-
Journal of Clinical Oncology : Official... Dec 2022To compare taxane maintenance chemotherapy, paclitaxel (P) and paclitaxel poliglumex (PP), with surveillance (S) in women with ovarian, peritoneal, or fallopian tube... (Randomized Controlled Trial)
Randomized Controlled Trial
Phase III Randomized Trial of Maintenance Taxanes Versus Surveillance in Women With Advanced Ovarian/Tubal/Peritoneal Cancer: A Gynecologic Oncology Group 0212:NRG Oncology Study.
PURPOSE
To compare taxane maintenance chemotherapy, paclitaxel (P) and paclitaxel poliglumex (PP), with surveillance (S) in women with ovarian, peritoneal, or fallopian tube (O/PC/FT) cancer who attained clinical complete response after first-line platinum-taxane therapy.
METHODS
Women diagnosed with O/PC/FT cancer who attained clinical complete response after first-line platinum-taxane-based chemotherapy were randomly allocated 1:1:1 to S or maintenance, P 135 mg/m once every 28 days for 12 cycles, or PP at the same dose and schedule. Overall survival (OS) was the primary efficacy end point.
RESULTS
Between March 2005 and January 2014, 1,157 individuals were enrolled. Grade 2 or worse GI adverse events were more frequent among those treated with taxane (PP: 20%, P: 27% S: 11%). Grade 2 or worse neurologic adverse events occurred more often with taxane treatment (PP: 46%, P: 36% S: 14%). At the fourth scheduled interim analysis, both taxane regimens passed the OS futility boundary and the Data Monitoring Committee approved an early release of results. With a median follow-up of 8.1 years, 653 deaths were reported; none were attributed to the study treatment. Median survival durations were 58.3, 56.8, and 60.0 months for S, P, and PP, respectively. Relative to S, the hazard of death for P was 1.091 (95% CI, 0.911 to 1.31; = .343) and for PP, it was 1.033 (95% CI, 0.862 to 1.24; = .725). The median times to first progression or death (PFS) were 13.4, 18.9, and 16.3 months for S, P, and PP, respectively. Hazard ratio = 0.801; 95% CI, 0.684 to 0.938; = .006 for P and hazard ratio = 0.854; 95% CI, 0.729 to 1.00; = .055 for PP.
CONCLUSION
Maintenance therapy with P and PP did not improve OS among patients with newly diagnosed O/tubal/peritoneal cancer, but may modestly increase PFS. GI and neurologic toxicities were more frequent in the taxane treatment arms.
Topics: Female; Humans; Platinum; Medical Futility; Neoplasms
PubMed: 35759733
DOI: 10.1200/JCO.22.00146 -
Current Pharmaceutical Design 2021Background and Introduction: Peripheral neuropathy is one of the most common dose-limiting side effects of solvent-based paclitaxel. Paclitaxel poliglumex (PPX) and... (Meta-Analysis)
Meta-Analysis
UNLABELLED
Background and Introduction: Peripheral neuropathy is one of the most common dose-limiting side effects of solvent-based paclitaxel. Paclitaxel poliglumex (PPX) and NK105 were developed to overcome the paclitaxel induced peripheral neuropathy. However, the incidence of peripheral neuropathy induced by PPX and NK105 was reported higher than solvent-based paclitaxel, but evidence remains inconsistent.
METHODS
The article was reported in accordance with PRISMA Guidelines (Registration number: CRD42021245313). We conducted a meta-analysis to compare the incidence and severity of peripheral neuropathy between solvent-based paclitaxel, PPX and NK105 mono-chemotherapy.
RESULTS
Results revealed that no significant difference exists between the incidence of all grade peripheral neuropathy among the solvent-based paclitaxel, PPX and NK105 treated groups. While, the incidence of high grade peripheral neuropathy induced by NK105 was lower than two other groups. Moreover, the overall survival was not improved in PPX compared with other groups. However, NK105 demonstrated significant longer overall survival in patients with cancer.
CONCLUSION
Current evidence suggests more attention should be paid to the paclitaxel poliglumex re-formulation.
Topics: Antineoplastic Agents, Phytogenic; Humans; Paclitaxel; Peripheral Nervous System Diseases; Polyglutamic Acid; Solvents
PubMed: 32940171
DOI: 10.2174/1381612826666200917145551 -
Anti-cancer Agents in Medicinal... 2019Cancer is a disease characterized by uncontrolled cell growth and proliferation. It has become a major health problem in the past decades and is now the second leading... (Review)
Review
BACKGROUND
Cancer is a disease characterized by uncontrolled cell growth and proliferation. It has become a major health problem in the past decades and is now the second leading cause of death globally. Although, there are different types of treatment such as chemotherapy, immune therapy, radiation, hormone therapy and targeted therapy used against cancer, they have possible side effects and significant deficiencies.
METHODS
This review aims to outline the benefits of medicinal plants and plant-derived products and highlight why they should be used as novel anti-cancer therapeutics. Electronic databases, including PubMed, Scopus, ScienceDirect, Cochrane library, and MedlinePlus were searched to summarize , and clinical studies on anticancer effects of medicinal plants and their bioactive compounds up-to-date.
RESULTS
In recent years, a number of medicinal plants have been administered to cancer patients in order to prevent and treat cancer as an alternative therapy. These plants were used because of their rich anticarcinogenic and chemoprotective potentials. In addition to these remarkable properties, these plants have less toxic anticancer, anti-tumor and anti-proliferation agents than traditional therapeutics. Nevertheless, only a small number of natural anti-tumor products including vinblastine, vincristine, podophyllotoxin, paclitaxel (Taxol) and camptothecin have been tested clinically, while vinflunine ditartrate, anhydrovinblastine, NK-611, tafluposide, paclitaxel poliglumex, combretastatins, salvicine, curcumin, indirubin, triptolide, homoharringtonine are still on trial.
CONCLUSION
Consequently, more effective anticancer compounds are identified during the clinical trials; these natural products could be a key source of antitumor agents in modern anticancer therapy. It is expected that novel anticancer phytopharmaceuticals produced from medicinal plants could be effectively used in prevention and therapy for the cancers.
Topics: Animals; Antineoplastic Agents, Phytogenic; Biological Products; Humans; Molecular Structure; Neoplasms; Plants, Medicinal
PubMed: 30582485
DOI: 10.2174/1871520619666181224121004 -
Wiley Interdisciplinary Reviews.... May 2018Chemotherapy for cancer treatment is limited by the excessive toxicity to normal tissues. The design of chemodrug-loaded nanoformulations provides a unique approach to... (Review)
Review
Chemotherapy for cancer treatment is limited by the excessive toxicity to normal tissues. The design of chemodrug-loaded nanoformulations provides a unique approach to improve the treatment efficacy while minimizing toxicity. Despite the numerous publications of nanomedicine for the last several decades, however, only a small fraction of the developed nanoformulations have entered clinical trials, with even fewer being approved for clinical application. Poly(l-glutamic acid)-paclitaxel (PG-TXL) belongs to the few formulations that reached phase III clinical trials. Unfortunately, the development of PG-TXL stopped in 2016 due to the inability to show significant improvement over current standard care. This review will provide an overview of the preclinical and clinical evaluations of PG-TXL, and discuss lessons to be learned from this ordeal. The precise identification of suitable patients for clinical trial studies, deep understanding of the mechanisms of action, and an effective academic-industry partnership throughout all phases of drug development are important for the successful bench-to-bedside translation of new nanoformulations. This article is categorized under: Implantable Materials and Surgical Technologies > Nanomaterials and Implants Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Biology-Inspired Nanomaterials > Peptide-Based Structures.
Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Clinical Trials as Topic; Drug Discovery; Drug Evaluation, Preclinical; Humans; Mice; Nanomedicine; Paclitaxel; Polyglutamic Acid; Research Design
PubMed: 28895304
DOI: 10.1002/wnan.1497 -
Scientific Reports Jun 2017The conventional chemotherapeutics could not be traced in vivo and provide timely feedback on the clinical effectiveness of drugs. In this study,...
The conventional chemotherapeutics could not be traced in vivo and provide timely feedback on the clinical effectiveness of drugs. In this study, poly(L-γ-glutamyl-glutamine)-paclitaxel (PGG-PTX), as a model polymer, was chemically conjugated with Gd-DTPA (Gd-diethylenetriaminepentaacetic acid), a T-contrast agent of MRI, to prepare a Gd-DTPA-conjugated PGG-PTX (PGG-PTX-DTPA-Gd) delivery system used for tumor theranostics. PGG-PTX-DTPA-Gd can be self-assembled to NPs in water with a z-average hydrodynamic diameter about 35.9 nm. The 3 T MRI results confirmed that the relaxivity of PGG-PTX-DTPA-Gd NPs (r = 18.98 mMS) was increased nearly 4.9 times compared with that of free Gd-DTPA (r = 3.87 mMS). The in vivo fluorescence imaging results showed that PGG-PTX-DTPA-Gd NPs could be accumulated in the tumor tissue of NCI-H460 lung cancer animal model by EPR effect, which was similar to PGG-PTX NPs. The MRI results showed that compared with free Gd-DTPA, PGG-PTX-DTPA-Gd NPs showed significantly enhanced and prolonged signal intensity in tumor tissue, which should be attributed to the increased relaxivity and tumor accumulation. PGG-PTX-DTPA-Gd NPs also showed effective antitumor effect in vivo. These results indicated that PGG-PTX-DTPA-Gd NPs are an effective delivery system for tumor theranostics, and should have a potential value in personalized treatment of tumor.
Topics: Animals; Cell Line, Tumor; Drug Delivery Systems; Gadolinium; Humans; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Paclitaxel; Pentetic Acid; Polyglutamic Acid; Theranostic Nanomedicine; Xenograft Model Antitumor Assays
PubMed: 28630436
DOI: 10.1038/s41598-017-03633-9 -
Journal of Controlled Release :... Mar 2017Neural cell adhesion molecule (NCAM) expression is known to be associated with an aggressive biological behavior, increased metastatic capacity and expression of...
Neural cell adhesion molecule (NCAM) expression is known to be associated with an aggressive biological behavior, increased metastatic capacity and expression of stem-cell markers in several tumor types. NCAM was also found to be expressed on tumor endothelial cells while forming new capillary-like tubes, but not on normal endothelial cells. An NCAM-targeted polymer-drug conjugate can be used both to target tumors expressing high levels of NCAM as well as the angiogenic vessels and cancer stem cells populations characterized by NCAM expression within tumors. Here, we describe the design, synthesis, physico-chemical characterization and the biological evaluation of an NCAM-targeted conjugate of polyglutamic acid with paclitaxel that was developed and evaluated on neuroblastoma, a high NCAM-expressing tumor. This conjugate inhibited tumor growth to a higher extent compared to the control conjugates and was less toxic than free paclitaxel. The dose of the conjugate could be increased at least twice than the maximum tolerated dose of paclitaxel to achieve better activity without aggravating toxicity. This work presents evidence that NCAM targeting can highly increase the efficacy of nanomedicines in the appropriate tumor models.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Carriers; Drug Delivery Systems; Human Umbilical Vein Endothelial Cells; Humans; Mice, SCID; Nanomedicine; Neural Cell Adhesion Molecules; Neuroblastoma; Paclitaxel; Peptides; Polyglutamic Acid
PubMed: 28159518
DOI: 10.1016/j.jconrel.2017.01.044 -
American Journal of Clinical Oncology Feb 2018Efficacy signals but substantial myelosuppression were demonstrated in a single arm phase II study of paclitaxel poliglumex (PPX) in combination with temozolomide (TMZ)... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Efficacy signals but substantial myelosuppression were demonstrated in a single arm phase II study of paclitaxel poliglumex (PPX) in combination with temozolomide (TMZ) and radiation therapy (RT) for first-line treatment of glioblastoma. The objective of this randomized phase II trial was to assess the efficacy and safety of single-agent PPX with RT (PPX/RT) versus TMZ with RT (TMZ/RT) for glioblastoma without O-methylguanine-DNA methyltransferase (MGMT) methylation.
MATERIALS AND METHODS
Patients with glioblastoma with unmethylated MGMT without prior chemotherapy or RT were eligible. Patients were randomly assigned 2:1 to PPX, 50 mg/m/wk for 6 weeks, or standard TMZ, with concurrent 60.0 Gy RT. One month after completion of chemoradiation all patients received standard maintenance TMZ. The primary endpoint was progression-free survival (PFS).
RESULTS
Of the 164 patients enrolled, 86 were MGMT unmethylated. Of these, 63 patients were randomized (42 to PPX/RT and 21 to TMZ/RT). Fifty-nine patients could be analyzed. The median PFS was 9 months in the PPX/RT group and 9.5 months in the TMZ/RT group (hazard ratio in the PPX/RT group, 1.10; 95% confidence interval, 0.79-2.08; P=0.75). Median overall survival was 16 versus 14.8 months for PPX/RT and TMZ/RT groups, respectively (hazard ratio, 1.44; 95% confidence interval, 0.75-2.77; P=0.27). In the PPX and TMZ groups 44% versus 22% of patients, respectively, experienced one or more grade 3 or higher toxicities during chemoradiation.
CONCLUSIONS
PPX/RT did not improve PFS or overall survival. This study provides an effective trial design for screening RT sensitizers in glioblastoma.
Topics: Academic Medical Centers; Adult; Aged; Aged, 80 and over; Brain Neoplasms; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Disease-Free Survival; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Female; Follow-Up Studies; Glioblastoma; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Paclitaxel; Polyglutamic Acid; Radiotherapy, Adjuvant; Single-Blind Method; Survival Analysis; Treatment Outcome; Tumor Suppressor Proteins; United States
PubMed: 26658237
DOI: 10.1097/COC.0000000000000247 -
JAMA Dermatology Nov 2015Patients with stage T2 multilesion angiosarcomas of the scalp and face that are larger than 10 cm demonstrate a 2-year survival rate of 0%. To our knowledge, major...
IMPORTANCE
Patients with stage T2 multilesion angiosarcomas of the scalp and face that are larger than 10 cm demonstrate a 2-year survival rate of 0%. To our knowledge, major therapeutic advances against this disease have not been reported for decades. Preclinical data indicate that blocking β-adrenergic signaling with propranolol hydrochloride disrupts angiosarcoma cell survival and xenograft angiosarcoma progression.
OBSERVATIONS
A patient presented with a β-adrenergic-positive multifocal stage T2 cutaneous angiosarcoma (≥20 cm) involving 80% of the scalp, left forehead, and left cheek, with no evidence of metastasis. The patient was immediately administered propranolol hydrochloride, 40 mg twice a day, as his workup progressed and treatment options were elucidated. Evaluation of the proliferative index of the tumor before and after only 1 week of propranolol monotherapy revealed a reduction in the proliferative index of the tumor by approximately 34%. A combination of propranolol hydrochloride, 40 mg 3 times a day, paclitaxel poliglumex, 2 mg/m2 infused weekly, and radiotherapy during the subsequent 8 months resulted in extensive tumor regression with no detectable metastases.
CONCLUSIONS AND RELEVANCE
Our data suggest that β-blockade alone substantially reduced angiosarcoma proliferation and, in combination with standard therapy, is effective for reducing the size of the tumor and preventing metastases. If successful, β-blockade could be the first major advancement in the treatment of angiosarcoma in decades.
Topics: Adrenergic beta-Antagonists; Antineoplastic Agents, Phytogenic; Combined Modality Therapy; Face; Hemangiosarcoma; Humans; Male; Middle Aged; Paclitaxel; Propranolol; Scalp; Skin Neoplasms; Treatment Outcome
PubMed: 26375166
DOI: 10.1001/jamadermatol.2015.2554 -
American Journal of Clinical Oncology Jun 2017For patients with high-grade glioma on clinical trials it is important to accurately assess time of disease progression. However, differentiation between...
OBJECTIVE
For patients with high-grade glioma on clinical trials it is important to accurately assess time of disease progression. However, differentiation between pseudoprogression (PsP) and progressive disease (PD) is unreliable with standard magnetic resonance imaging (MRI) techniques. Dynamic susceptibility contrast perfusion MRI (DSC-MRI) can measure relative cerebral blood volume (rCBV) and may help distinguish PsP from PD.
METHODS
A subset of patients with high-grade glioma on a phase II clinical trial with temozolomide, paclitaxel poliglumex, and concurrent radiation were assessed. Nine patients (3 grade III, 6 grade IV), with a total of 19 enhancing lesions demonstrating progressive enhancement (≥25% increase from nadir) on postchemoradiation conventional contrast-enhanced MRI, had serial DSC-MRI. Mean leakage-corrected rCBV within enhancing lesions was computed for all postchemoradiation time points.
RESULTS
Of the 19 progressively enhancing lesions, 10 were classified as PsP and 9 as PD by biopsy/surgery or serial enhancement patterns during interval follow-up MRI. Mean rCBV at initial progressive enhancement did not differ significantly between PsP and PD (2.35 vs. 2.17; P=0.67). However, change in rCBV at first subsequent follow-up (-0.84 vs. 0.84; P=0.001) and the overall linear trend in rCBV after initial progressive enhancement (negative vs. positive slope; P=0.04) differed significantly between PsP and PD.
CONCLUSIONS
Longitudinal trends in rCBV may be more useful than absolute rCBV in distinguishing PsP from PD in chemoradiation-treated high-grade gliomas with DSC-MRI. Further studies of DSC-MRI in high-grade glioma as a potential technique for distinguishing PsP from PD are indicated.
Topics: Adult; Aged; Biopsy; Brain; Brain Neoplasms; Cerebral Blood Volume; Contrast Media; Disease Progression; Female; Glioma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Grading; Neoplasm Recurrence, Local; Time Factors
PubMed: 25436828
DOI: 10.1097/COC.0000000000000156 -
American Journal of Clinical Oncology Oct 2014Paclitaxel poliglumex (PPX), a drug conjugate that links paclitaxel to poly-L-glutamic acid, is a potent radiation sensitizer. Prior studies in esophageal cancer have...
OBJECTIVES
Paclitaxel poliglumex (PPX), a drug conjugate that links paclitaxel to poly-L-glutamic acid, is a potent radiation sensitizer. Prior studies in esophageal cancer have demonstrated that PPX (50 mg/m/wk) can be administered with concurrent radiation with acceptable toxicity. The primary objective of this study was to determine the safety of the combination of PPX with temozolomide and concurrent radiation for high-grade gliomas.
METHODS
Eligible patients were required to have WHO grade 3 or 4 gliomas. Patients received weekly PPX (50 mg/m/wk) combined with standard daily temozolomide (75 mg/m) for 6 weeks with concomitant radiation (2.0 Gy, 5 d/wk for a total dose of 60 Gy).
RESULTS
Twenty-five patients were enrolled, 17 with glioblastoma and 8 with grade 3 gliomas. Seven of 25 patients had grade 4 myelosuppression. Hematologic toxicity lasted up to 5 months suggesting a drug interaction between PPX and temozolomide. For patients with glioblastoma, the median progression-free survival was 11.5 months and the median overall survival was 18 months.
CONCLUSIONS
PPX could not be safely combined with temozolomide due to grade 4 hematologic toxicity. However, the favorable progression-free and overall survival suggest that PPX may enhance radiation for glioblastoma. A randomized study of single agent PPX/radiation versus temozolomide/radiation for glioblastoma without MGMT methylation is underway.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brachytherapy; Brain Neoplasms; Chemoradiotherapy; Combined Modality Therapy; Dacarbazine; Disease-Free Survival; Female; Glioma; Humans; Male; Middle Aged; Paclitaxel; Polyglutamic Acid; Survival Analysis; Temozolomide
PubMed: 23388562
DOI: 10.1097/COC.0b013e31827de92b