Docetaxel Chemotherapy Research Articles

Baseline Modified Glasgow Prognostic Score (mGPS) Predicts Radiologic Response and Overall Survival in Metastatic Hormone-sensitive Prostate Cancer Treated With Docetaxel Chemotherapy.

To assess the baseline inflammatory markers modified Glasgow Prognostic Score (mGPS), systemic immune-inflammation index (SII), and neutrophile-to-lymphocyte ratio (NLR) as pragmatic tools for predicting response to chemohormonal therapy (docetaxel plus ADT) and prognosis in men with metastatic hormone-sensitive prostate cancer (mHSPC). Male patients who received docetaxel at a tertiary university care center between 2014 and 2019 were screened for completion of 6 cycles. NLR, SII, mGPS, overall survival (OS), three-year survival, and radiologic response were assessed. Complete response (CR), partial response (PR), and stable disease (SD) were analyzed alone and in combination. Thirty-six mHSPC-patients were included. In thirty patients, baseline mGPS was assessed and was either 0 (n=22) or 2 (n=8). In Cochran-Armitage Trend Test, mGPS showed significant association with the combined radiologic endpoint of "CR, PR, or SD" (p=0.01), three-year survival (p=0.02), and OS (p<0.01). Next to prostate-specific antigen (PSA) (HR per 100 units 1.16, 95%CI=1.04-1.30, p<0.01), NLR (HR=1.31, 95%CI=1.03-1.66, p=0.03), and mGPS (2 vs. 0, HR=6.53, 95%CI=1.6-27.0, p<0.01) at baseline showed significant association with OS in univariable cox regression. However, mGPS remained the only independent predictor for OS in multivariable cox regression (p<0.01) and for the combined radiologic endpoint of "CR, PR or SD" (p=0.01) in multivariable logistic regression. SII showed no statistical relevance. Baseline mGPS seems to be a pragmatic tool for clinical decision-making in patients with mHSPC in daily routine.

Intraperitoneal perforation through lymph node metastases in a patient with esophageal squamous cell carcinoma during intensive chemotherapy: A case report with literature review.

IntroductionEsophageal fistula after treatment is a critical and fatal complication of esophageal cancer. A fistula forming from lower thoracic esophageal cancer to the peritoneum through lymph node metastases following chemotherapy has not been reported. We report a case of peritonitis due to lymph node perforation through the tumor ulcer after induction of biweekly docetaxel, cisplatin, and 5FU combined chemotherapy (Bi-DCF) for advanced esophageal squamous cell carcinoma (ESCC).Presentation of caseA 48-year-old woman was referred to us with a diagnosis of lower thoracic ESCC and thoracoabdominal aortic aneurysm. Esophagogastroduodenoscopy showed a circumferential type 3 tumor with stenosis in the lower thoracic esophagus. Contrast-enhanced computed tomography (CT) showed a thoracoabdominal aortic aneurysm and wall thickening of the lower thoracic esophagus that was suspicious of esophageal cancer. Lymph node metastases dumpling from around the tumor to abdominal cavity were also observed. The initial diagnosis was ESCC T3 N3 M1 (para-aortic lymph nodes and liver) Stage IVB. She was started on Bi-DCF (docetaxel 35 mg/m2 days 1/15, cisplatin 40 mg/m2 days 1/15, 5FU 400 mg/m2 days 1–5, 15–19) as the first-line regimen. The third day after starting chemotherapy, she felt strong abdominal pain, and internal necrosis of lymph nodes around the primary lesion and free air in the abdominal cavity were found. Peritonitis was diagnosed due to a fistula formed from the lower thoracic ESCC to the peritoneum through lymph node metastases. She underwent emergency laparoscopic drainage, omental filling, and jejunostomy. Postoperatively, her general condition and inflammatory findings improved within 10 days, and she could continue intensive chemotherapy as scheduled.DiscussionBecause of the risk of perforation and fistula in regimens that are expected to cause tumor shrinkage, careful observation may be required after starting chemotherapy.ConclusionWe report the first case of peritonitis caused by perforation through lymph node metastasis of thoracic esophageal cancer.

Dynamic changes in gene alterations during chemotherapy in metastatic castrate resistant prostate cancer

Docetaxel chemotherapy is a standard treatment option for metastatic castrate resistant prostate cancer (mCRPC) patients. To date, the genomic perturbations underlying the emergence of resistance in mCRPC patients during chemotherapy treatment have not been fully characterized. Previous studies have established that AR, TP53, RB1 and PTEN gene alterations are frequent at this stage of progression and that TP53, RB1 and PTEN, but not AR alterations are associated with poor outcome. However, the clonal dynamics of these key driver cancer genes during chemotherapy in mCRPC patients have not been described. Toward this goal, we performed a retrospective analysis of serially profiled cell-free DNA (cfDNA) alterations in blood samples collected from mCRPC patients before and after starting chemotherapy who were followed for response and clinical outcomes. While AR alterations and measures of mutational load were significantly reduced in patients with stable or decreased PSA levels after 3 cycles of chemotherapy, reductions in RB1, TP53 and PTEN alterations were relatively modest, which may represent the persistence of a clonal signature associated with the emergence of treatment-induced lineage plasticity (TILP) underlying resistance. The ability to monitor these driver gene clonal dynamics during chemotherapy may have utility in the clinical setting.

Clinical Efficacy Analysis of Docetaxel Chemotherapy Combined with Radiotherapy for Esophageal Cancer

Clinical Efficacy Analysis of Docetaxel Chemotherapy Combined with Radiotherapy for Esophageal Cancer

Circulating Tumor Cell Detection during Neoadjuvant Chemotherapy to Predict Early Response in Locally Advanced Oropharyngeal Cancers: A Prospective Pilot Study.

Patients with locally advanced oropharyngeal carcinoma treated with neoadjuvant chemotherapy are reassessed both radiologically and clinically to adapt their treatment after the first cycle. However, some responders show early tumor progression after adjuvant radiotherapy. This cohort study evaluated circulating tumor cells (CTCs) from a population of locally advanced oropharyngeal carcinoma patients treated with docetaxel, cisplatin, and 5-fluorouracil (DCF) induction chemotherapy or DCF with a modified dose and fractioned administration. The counts and phenotypes of CTCs were assessed at baseline and at day 21 of treatment, after isolation using the RosetteSepTM technique based on negative enrichment. At baseline, 6 out of 21 patients had CTCs (28.6%). On day 21, 5 out of 11 patients had CTCs (41.6%). There was no significant difference in the overall and progression-free survival between patients with or without CTCs at baseline (p = 0.44 and 0.78) or day 21 (p = 0.88 and 0.5). Out of the 11 patients tested at day 21, 4 had a positive variation of CTCs (33%). Patients with a positive variation of CTCs display a lower overall survival. Our findings suggest that the variation in the number of CTCs would be a better guide to the management of treatment, with possible early changes in treatment strategy.

A Prospective Study to Evaluate the Efficacy of the Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel Chemotherapy Regimen in Patients with Locally Advanced and Metastatic Adenocarcinoma of Stomach

Abstract Introduction In India, patients with gastric cancer present at an advanced stage, and there is no standard chemotherapy regimen. Al-Batran's fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy gave us a glimmer of hope. Objectives Hence, we intended to evaluate the efficacy of FLOT chemotherapy in locally advanced and metastatic adenocarcinoma of stomach. Materials and Methods In this single-center, prospective cohort, patients with locally advanced and metastatic gastric adenocarcinoma who required chemotherapy between March 2016 and November 2017 were included in the study. All patients received standard FLOT chemotherapy. The primary objective was to evaluate the safety and efficacy of FLOT chemotherapy in the Indian population. Overall survival (OS) and progression-free survival (PFS) were calculated through the plotted Kaplan–Meier curves. Results In our study, 28 patients received FLOT chemotherapy. Their mean age was 55 years (range, 28–70 years) with a male preponderance (89.3%). Twenty-five patients had metastatic disease (89.3%), and three had locally advanced disease (10.7%). The median number of cycles was 4.5 (range, 1–8), and 75% received at least four cycles (n = 21). The hematological toxicities exhibited were neutropenia (50%) and febrile neutropenia (35.7%). Sixteen (57.1%) patients needed dose modifications due to treatment-related adverse effects (AEs). AEs led to treatment discontinuation in seven (25%) patients after the first cycle. The overall response rate in the intent-to-treat population was 52.7%, with the best-obtained response being a partial response, median PFS of 5 months, and median OS of 13 months. Conclusion FLOT chemotherapy regimens induced excellent responses but with significantly increased toxicity, needing dose modifications, and hence, should be considered only in a young and fit patient.

PEARLS: A multicenter phase II/III trial of extended field radiotherapy for androgen-sensitive prostate cancer patients with PSMA‐avid pelvic and para-aortic lymph nodes at presentation.

TPS199 Background: Optimal management for lymph node (LN) positive prostate cancer has not yet been determined. With the emerging role of PSMA-PET/CT in diagnostic staging, identification of this disease status is increasing. The superior border for prostate nodal radiotherapy is variable across different centres. PEARLS (CRUK/19/016) aims to show that extending the radiotherapy field to cover the para-aortic LN (up to L1/L2 vertebral interspace) can improve outcomes for prostate cancer patients with PSMA-avid pelvic LN at presentation. The trial is registered: ISRCTN36344989. Methods: PEARLS is a multi‐stage randomised controlled trial. Men with histologically confirmed prostate cancer with PSMA‐avid nodal disease within the pelvis +/‐ para‐aortic region receiving androgen deprivation therapy +/‐ androgen receptor targeted therapy or docetaxel chemotherapy are eligible. Two cohorts defined by extent of LN disease determined by PSMA‐PET/CT will be recruited: cohort A (pelvic LN at or below the L4/L5 vertebral interspace) and cohort B (para-aortic LN below L1/L2 vertebral interspace). Patients are randomly allocated (1:1) to standard field (dependent on cohort) intensity modulated radiotherapy (IMRT) (control) or extended-field IMRT (experimental) in 20 fractions over 4 weeks. In the control group, cohort A will receive 60Gy to the prostate and 44Gy to the pelvis with an integrated boost of 51Gy to PSMA-avid LN and cohort B will receive 60Gy to the prostate only. In the experimental group, participants in both cohorts will receive 60Gy to the prostate and 44Gy to the pelvis and para‐aortic region with an integrated boost of 51Gy to involved LN. In phase II, the primary endpoint is lower gastrointestinal RTOG grade 2+ toxicity at week 18 from start of radiotherapy. Assuming acceptable toxicity in the first 75 participants receiving extended-field IMRT, the study will move to phase III where the primary endpoint is metastasis‐free survival. The trial aims to recruit 714 patients with pelvic LN to detect a hazard ratio of 0.62 in favour of extended-field IMRT and a further 179 patients with para‐aortic LN disease. The trial was launched in the UK on 25 June 2021. Phase II will be conducted in 20 NHS Trusts across the UK. Clinical trial information: ISRCTN36344989.

A phase 1b clinical trial of cabozantinib (CABO) and abiraterone (ABI) with checkpoint inhibitor immunotherapy (CPI) in metastatic hormone-sensitive prostate cancer (mHSPC) (CABIOS Trial).

TPS214 Background: Multiple systemic therapies have resulted in improved overall survival (OS) for mHSPC, including several AR-targeted agents (ARTA) and docetaxel chemotherapy. However, patients (pts) with high volume de novo metastatic prostate cancer still only have an OS of approximately 50 months. Thus, more effective combination strategies for initial treatment of mHSPC are urgently needed. CABO, a multi-tyrosine kinase inhibitor (including MET, VEGFR-1, -2,-3, AXL) has shown synergy with ABI as well as with CPI in preclinical studies. CABO and ABI have demonstrated an acceptable safety profile in metastatic castration resistant prostate cancer (mCRPC) (Choudhury et al Prostate 2018), and CABO and atezolizumab (ATEZO) in combination have showed a promising efficacy signal and manageable safety profile in mCRPC (COSMIC-021, NCT03170960; Agarwal ESMO 2021). The phase 3 CONTACT-02 trial (NCT04446117) is randomizing mCRPC pts to either CABO and ATEZO or a second generation ARTA. Given the robust preclinical and emerging clinical data for the use of both CABO and CPI therapy in advanced prostate cancer and the need to optimize therapy earlier in the course of disease, in the present trial we intend to evaluate the safety and tolerability of ABI, CABO, and CPI in mHSPC. Methods: CABIOS (NCT04477512) is a phase Ib, single center, open label trial of ABI, CABO and the CPI nivolumab (NIVO), an anti-PD-1 monoclonal antibody, in pts with mHSPC. Key inclusion criteria include histologically or cytologically confirmed metastatic prostate adenocarcinoma without neuroendocrine/small cell differentiation and radiographic evidence of metastatic disease. Ongoing androgen deprivation (ADT) within 12 weeks of study start is allowed. Key exclusion criteria include evidence of castration resistance, prior treatment with second-generation androgen receptor inhibitors, CYP17 inhibitors, CABO, or checkpoint inhibitor immunotherapy (anti-PD-1/PD-L1, CTLA-4), active autoimmune disease, and ongoing treatment with systemic corticosteroids daily. The primary objective of the trial is evaluation of the safety and tolerability of this combination therapy in the trial population; the primary endpoint is the frequency of dose-limiting toxicities (DLTs) as measured by CTCAE v5.0. The study will employ a 3 + 3 design evaluating ABI 1,000 mg once daily with prednisone 5 mg daily, NIVO 480 mg IV every 4 weeks, and a CABO starting dose of 20 mg once daily at dose level 1 (DL1). If 0 of 3 pts at DL1 experience a DLT, 3 pts will be enrolled at DL2 with CABO 40 mg once daily. If 1 of 3 pts at DL1 experience a DLT, 3 additional pts will be enrolled at DL1. If 0 of 3 pts experience a DLT at DL2, the study will move to a recommended phase 2 dose (RP2D) expansion cohort. Total sample size of approximately 20 pts is expected depending on DLT frequencies. Enrollment is ongoing. Clinical trial information: NCT04477512.

AbiDex: Retrospective U.K. analysis of steroid switching in patients with progression of mCRPC treated with abiraterone acetate.

114 Background: Abiraterone acetate (AA) is a mainstay of treatment for metastatic castrate resistant prostate cancer (mCRPC). Due to inhibition of glucocorticoid synthesis, AA can cause mineralocorticoid excess which is suppressed by the co-administration of a glucocorticoid. Prednisolone (P) is widely used to counter the side effects of AA. There is an expanding body of retrospective evidence that dexamethasone (D) may be a more suitable partner for AA and on biochemical progression with AA+P, a ‘steroid switch’ to AA+D may be efficacious in regaining PSA control. Methods: Retrospective analysis patients treated with AA at a UK, tertiary cancer centre, were included to a data cutoff of 28th April 2021. Those who had undergone a steroid switch were identified and baseline data of demographics and clinical history were collected, as well as biochemical and radiological data whilst on AA. Analysis was conducted using SPSS. Biochemical progression free survival (bPFS) analysis was conducted using the Kaplan-Meier U test. Response steroid switch and survival when compared to potential predictive factors was analysed using binomial logistic and Cox regression models. Results: Thirty-three patients were treated with AA and received a steroid switch, AA+P(5mg BD) to AA+D(0.5mg OD) between 2012 and data cutoff. The median age at diagnosis was 71, the majority had Gleason 7 disease (7-10). Nine patients had received prior Docetaxel chemotherapy. Four patients failed to respond to AA+P; three of which achieved a biochemical response after steroid switch. Following switch to AA+D, 24 (73%) of patient achieved a rebound biochemical response after progression on AA+P, of those who achieved a response, 4 (12%) achieved a &gt;30% reduction in PSA, and 12( 36%) achieved a &gt;50% reduction in PSA. The median bPFS before and after steroid switch was 9 (AA+P) vs 19 (AA+P&amp;+D) months (HR 0.28; 95% CI 0.16-0.51; p&lt;.001). Analysis of response to steroid switch showed no significant correlation between response and any investigated clinical factor. A raised ALP(&gt;130U/L) on commencing AA+D predicted for a poorer bPFS (HR 2.4; 95% CI 1.1-5.5; p=0.038) and OS (HR 3.2; 95% CI 1.2-8.5; p=0.02). Conclusions: A steroid switch from AA+P to AA+D on biochemical progression is gaining more evidence as a beneficial technique to improve duration of treatment on AA. This study again suggests that bPFS is significantly improved by a steroid switch from P to D. Although negative in this study, several predictive models have been reported to help clinical selection of who may benefit most from a switch. Despite this, there is no official guidance or consensus on when and how a steroid switch should be used and whether this improves overall survival of those with mCRCP. Further randomised, prospective studies are needed to to better define the utility of AA+D, including in the first line setting.

Patterns of progression of patients with high-volume metastatic castration-sensitive prostate cancer treated with early docetaxel chemotherapy: The LONGITUDE observational study.

107 Background: In patients (pts) with high-volume (HV) metastatic castration sensitive prostate cancer (mCSPC) the addition of six cycles of docetaxel (TXT) to androgen deprivation therapy (ADT) in the CHAARTED and STAMPEDE trials prolonged survival by 10-18 months (mo). Aim of our study was to evaluate the principal patterns of relapse after TXT and their clinical and prognostic significance. Methods: We conducted a multicentric (14 Italian Centers), prospective, observational study enrolling HV mCSPC patients treated with ADT plus early TXT. Clinical and pathological features were recorded. Time to castration resistance (TCR) and overall survival (OS) were estimated by the Kaplan-Meier method and compared with the log-rank test. The Chi-Square test, t-test or Wilcoxon-Mann-Whitney test were used to assess difference between the groups as appropriate. Results: We identified 166 de novo mCSPC pts, with a median age of 64 years (range 38-84). The most common metastatic sites at diagnosis were: bone (93%) and lymph nodes (81%); visceral disease (lung and liver) was present in 36% of cases. 87% of pts had good Eastern Cooperative Oncology Group Performance Status (0-1), the median baseline PSA was 359 ng/ml (range 2.64-5800) and 43% experienced cancer pain. 87% of 158 evaluable pts had a Grade Group (GG) ³4. The majority of pts (81%) completed six cycles of TXT. The median time to PSA nadir was 10.2 months (mo), PSA response &gt; 50% was achieved in 96% of pts and the most common best response reported was partial response (58%). At the time of this analysis, 122 pts (67%) had biochemical or radiographic progressive disease (PD) to TXT and 67 of these (60%) developing new metastatic sites (NMS). No differences with respect of main clinical features was found between NMS pts and nonNMS, with the exception of GG (96% of NMS pts had GG 4-5 vs 74% of nonNMS; p = 0.002). In NMS group we found a higher rate of nodal PD (52% vs 22%, p = 0.001) and higher rate of bone PD (73% vs 47%, p = 0.005) compared to nonNMS. No differences in the rate of visceral PD. With a median follow-up of 27.9 mo, the median TCR was 14.3 mo (95%CI 12.8-16.7), without significant differences between NMS and nonNMS groups. About 90% of progressed pts received first-line treatment for mCRPC disease with similar outcomes. The median OS was 41.8 mo for the overall population, with not significant differences between NMS and nonNMS groups (22 mo and 25 mo). Overall, median OS from mCRPC diagnosis was 19.6 mo, similar in NMS and no-NMS pts (10 mo and 12 mo). Conclusions: In progressive mCSPC pts receiving early TXT, we observed more frequently the development of NMS with an elevated GG and a trophism for bone and lymph nodes. However, the NMS progression does not seem to have a prognostic role. An extended follow up and the prospective data will be provided.

Efficacy and safety of Androgen Deprivation Therapy (ADT) combined with modified docetaxel chemotherapy versus ADT combined with standard docetaxel chemotherapy in patients with metastatic castration-resistant prostate cancer: study protocol for a multicentre prospective randomized controlled trial

BackgroundAndrogen deprivation therapy (ADT) combined with docetaxel chemotherapy is the standard treatment for metastatic castration-resistant prostate cancer (mCRPC) patients. However, mCRPC patients are mainly frail elderly men, constantly accompanied by comorbidities and showing poor tolerance to standard docetaxel chemotherapy. Some exploratory studies administering modified chemotherapy regimens have reported noninferior oncologic outcomes with fewer adverse events, yet most are retrospective or small studies, and prospective randomized controlled trials have rarely been conducted. Therefore, we designed this modified docetaxel chemotherapy regimen in patients with mCRPC, aiming to evaluate its efficacy and safety compared with the standard docetaxel chemotherapy regimen.MethodsThis is an open-label, multi-institutional, prospective, randomized non-inferiority trial. A total of 128 patients with mCRPC will be randomized to receive ADT combined with modified docetaxel chemotherapy (experimental group, n=64) or ADT combined with standard docetaxel chemotherapy (control group, n=64). Patients in the experimental group will receive a modified regimen with docetaxel 40 mg/m2 on the 1st day and 35 mg/m2 on the 8th day, repeated every 21 days. The primary endpoint is progression-free survival at 2 years. Secondary endpoints include overall survival, prostate-specific antigen response rate, pain response rate, toxicity and quality of life.DiscussionThe expected benefit for the patient in the experimental arm is noninferior efficacy with decreased toxicity and improved quality of life compared with that in the control arm. To the best of our knowledge, this will be the first multicentre prospective randomized study to assess the efficacy and safety of modified docetaxel chemotherapy in patients with mCRPC in China. The results of this trial may provide benefit to mCRPC patients, especially those with poor performance.Trial registrationchictr.org.cn Identifier: ChiCTR2100046636 (May 24, 2021). Ongoing study.

Impact of the COVID-19 pandemic on the diagnosis and treatment of men with prostate cancer.

To determine the impact of the COVID-19 pandemic on diagnostic and treatment activity in 2020 across hospital providers of prostate cancer (PCa) care in the English National Health Service. Diagnostic and treatment activity between 23 March (start of first national lockdown in England) and 31 December 2020 was compared with the same calendar period in 2019. Patients newly diagnosed with PCa were identified from national rapid cancer registration data linked to other electronic healthcare datasets. There was a 30.8% reduction (22 419 vs 32 409) in the number of men with newly diagnosed PCa in 2020 after the start of the first lockdown, compared with the corresponding period in 2019. Men diagnosed in 2020 were typically at a more advanced stage (Stage IV: 21.2% vs 17.4%) and slightly older (57.9% vs 55.9% ≥ 70 years; P < 0.001). Prostate biopsies in 2020 were more often performed using transperineal (TP) routes (64.0% vs 38.2%). The number of radical prostatectomies in 2020 was reduced by 26.9% (3896 vs 5331) and the number treated by external beam radiotherapy (EBRT) by 14.1% (9719 vs 11 309). Other changes included an increased use of EBRT with hypofractionation and reduced use of docetaxel chemotherapy in men with hormone-sensitive metastatic PCa (413 vs 1519) with related increase in the use of enzalutamide. We found substantial deficits in the number of diagnostic and treatment procedures for men with newly diagnosed PCa after the start of the first lockdown in 2020. The number of men diagnosed with PCa decreased by about one-third and those diagnosed had more advanced disease. Treatment patterns shifted towards those that limit the risk of COVID-19 exposure including increased use of TP biopsy, hypofractionated radiation, and enzalutamide. Urgent concerted action is required to address the COVID-19-related deficits in PCa services to mitigate their impact on long-term outcomes.

Hypersensitivity Reactions in Men with Prostate Cancer Undergoing Docetaxel Chemotherapy

Purpose: To review hypersensitivity reactions in men receiving docetaxel chemotherapy for prostate cancer using a conservative steroid schedule.

Efficacy of Plinabulin vs Pegfilgrastim for Prevention of Docetaxel-Induced Neutropenia in Patients With Solid Tumors

Prevention of chemotherapy-induced neutropenia (CIN) and its clinical consequences is an unmet need for which plinabulin, a selective immunomodulating microtubule-binding agent, is being tested. To demonstrate noninferiority between plinabulin and pegfilgrastim for days of severe neutropenia in cycle 1 in patients with solid tumors treated with docetaxel. The Plinabulin vs Pegfilgrastim for the Prevention of Docetaxel-Induced Neutropenia in Patients With Solid Tumors (PROTECTIVE-1) double-blind phase 3 randomized clinical trial was performed in multiple centers in China, Russia, Ukraine, and the US. Participants included patients with breast, prostate, or non-small cell lung cancer treated with single-agent docetaxel chemotherapy. Data were collected from June 1, 2018, to January 31, 2019. The database was locked on February 18, 2021. Data analysis was based on intention to treat and safety and performed from October 5, 2018, to February 23, 2021. Plinabulin, 40 mg, plus placebo or pegfilgrastim, 6 mg, plus placebo. The primary end point was day of severe neutropenia in cycle 1. Additional end points included clinical consequences of CIN (febrile neutropenia, hospitalizations, infections, antibiotic use, and modifications of chemotherapy dose), patient-reported outcomes for bone pain score, markers for immune suppression (neutrophil-to-lymphocyte ratio [NLR] of >5), immature neutrophils (band, promyelocyte, and myelocyte counts >0), and safety. Among the 105 patients included in the analysis (65 [6.19%] women; median age, 59 [range, 31-81] years), the primary end point was met within a noninferiority margin of 0.65 days, with a mean difference of 0.52 days (98.52% CI, 0.40-0.65 days). Grade 4 neutropenia frequency in cycle 1 was not significantly different. Plinabulin had earlier onset of action with less grade 4 neutropenia in week 1 of cycle 1. Plinabulin had fewer adverse clinical consequences with rates of febrile neutropenia (0 of 52 vs 1 of 53 [1.9%]), infections (4 of 52 [7.7%] vs 8 of 53 [15.1%]), chemotherapy dose delay of more than 7 days (2 of 52 [3.8%] vs 3 of 53 [5.7%]), and permanent chemotherapy discontinuation (7 of 52 [13.5%] vs 14 of 53 [26.4%]). Patients receiving plinabulin had significantly less bone pain (difference, -0.67 [95% CI, -1.17 to -0.16]; P = .01) and a better immunosuppressive profile (NLR >5 at day 8, 2 of 52 [3.8%] vs 24 of 51 [46.0%]; P < .001). Plinabulin was well tolerated, with comparable safety to pegfilgrastim. Plinabulin has comparable efficacy to pegfilgrastim for the prevention of CIN, with better safety and a better immunosuppressive profile. Plinabulin's same-day dosing compared with pegfilgrastim's next-day dosing offers distinct advantages, including reducing use of health care services. ClinicalTrials.gov Identifier: NCT03102606.

Immunotherapeutic HCW9218 augments anti-tumor activity of chemotherapy via NK cell-mediated reduction of therapy-induced senescent cells

Therapy induced senescence (TIS) in tumors and TIS cancer cells secrete proinflammatory senescence-associated secretory phenotype (SASP) factors. SASP factors promote TIS cancer cells to re-enter the growth cycle with stemness characteristics, resulting in chemo-resistance and disease relapse. Herein, we show that the immunotherapeutic HCW9218, comprising transforming growth factor-β (TGF-β) receptor II and interleukin (IL)-15/IL-15 receptor α domains, enhances metabolic and cytotoxic activities of immune cells and reduces TIS tumor cells invivo to improve the efficacy of docetaxel and gemcitabine plus nab-paclitaxel against B16F10 melanoma and SW1990 pancreatic tumors, respectively. Mechanistically, HCW9218 treatment reduces the immunosuppressive tumor microenvironment and enhances immune cell infiltration and cytotoxicity in the tumors to eliminate TIS cancer cells. Immuno-depletion analysis suggests that HCW9218-activated natural killer cells play a pivotal role in TIS cancer cell removal. HCW9218 treatment following docetaxel chemotherapy further enhances efficacy of tumor antigen-specific and anti-programmed death-ligand 1 (PD-L1) antibodies in B16F10 tumor-bearing mice. We also show that HCW9218 treatment decreases TIS cells and lowers SASP factors in off-target tissues caused by chemotherapy of tumor-bearing mice. Collectively, HCW9218 has the potential to significantly enhance anti-tumor efficacy of chemotherapy, therapeutic antibodies, and checkpoint blockade by eliminating TIS cancer cells while reducing TIS-mediated proinflammatory side effects in normal tissues.

Association of MLH1-93G>A polymorphisms toward lung cancer susceptibility and its association with clinical outcome in North Indian patients treated with platinum-based chemotherapy.

Lung cancer is one of the most prevalent and main causes of malignancy-related deaths worldwide, especially in developed countries. Epidemiological studies have demonstrated that individuals having alterations in a particular gene may have a high risk of developing certain types of cancer. In the present study, 500 Indian lung cancer patients and 500 healthy controls were enrolled. Polymerase chain reaction-restriction fragment length polymorphism method was used to identify the genotype of enrolled individuals and MedCalc statistical package was used for carrying out statistical analysis. In this study, we found a reduced risk of developing adenocarcinoma in patients harboring variant (P = 0.0007) and combined type genotype (P = 0.008), whereas an increased risk for small-cell lung carcinoma (SCLC) development for those subject harboring GA genotypes (P = 0.03) was also observed. Further, heterozygous type and combined type genotype of heavy smokers for MLH1 polymorphism reported a 2-fold (P = 0.001) and 1.8-fold increased risk toward lung cancer development, respectively (P = 0.007). In case of females, the subjects harboring a variant allele have a significantly reduced risk for lung cancer development (P = 0.0001). For MLH1 polymorphism, reduced risk of developing tumor to T3 or T4 stage was observed (P = 0.04). Moreover, this is the first study reporting overall survival (OS) association for north Indian lung cancer patients with platinum-based doublet chemotherapy; for docetaxel, a three-fold increase in hazard ratio and corresponding low median standard survival time (8.4 months) for mutant and combined type genotype (P = 0.04) was observed. These results suggest that MLH1-93G>A polymorphism is involved in modulating the risk toward lung cancer. Our study also concluded a negative association of OS in patients undergoing carboplatin/cisplatin and docetaxel chemotherapy.

Acquired resistance to irradiation or docetaxel is not associated with cross-resistance to cisplatin in prostate cancer cell lines

PurposePlatinum chemotherapy can be considered to treat metastatic castration-resistant prostate cancer (mCRPC) with features of neuroendocrine differentiation. However, platinum compounds are generally only applied after the failure of multiple prior-line treatment options. This study investigated whether acquired resistance against ionizing radiation or docetaxel chemotherapy—two commonly applied treatment modalities in prostate cancer—influences the cisplatin (CDDP) tolerance in mCRPC cell line models.MethodsAge-matched parental as well as radio- or docetaxel-resistant DU145 and PC-3 cell lines were treated with CDDP and their sensitivity was assessed by measurements of growth rates, viability, apoptosis, metabolic activity and colony formation ability.ResultsThe data suggest that docetaxel resistance does not influence CDDP tolerance in all tested docetaxel-resistant cell lines. Radio-resistance was associated with sensitization to CDDP in PC-3, but not in DU145 cells. In general, DU145 cells tolerated higher CDDP concentrations than PC-3 cells regardless of acquired resistances. Furthermore, non-age-matched treatment-naïve PC-3 cells exhibited significantly different CDDP tolerances.ConclusionLike patients, different mCRPC cell lines exhibit significant variability regarding CDDP tolerance. The presented in vitro data suggest that previous radiation treatment may be associated with a moderate sensitization to CDDP in an isogenic and age-matched setting. Therefore, previous radiotherapy or docetaxel chemotherapy might be no contraindication against initiation of platinum chemotherapy in selected mCRPC patients.

Is Triple Therapy the New Standard for Metastatic Hormone-sensitive Prostate Cancer?

The treatment of metastatic hormone-sensitive prostate cancer has rapidly changed over the last decade. Currently, standard of care (SOC) options for first-line treatment are androgen deprivation therapy (ADT) in combination with either docetaxel chemotherapy or an androgen receptor pathway inhibitor such as abiraterone, enzalutamide or apalutamide. Recent results from both the PEACE-1 and ARASENS trials show an overall survival and progression-free survival benefit from the addition of an androgen-receptor pathway inhibitor for patients in whom the SOC option of ADT plus docetaxel has been chosen in de novo metastatic hormone-sensitive prostate cancer, with a more pronounced benefit in those with high-volume metastatic disease. However, many clinicians now preferentially use ADT plus an androgen-receptor pathway inhibitor as SOC first-line treatment, and no prospective trial has addressed whether there is a benefit from the addition of docetaxel to this version of SOC combination therapy. The benefit of triplet combination therapy in those with recurrent or low-volume metastatic disease is less clear and longer follow-up is required before conclusions can be drawn about these patient groups.

Clinical features of lower limb edema in patients with breast cancer who underwent docetaxel chemotherapy: a retrospective observational study

Clinical features of lower limb edema in patients with breast cancer who underwent docetaxel chemotherapy: a retrospective observational study

GUIDE: a randomised non-comparative phase II trial of biomarker-driven intermittent docetaxel versus standard-of-care docetaxel in metastatic castration-resistant prostate cancer (clinical trial protocol).

Objective:To determine the efficacy and safety of intermittent docetaxel chemotherapy guided by circulating methylated glutathione S-transferase Pi-1 (mGSTP1) in men with metastatic castration-resistant prostate cancer (CRPC).Patients and Methods:GUIDE (NCT04918810) is a randomised, two-arm, non-comparative phase-2 trial recruiting 120 patients at six Australian centres. Patients with Prostate Cancer Working Group-3 defined metastatic CRPC who are commencing docetaxel 75 mg/m2 q3w will be pre-screened for detectable mGSTP1 at baseline ± following two cycles of treatment. Those with detectable plasma mGSTP1 at baseline that becomes undetectable after two cycles of chemotherapy will be eligible for GUIDE. Prior to Cycle 4 of docetaxel, these patients are randomised 2:1 to one of two treatment arms: Arm A (cease docetaxel and reinstitute if mGSTP1 becomes detectable) or Arm B (continue docetaxel 75 mg/m2 q3w in accordance with clinician’s usual practice). The primary endpoint is radiographic progression-free survival. Secondary endpoints include time on treatment holidays, safety, patient-reported outcomes, overall survival, health resource use, and cost associated with treatment. Enrolment commenced November 2021.Results and Conclusion:The results of this trial will generate data on the clinical utility of mGSTP1 as a novel biomarker to guide treatment de-escalation in metastatic CRPC.