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The Lancet. Oncology Jul 2023Adding docetaxel to androgen deprivation therapy (ADT) improves survival in patients with metastatic, hormone-sensitive prostate cancer, but uncertainty remains about... (Meta-Analysis)
Meta-Analysis
Which patients with metastatic hormone-sensitive prostate cancer benefit from docetaxel: a systematic review and meta-analysis of individual participant data from randomised trials.
BACKGROUND
Adding docetaxel to androgen deprivation therapy (ADT) improves survival in patients with metastatic, hormone-sensitive prostate cancer, but uncertainty remains about who benefits most. We therefore aimed to obtain up-to-date estimates of the overall effects of docetaxel and to assess whether these effects varied according to prespecified characteristics of the patients or their tumours.
METHODS
The STOPCAP M1 collaboration conducted a systematic review and meta-analysis of individual participant data. We searched MEDLINE (from database inception to March 31, 2022), Embase (from database inception to March 31, 2022), the Cochrane Central Register of Controlled Trials (from database inception to March 31, 2022), proceedings of relevant conferences (from Jan 1, 1990, to Dec 31, 2022), and ClinicalTrials.gov (from database inception to March 28, 2023) to identify eligible randomised trials that assessed docetaxel plus ADT compared with ADT alone in patients with metastatic, hormone-sensitive prostate cancer. Detailed and updated individual participant data were requested directly from study investigators or through relevant repositories. The primary outcome was overall survival. Secondary outcomes were progression-free survival and failure-free survival. Overall pooled effects were estimated using an adjusted, intention-to-treat, two-stage, fixed-effect meta-analysis, with one-stage and random-effects sensitivity analyses. Missing covariate values were imputed. Differences in effect by participant characteristics were estimated using adjusted two-stage, fixed-effect meta-analysis of within-trial interactions on the basis of progression-free survival to maximise power. Identified effect modifiers were also assessed on the basis of overall survival. To explore multiple subgroup interactions and derive subgroup-specific absolute treatment effects we used one-stage flexible parametric modelling and regression standardisation. We assessed the risk of bias using the Cochrane Risk of Bias 2 tool. This study is registered with PROSPERO, CRD42019140591.
FINDINGS
We obtained individual participant data from 2261 patients (98% of those randomised) from three eligible trials (GETUG-AFU15, CHAARTED, and STAMPEDE trials), with a median follow-up of 72 months (IQR 55-85). Individual participant data were not obtained from two additional small trials. Based on all included trials and patients, there were clear benefits of docetaxel on overall survival (hazard ratio [HR] 0·79, 95% CI 0·70 to 0·88; p<0·0001), progression-free survival (0·70, 0·63 to 0·77; p<0·0001), and failure-free survival (0·64, 0·58 to 0·71; p<0·0001), representing 5-year absolute improvements of around 9-11%. The overall risk of bias was assessed to be low, and there was no strong evidence of differences in effect between trials for all three main outcomes. The relative effect of docetaxel on progression-free survival appeared to be greater with increasing clinical T stage (p=0·0019), higher volume of metastases (p=0·020), and, to a lesser extent, synchronous diagnosis of metastatic disease (p=0·077). Taking into account the other interactions, the effect of docetaxel was independently modified by volume and clinical T stage, but not timing. There was no strong evidence that docetaxel improved absolute effects at 5 years for patients with low-volume, metachronous disease (-1%, 95% CI -15 to 12, for progression-free survival; 0%, -10 to 12, for overall survival). The largest absolute improvement at 5 years was observed for those with high-volume, clinical T stage 4 disease (27%, 95% CI 17 to 37, for progression-free survival; 35%, 24 to 47, for overall survival).
INTERPRETATION
The addition of docetaxel to hormone therapy is best suited to patients with poorer prognosis for metastatic, hormone-sensitive prostate cancer based on a high volume of disease and potentially the bulkiness of the primary tumour. There is no evidence of meaningful benefit for patients with metachronous, low-volume disease who should therefore be managed differently. These results will better characterise patients most and, importantly, least likely to gain benefit from docetaxel, potentially changing international practice, guiding clinical decision making, better informing treatment policy, and improving patient outcomes.
FUNDING
UK Medical Research Council and Prostate Cancer UK.
Topics: Male; Humans; Docetaxel; Prostatic Neoplasms; Androgen Antagonists; Disease-Free Survival; Hormones; Antineoplastic Combined Chemotherapy Protocols; Randomized Controlled Trials as Topic
PubMed: 37414011
DOI: 10.1016/S1470-2045(23)00230-9 -
Cancers Sep 2023Savolitinib is a highly selective small molecule inhibitor of the mesenchymal epithelial transition factor (MET) tyrosine kinase, primarily developed for the treatment... (Review)
Review
Savolitinib is a highly selective small molecule inhibitor of the mesenchymal epithelial transition factor (MET) tyrosine kinase, primarily developed for the treatment of non-small cell lung cancer (NSCLC) with mutations. It is also being investigated as a treatment for breast, head and neck, colorectal, gastric, pancreatic, and other gastrointestinal cancers. In both preclinical and clinical studies, it has demonstrated efficacy in lung, kidney, and stomach cancers. Savolitinib is an oral anti-cancer medication taken as a 600 mg dose once daily. It can be used as a monotherapy in patients with non-small cell lung cancer with mutations and in combination with epidermal growth factor receptor (EGFR) inhibitors for patients who have developed resistance to them. Furthermore, savolitinib has shown positive results in gastric cancer treatment, particularly in combination with docetaxel. As a result, this review aims to validate its efficacy in NSCLC and suggests its potential application in other gastrointestinal cancers, such as pancreatic cancer, based on related research in gastric and renal cancer.
PubMed: 37835402
DOI: 10.3390/cancers15194708 -
Targeted Oncology Sep 2023Darolutamide (NUBEQA) is an oral androgen receptor inhibitor (ARi) that is approved for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) in... (Review)
Review
Darolutamide (NUBEQA) is an oral androgen receptor inhibitor (ARi) that is approved for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy (ADT) and docetaxel. In a pivotal trial, darolutamide plus ADT and docetaxel was superior to placebo plus ADT and docetaxel in prolonging the primary endpoint of overall survival, with improvements also reported in most secondary endpoints. Treatment with darolutamide plus ADT and docetaxel was associated with a manageable tolerability profile. Furthermore, the adverse events reported with darolutamide plus ADT and docetaxel were generally consistent with the safety profiles previously reported for ADT and docetaxel. Darolutamide expands the availability of treatment options in mHSPC and may be useful as a treatment for high-volume disease (typically defined as ≥ 4 bone metastases with spread outside of the pelvis and vertebral column).
Topics: Male; Humans; Prostatic Neoplasms; Docetaxel; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Hormones
PubMed: 37542594
DOI: 10.1007/s11523-023-00984-4 -
Cureus Jul 2023Trastuzumab is a recombinant immunoglobulin G1 monoclonal antibody used to treat human epidermal growth factor receptor 2 (HER2) cancers. Trastuzumab-induced...
Trastuzumab is a recombinant immunoglobulin G1 monoclonal antibody used to treat human epidermal growth factor receptor 2 (HER2) cancers. Trastuzumab-induced interstitial pneumonitis is a rare adverse effect reported in a few patients. Interstitial pneumonitis presents as symptoms of dyspnea, hypoxia, cough, and fever. If the patient is treated early, corticosteroids can slow or reverse the disease progression. A 41-year-old woman presented with dyspnea and a dry cough three weeks after her third cycle of trastuzumab therapy for breast cancer. A diagnosis of trastuzumab-induced interstitial pneumonitis was made after multiple other disease processes were ruled out. The patient was started on methylprednisolone while inpatient and transitioned to prednisone for outpatient therapy. The patient was maintained on 2-3L of oxygen throughout her hospital stay and was discharged on 3L of oxygen through nasal cannula. Trastuzumab was never restarted after discharge. There have been many trials evaluating the safety, efficacy, and optimal treatment regimen of trastuzumab, but there are only a few reports of interstitial pneumonitis adverse reaction. The lack of correlation and limited cases make this adverse effect very difficult to diagnose and monitor. New trials and case reports can bring an insight into contributing factors, symptoms at onset, and treatment for future patients. With the increase in use of trastuzumab therapy, physicians should be aware of how to diagnose and treat the rare adverse reaction of trastuzumab-induced interstitial pneumonitis.
PubMed: 37602136
DOI: 10.7759/cureus.42116 -
Clinical Cancer Research : An Official... Sep 2023Efficacy of MEK inhibitors in KRAS+ NSCLC may differ based on specific KRAS mutations and comutations. Our hypothesis was that docetaxel and trametinib would improve...
PURPOSE
Efficacy of MEK inhibitors in KRAS+ NSCLC may differ based on specific KRAS mutations and comutations. Our hypothesis was that docetaxel and trametinib would improve activity in KRAS+ NSCLC and specifically in KRAS G12C NSCLC.
PATIENTS AND METHODS
S1507 is a single-arm phase II study assessing the response rate (RR) with docetaxel plus trametinib in recurrent KRAS+ NSCLC and secondarily in the G12C subset. The accrual goal was 45 eligible patients, with at least 25 with G12C mutation. The design was two-stage design to rule out a 17% RR, within the overall population at the one-sided 3% level and within the G12C subset at the 5% level.
RESULTS
Between July 18, 2016, and March 15, 2018, 60 patients were enrolled with 53 eligible and 18 eligible in the G12C cohort. The RR was 34% [95% confidence interval (CI), 22-48] overall and 28% (95% CI, 10-53) in G12C. Median PFS and OS were 4.1 and 3.3 months and 10.9 and 8.8 months, overall and in the subset, respectively. Common toxicities were fatigue, diarrhea, nausea, rash, anemia, mucositis, and neutropenia. Among 26 patients with known status for TP53 (10+ve) and STK11 (5+ve), OS (HR, 2.85; 95% CI, 1.16-7.01), and RR (0% vs. 56%, P = 0.004) were worse in patients with TP53 mutated versus wild-type cancers.
CONCLUSIONS
RRs were significantly improved in the overall population. Contrary to preclinical studies, the combination showed no improvement in efficacy in G12C patients. Comutations may influence therapeutic efficacy of KRAS directed therapies and are worthy of further evaluation. See related commentary by Cantor and Aggarwal, p. 3563.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Docetaxel; Proto-Oncogene Proteins p21(ras); Lung Neoplasms; Neoplasm Recurrence, Local; Mutation
PubMed: 37233987
DOI: 10.1158/1078-0432.CCR-22-3947 -
The Lancet. Gastroenterology &... Nov 2023The optimum curative approach to adenocarcinoma of the oesophagus and oesophagogastric junction is unknown. We aimed to compare trimodality therapy (preoperative... (Randomized Controlled Trial)
Randomized Controlled Trial
Trimodality therapy versus perioperative chemotherapy in the management of locally advanced adenocarcinoma of the oesophagus and oesophagogastric junction (Neo-AEGIS): an open-label, randomised, phase 3 trial.
BACKGROUND
The optimum curative approach to adenocarcinoma of the oesophagus and oesophagogastric junction is unknown. We aimed to compare trimodality therapy (preoperative radiotherapy with carboplatin plus paclitaxel [CROSS regimen]) with optimum contemporaneous perioperative chemotherapy regimens (epirubicin plus cisplatin or oxaliplatin plus fluorouracil or capecitabine [a modified MAGIC regimen] before 2018 and fluorouracil, leucovorin, oxaliplatin, and docetaxel [FLOT] subsequently).
METHODS
Neo-AEGIS (CTRIAL-IE 10-14) was an open-label, randomised, phase 3 trial done at 24 centres in Europe. Patients aged 18 years or older with clinical tumour stage T2-3, nodal stage N0-3, and M0 adenocarcinoma of the oesophagus and oesophagogastric junction were randomly assigned to perioperative chemotherapy (three preoperative and three postoperative 3-week cycles of intravenous 50 mg/m epirubicin on day 1 plus intravenous 60 mg/m cisplatin or intravenous 130 mg/m oxaliplatin on day 1 plus continuous infusion of 200 mg/m fluorouracil daily or oral 625 mg/m capecitabine twice daily up to 2018, with four preoperative and four postoperative 2-week cycles of 2600 mg/m fluorouracil, 85 mg/m oxaliplatin, 200 mg/m leucovorin, and 50 mg/m docetaxel intravenously on day 1 as an option from 2018) or trimodality therapy (41·4 Gy in 23 fractions on days 1-5, 8-12, 15-19, 22-26, and 29-31 with intravenous area under the curve 2 mg/mL per min carboplatin plus intravenous 50 mg/m paclitaxel on days 1, 8, 15, 22, and 29). The primary endpoint was overall survival, assessed in all randomly assigned patients who received at least one dose of study drug, regardless of which study drug they received, by intention to treat. Secondary endpoints were disease-free survival, site of treatment failure, operative complications, toxicity, pathological response (complete [ypT0N0] and major [tumour regression grade 1 and 2]), margin-free resection (R0), and health-related quality of life. Toxicity and safety data were analysed in the safety population, defined as patients who took at least one dose of study drug, according to treatment actually received. The initial power calculation was based on superiority of trimodality therapy (n=366 patients); it was adjusted after FLOT became an option to a non-inferiority design with a margin of 5% for perioperative chemotherapy (n=540). This study is registered with ClinicalTrials.gov, NCT01726452.
FINDINGS
Between Jan 24, 2013, and Dec 23, 2020, 377 patients were randomly assigned, of whom 362 were included in the intention-to treat population (327 [90%] male and 360 [99%] White): 184 in the perioperative chemotherapy group and 178 in the trimodality therapy group. The trial closed prematurely in December, 2020, after the second interim futility analysis (143 deaths), on the basis of similar survival metrics and the impact of the COVID-19 pandemic. At a median follow-up of 38·8 months (IQR 16·3-55·1), median overall survival was 48·0 months (95% CI 33·6-64·8) in the perioperative chemotherapy group and 49·2 months (34·8-74·4) in the trimodality therapy group (3-year overall survival 55% [95% CI 47-62] vs 57% [49-64]; hazard ratio 1·03 [95% CI 0·77-1·38]; log-rank p=0·82). Median disease-free survival was 32·4 months (95% CI 22·8-64·8) in the perioperative chemotherapy group and 24·0 months (18·0-40·8) in the trimodality therapy group [hazard ratio 0·89 [95% CI 0·68-1·17]; log-rank p=0·41). The pattern of recurrence, locoregional or systemic, was not significantly different (odds ratio 1·35 [95% CI 0·63-2·91], p=0·44). Pathological complete response (odds ratio 0·33 [95% CI 0·14-0·81], p=0·012), major pathological response (0·21 [0·12-0·38], p<0·0001), and R0 rates (0·21 [0·08-0·53], p=0·0003) favoured trimodality therapy. The most common grade 3-4 adverse event was neutropenia (49 [27%] of 183 patients in the perioperative chemotherapy group vs 11 [6%] of 178 patients in the trimodality therapy group), followed by diarrhoea (20 [11%] vs none), and pulmonary embolism (ten [5%] vs nine [5%]). One (1%) patient in the perioperative chemotherapy group and three (2%) patients in the trimodality therapy group died from serious adverse events, two (one in each group) of which were possibly related to treatment. No differences were seen in operative mortality (five [3%] deaths in the perioperative chemotherapy group vs four [2%] in the trimodality therapy group), major morbidity, or in global health status at 1 and 3 years.
INTERPRETATION
Although underpowered and incomplete, Neo-AEGIS provides the largest comprehensive randomised dataset for patients with adenocarcinoma of the oesophagus and oesophagogastric junction treated with perioperative chemotherapy (predominantly the modified MAGIC regimen), and CROSS trimodality therapy, and reports similar 3-year survival and no major differences in operative and health-related quality of life outcomes. We suggest that these data support continued clinical equipoise.
FUNDING
Health Research Board, Cancer Research UK, Irish Cancer Society, Oesophageal Cancer Fund, and French National Cancer Institute.
Topics: Humans; Male; Female; Capecitabine; Cisplatin; Docetaxel; Oxaliplatin; Epirubicin; Leucovorin; Carboplatin; Quality of Life; Pandemics; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Esophageal Neoplasms; Esophagogastric Junction; Adenocarcinoma; Paclitaxel
PubMed: 37734399
DOI: 10.1016/S2468-1253(23)00243-1 -
Molecular Cancer Sep 2023Multidrug resistance renders treatment failure in a large proportion of head and neck squamous cell carcinoma (HNSCC) patients that require multimodal therapy involving...
Multidrug resistance renders treatment failure in a large proportion of head and neck squamous cell carcinoma (HNSCC) patients that require multimodal therapy involving chemotherapy in conjunction with surgery and/or radiotherapy. Molecular events conferring chemoresistance remain unclear. Through transcriptome datamining, 28 genes were subjected to pharmacological and siRNA rescue functional assays on 12 strains of chemoresistant cell lines each against cisplatin, 5-fluorouracil (5FU), paclitaxel (PTX) and docetaxel (DTX). Ten multidrug chemoresistance genes (TOP2A, DNMT1, INHBA, CXCL8, NEK2, FOXO6, VIM, FOXM1B, NR3C1 and BIRC5) were identified. Of these, four genes (TOP2A, DNMT1, INHBA and NEK2) were upregulated in an HNSCC patient cohort (n = 221). Silencing NEK2 abrogated chemoresistance in all drug-resistant cell strains. INHBA and TOP2A were found to confer chemoresistance in majority of the drug-resistant cell strains whereas DNMT1 showed heterogeneous results. Pan-cancer Kaplan-Meier survival analysis on 21 human cancer types revealed significant prognostic values for INHBA and NEK2 in at least 16 cancer types. Drug library screens identified two compounds (Sirodesmin A and Carfilzomib) targeting both INHBA and NEK2 and re-sensitised cisplatin-resistant cells. We have provided the first evidence for NEK2 and INHBA in conferring chemoresistance in HNSCC cells and siRNA gene silencing of either gene abrogated multidrug chemoresistance. The two existing compounds could be repurposed to counteract cisplatin chemoresistance in HNSCC. This finding may lead to novel personalised biomarker-linked therapeutics that can prevent and/or abrogate chemoresistance in HNSCC and other tumour types with elevated NEK2 and INHBA expression. Further investigation is necessary to delineate their signalling mechanisms in tumour chemoresistance.
Topics: Humans; Squamous Cell Carcinoma of Head and Neck; Cisplatin; Signal Transduction; Cell Line; Head and Neck Neoplasms; Forkhead Transcription Factors; NIMA-Related Kinases
PubMed: 37667354
DOI: 10.1186/s12943-023-01846-3 -
BMC Cancer Jul 2023A majority of prostate cancer cells are in a non-proliferating, G (quiescent) phase of the cell cycle and may lie dormant for years before activation into a...
BACKGROUND
A majority of prostate cancer cells are in a non-proliferating, G (quiescent) phase of the cell cycle and may lie dormant for years before activation into a proliferative, rapidly progressing, disease phase. Many mechanisms which influence proliferation and quiescence choices remain to be elucidated, including the role of non-coding RNAs. In this study, we investigated the role of a long non-coding RNA (lncRNA), SNHG1, on cell proliferation, quiescence, and sensitivity to docetaxel as a potential factor important in prostate cancer biology.
METHODS
Publically available, anonymous, clinical data was obtained from cBioPortal for analysis. RNAi and prostate cancer cell lines were utilized to investigate SNHG1 in vitro. We measured G cells, DNA synthesis, and cell cycle distribution by flow cytometry. Western blotting was used to assess G arrest and apoptosis. These parameters were also investigated following docetaxel treatment.
RESULTS
We discovered that in prostate cancer patients from The Cancer Genome Atlas (TCGA) data set, high SNHG1 expression in localized tumors correlated with reduced progression-free survival, and in a data set of both primary and metastatic tumors, high SNHG1 expression was associated with metastatic tumors. In vitro analysis of prostate cancer cell lines showed SNHG1 expression correlated with a quiescent versus proliferative phenotype. Knockdown of SNHG1 by RNAi in PC3 and C4-2B cells resulted in an accumulation of cells in the G phase. After knockdown, 60.0% of PC3 cells were in G, while control cultures had 13.2% G. There were reciprocal decreases in G phase, but little impact on the proportion of cells in S and G/M phases, depending on cell line. DNA synthesis and proliferation were largely halted- decreasing by 75% and 81% in C4-2B and PC3 cells, respectively. When cells were treated with docetaxel, SNHG1-depleted C4-2B and PC3 cells were resistant to G arrest, and displayed reduced apoptosis, as indicated by reduced cyclin B1 and cleaved caspase 3, suggesting SNHG1 levels may modulate drug response.
CONCLUSIONS
Overall, these results indicate SNHG1 has complex roles in prostate cancer, as it stimulates cell cycle entry and disease progression, but sensitizes cells to docetaxel treatment.
Topics: Humans; Male; Docetaxel; Cell Division; Cell Proliferation; Prostatic Neoplasms; Apoptosis; Cell Line, Tumor; DNA; RNA, Long Noncoding
PubMed: 37464317
DOI: 10.1186/s12885-023-11006-x -
European Urology Aug 2023Intensification of therapy may improve outcomes for patients with high-risk localized prostate cancer. (Randomized Controlled Trial)
Randomized Controlled Trial
Androgen Deprivation and Radiotherapy with or Without Docetaxel for Localized High-risk Prostate Cancer: Long-term Follow-up from the Randomized NRG Oncology RTOG 0521 Trial.
BACKGROUND
Intensification of therapy may improve outcomes for patients with high-risk localized prostate cancer.
OBJECTIVE
To provide long-term follow-up data from phase III RTOG 0521, which compared a combination of androgen deprivation therapy (ADT) + external beam radiation therapy (EBRT) + docetaxel with ADT + EBRT.
DESIGN, SETTING, AND PARTICIPANTS
High-risk localized prostate cancer patients (>50% of patients had Gleason 9-10 disease) were prospectively randomized to 2 yr of ADT + EBRT or ADT + EBRT + six cycles of docetaxel. A total of 612 patients were accrued, and 563 were eligible and included in the modified intent-to-treat analysis.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
The primary endpoint was overall survival (OS). Analyses with Cox proportional hazards were performed as prespecified in the protocol; however, there was evidence of nonproportional hazards. Thus, a post hoc analysis was performed using the restricted mean survival time (RMST). The secondary endpoints included biochemical failure, distant metastasis (DM) as detected by conventional imaging, and disease-free survival (DFS).
RESULTS AND LIMITATIONS
After 10.4 yr of median follow-up among survivors, the hazard ratio (HR) for OS was 0.89 (90% confidence interval [CI] 0.70-1.14; one-sided log-rank p = 0.22). Survival at 10 yr was 64% for ADT + EBRT and 69% for ADT + EBRT + docetaxel. The RMST at 12 yr was 0.45 yr and not statistically significant (one-sided p = 0.053). No differences were detected in the incidence of DFS (HR = 0.92, 95% CI 0.73-1.14), DM (HR = 0.84, 95% CI 0.73-1.14), or prostate-specific antigen recurrence risk (HR = 0.97, 95% CI 0.74-1.29). Two patients had grade 5 toxicity in the chemotherapy arm and zero patients in the control arm.
CONCLUSIONS
After a median follow-up of 10.4 yr among surviving patients, no significant differences are observed in clinical outcomes between the experimental and control arms. These data suggest that docetaxel should not be used for high-risk localized prostate cancer. Additional research may be warranted using novel predictive biomarkers.
PATIENT SUMMARY
No significant differences in survival were noted after long-term follow-up for high-risk localized prostate cancer patients in a large prospective trial where patients were treated with androgen deprivation therapy + radiation to the prostate ± docetaxel.
Topics: Male; Humans; Docetaxel; Androgen Antagonists; Androgens; Prostatic Neoplasms; Follow-Up Studies; Prospective Studies
PubMed: 37179241
DOI: 10.1016/j.eururo.2023.04.024 -
Cancer Research Communications Aug 2023Treatment of advanced pancreatic cancer with a single therapeutic at a maximal dose has been largely ineffective at increasing survival. Combination therapies are...
PURPOSE
Treatment of advanced pancreatic cancer with a single therapeutic at a maximal dose has been largely ineffective at increasing survival. Combination therapies are commonly studied but often limited by toxicity. We previously showed that low-dose multiagent therapy with gemcitabine, docetaxel (taxotere), capecitabine (xeloda), and cisplatin (GTX-C) was safe, well tolerated, and effective (NCT01459614). Here, we hypothesize that adding irinotecan to GTX-C may improve survival with minimal toxicity.
EXPERIMENTAL DESIGN
Patients with treatment-naïve metastatic pancreatic adenocarcinoma were treated with gemcitabine, docetaxel (taxotere), capecitabine (xeloda), cisplatin, and irinotecan (GTX-CI). Treatment consisted of capecitabine 500 mg twice daily on days 1-14 and gemcitabine 300 to 500 mg/m, docetaxel 20 mg/m, cisplatin 15 to 20 mg/m, and irinotecan 20 to 60 mg/m on days 4 and 11 of a 21-day cycle. The primary objective was 9-month overall survival (OS). Secondary objectives included response rate (RR), disease control rate (DCR), progression-free survival (PFS), and OS.
RESULTS
The regimen was well tolerated. The recommended phase II dose was gemcitabine 500 mg/m, docetaxel 20 mg/m, capecitabine 500 mg po bid, cisplatin 20 mg/m, and irinotecan 20 mg/m. Median follow-up in phase II was 11.02 months (2.37-45.17). Nine-month OS rate was 57% [95% confidence interval (CI): (41-77)]. RR was 57% [95% CI: (37-75) 50% PR and 7% CR]. DCR was 87% [95% CI: (69-96)]. Median OS and PFS were 11.02 [95% CI: (8.54-21.09)] and 8.34 [95% CI: (6.34-NA)] months, respectively.
CONCLUSIONS
The addition of irinotecan to GTX-C was safe and well tolerated. While the study did not meet its primary objective, the responses were clinically meaningful using a well-tolerated regimen.
SIGNIFICANCE
We aimed to optimize the previously reported efficacious regimen of low-dose multiagent therapy with GTX-C for the treatment of metastatic pancreatic ductal adenocarcinoma by adding irinotecan. The primary objective was not met, but GTX-CI was well tolerated. The RR of 57%, median PFS of 8.3 months, median OS of 11 months, and 36-month OS rate of 19% suggest clinical benefit. Further optimization of this regimen is warranted.
Topics: Humans; Pancreatic Neoplasms; Docetaxel; Irinotecan; Capecitabine; Cisplatin; Gemcitabine; Adenocarcinoma
PubMed: 37645623
DOI: 10.1158/2767-9764.CRC-23-0230