessed the prognostic effect of sTK1 in patients with hormone receptor-positive MBC treated on a prospective randomized trial of anastrozole (A) versus A plus fulvestrant (A + F). PATIENTS AND METHODS: sTK1 was assessed in 1,726 serums [baseline (BL), cycles 2, 3, 4, and 7] using the DiviTum assay. A prespecified cutoff of ≥200 Du/L was considered high. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier, log-rank tests, and Cox regression. RESULTS: BL sTK1 was elevated in 171 (40%) of 432 patients. Patients with high versus low BL sTK1 had significantly worse PFS [median 11.2 vs. 17.3 months, HR = 1.76; 95% confidence interval (CI; 1.43-2.16); P < 0.0001] and OS [median 30 vs. 58 months, HR = 2.38; 95% CI (1.91-2.98); P < 0.0001]. OS was significantly better for patients with high sTK1 who did not have prior adjuvant tamoxifen and who received A + F versus A alone [median 46 vs. 21 months, HR = 0.58; 95% CI (0.38-0.87); P = 0.0087]. Patients with low sTK1 had no difference in outcomes by therapy (P = 0.44). At serial timepoints, high versus low sTK1 had significantly worse subsequent PFS and OS [at cycle 2: PFS HR = 1.70, 95% CI (1.34-2.17); P < 0.0001, OS HR = 2.51, 95% CI (1.93-3.26); P < 0.0001]. CONCLUSIONS: High sTK1 at BL and subsequent timepoints is associated with worse prognosis in patients with MBC starting first-line endocrine therapy (ET). Patients with low sTK1 at BL have comparable outcomes on single-agent or combination ET.

Impact of COVID-19 Pandemic on Surgical Breast Cancer Patients Undergoing Neoadjuvant Therapy: A Multicentric Study.

BACKGROUND/AIM: Due to the SARS-CoV-2 pandemic, many scientific committees proposed neoadjuvant therapy (NACT) bridging treatment as a novel strategy and indication. The aim of the study was to evaluate the impact of COVID-19 pandemic on breast cancer patients undergoing NACT. PATIENTS AND METHODS: All breast cancer patients referred to two Breast Units during COVID-19-pandemic were enrolled. RESULTS: Out of 814 patients, 43(5.3%) were enrolled in the COVID-19-group and compared with 94 (7.9%) similar Pre-COVID-19 patients. We observed a reduction in the number of patients undergoing NACT, p=0.0019. No difference was reported in terms of clinical presentation, indications, and tumor response. In contrast, a higher number of vascular adverse events was reported (6.9% vs. 0% p=0.029). Immediate breast cancer reconstructions following invasive surgery suffered a significant slowdown (5.9% vs. 47.7%, p=0.019). CONCLUSION: COVID-19 caused a reduction in the number of patients undergoing NACT, with no changes in terms of indications, clinical presentation, and tumor response. Furthermore, there was an increased incidence of vascular events.

Accelerating drug access from advanced to early breast cancer: the special case of oral selective estrogen receptor degraders.

PURPOSE OF REVIEW: For hormone receptor positive breast cancer, the development of endocrine resistance commonly occurs, presenting as either disease progression in the metastatic setting or recurrence during or following adjuvant endocrine therapy. Various mechanisms of resistance have been described. In order to reduce or overcome endocrine resistance, there has been substantial interest in developing potent and orally bioavailable selective estrogen receptor degraders (SERDs) for metastatic disease and select patients with early-stage estrogen receptor positive breast cancer. RECENT FINDINGS: At least 11 oral SERDs have entered clinical development. We review current studies in both the metastatic and neoadjuvant/adjuvant setting and present the available evidence of benefit and toxicity for these novel agents. Further characterization of changes to tissue-based biomarkers such as estrogen receptor, progesterone receptor and Ki67 expression and blood-based biomarkers such as ctDNA and estrogen receptor 1 mutation may help to refine therapeutic strategies, combinations, and patient selection to identify women who are most likely to benefit from these novel endocrine agents. SUMMARY: Although SERDs have clear therapeutic potential based on nonclinical studies and have demonstrated early signs of activity in phase I and II studies in the metastatic setting, ongoing research is needed to clarify when and in whom these agents may have greatest clinical benefit.

Drug delivery strategies in maximizing anti-angiogenesis and anti-tumor immunity.

Metronomic chemotherapy has been shown to elicit anti-tumor immune response and block tumor angiogenesis distinct from that observed with maximal tolerated dose (MTD) therapy. This review delves into the mechanisms behind anti-tumor immunity and seeks to identify the differential effect of dosing regimens, including daily low-dose and medium-dose intermittent chemotherapy (MEDIC), on both innate and adaptive immune populations involved in observed anti-tumor immune response. Given reports of VEGF/VEGFR blockade antagonizing anti-tumor immunity, drug choice, dose, and selective delivery determined by advanced formulations/vehicles are highlighted as potential sources of innovation for identifying anti-angiogenic modalities that may be combined with metronomic regimens without interrupting key immune players in the anti-tumor response. Engineered drug delivery mechanisms that exhibit extended and local release of anti-angiogenic agents both alone and in combination with chemotherapeutic treatments have also been demonstrated to elicit a potent and potentially systemic anti-tumor immune response, favoring tumor regression and stasis over progression. This review examines this interplay between various cancer models, the host immune response, and select anti-cancer agents depending on drug dosing, scheduling/regimen, and delivery modality.

Non-toxic polymer nanovectors for improved delivery of dexamethasone.

Dexamethasone (Dex) is a highly insoluble front-line drug used in cancer therapy. Data from clinical trials indicates that the pharmacokinetics of Dex vary considerably between patients and prolonging drug exposure rather than increasing absolute dose may improve efficacy. Non-toxic, fully biodegradable Dex loaded nanovectors (NV) were formulated, via simple direct hydration within 10 min, as a vehicle to extend exposure and distribution in vivo. Dex-NV were just as effective as the free drug against primary human leukemia cells in vitro and in vivo. Importantly, high levels of DMSO solvent were not required in the NV formulations. Broad distribution of NV was seen rapidly following inoculation into mice. NV accumulated in major organs, including bone marrow and brain, known sanctuary sites for ALL. The study describes a non-toxic, more easily scalable system for improving Dex solubility for use in cancer and can be applied to other medical conditions associated with inflammation.

Pharmacokinetic and pharmacodynamic evaluation of the new prolonged-release leuprorelin acetate microspheres for injection compared with Enantone® in healthy Chinese male volunteers.

PURPOSE: To compare the pharmacokinetics, pharmacodynamics and safety of the new prolonged-release leuprorelin acetate microspheres for injection (3.75 mg) with the reference product Enantone® (3.75 mg). METHOD: 48 healthy male volunteers were enrolled and randomly received a single 3.75 mg dose of the test drug or Enantone®. RESULTS: There were no significant differences in Cmax, AUC0-t and AUC0-48 between the test group and reference group (P > 0.05). The 90% confidence intervals of the two groups were 87.49%~112.74%, 97.15%~154.25%, and 80.85%~109.01%, respectively. Twenty-eight days after administration, both groups reached 100.0% castration level; there was no difference in the time from administration to reaching castration level between the two groups (P > 0.05); However, the difference between the two groups in the duration of castration level was statistically significant (P < 0.05). There were no major or serious adverse events, and the severity was mild to moderate. CONCLUSION: The pharmacokinetic characteristics of leuprorelin in two groups were consistent. The two groups exhibited similar inhibitory effects on testosterone and more subjects in the test group maintained a longer castration time than those in the reference group.