Metronomic Therapy Research Articles

Oral Metronomic Therapy: An Effective Palliative Treatment Option for Epithelial Ovarian Cancer

Oral Metronomic Therapy: An Effective Palliative Treatment Option for Epithelial Ovarian Cancer

Metronomic Mild-Temperature Photothermal Therapy Modulating Tumor-Associated Macrophage Repolarization as a Neoadjuvant Immunotherapy

Metronomic Mild-Temperature Photothermal Therapy Modulating Tumor-Associated Macrophage Repolarization as a Neoadjuvant Immunotherapy

Body-worn and self-powered flexible optoelectronic device for metronomic photodynamic therapy

Photodynamic therapy (PDT) as a clinical method relies on appropriate light delivery to activate photosensitizers, usually necessitates the utilization of cumbersome surgical instruments and high irradiation intensity, along with the requirement for hospitalization. To extend the applicability of PDT beyond hospital for better patient mobility, we design a wearable and self-powered metronomic PDT (mPDT) system for chronic wound infection treatment. A flexible alternative current electroluminescent (ACEL) device is constructed through sandwiching an emissive layer between conductive hydrogel electrodes. This ACEL device works as a therapeutic patch by loading photosensitizer (PS) in its bottom hydrogel electrode, thus aviods the intravenous administration to patients. Under the triboelectric nanogenerator generated AC pulse, the electroluminescence produced from emissive layer can be absorbed by the PS-loaded electrode to generate reactive oxygen species for mPDT. Benefited from its arbitrary tailorability, this device can be customized into on-demand shapes and sizes. Using diabetic infected wound as a model condition, this ACEL mPDT device effectively eliminates drug-resistant bacteria and accelerates wound healing. Thus, the body-worn optoelectronic device successfully avoids the utilization of extracorporeal physical light and power sources, providing a promising strategy for convenient, user-friendly, and prolonged treatment of superficial diseases.

A phase III randomized, open-label study to establish the superiority of triple oral metronomic therapy (OMCT) used in addition to chemotherapy regimen (paclitaxel + carboplatin) over chemotherapy alone for the treatment of advanced unresectable head and neck cancer squamous cell cancer (HNSCC).

LBA6053 Background: Advanced HNSCC has poor outcomes and limited treatment options, especially in resource-constrained settings. Immunotherapy is affordable for less than 5% of patients in lower-middle-income countries (LMICs). Triple OMCT, employing low-dose continuous chemotherapy, shows promise, but its safety and efficacy along with chemotherapy remain unproven. We aimed to assess whether the addition of OMCT to first-line chemotherapy can improve overall survival (OS) as compared to chemotherapy alone. Methods: This phase 3 randomized, prospective, open-label, superiority design study enrolled patients with advanced HNSCC who were planned for palliative intent platinum-based chemotherapy. The patients were stratified for the site of the tumor and ECOG PS, and were randomly assigned 1:1 to receive either triple OMCT (Erlotinib 150 mg OD, Celecoxib 200 mg BD and Methotrexate 9mg/m2 once weekly) in addition to 3-weekly paclitaxel carboplatin (PC) chemotherapy (Arm A) or, PC chemotherapy alone (Arm B). Sample size calculation assumed no OS improvement with OMCT+PC (5% type I error, 80% type II error). The primary endpoint was OS, while secondary endpoints included PFS, quality of life (QoL) assessments, and safety. OS and PFS were analyzed via Kaplan-Meier and log-rank test; HR estimated via Cox proportional hazard models. QoL was assessed using EORTC QLQ-C30. The study was approved by Institutional Ethics Committee and registered with the Clinical Trials Registry India (CTRI/2022/10/046520). Results: Between Nov 02, 2022, and Dec 20, 2023, 238 patients were randomly assigned with 119 in each arm. Median age was 47 years, with 97.8% being males, and 78% of patients had ECOG PS 0-1. The median OS for patients in Arm A was 8.3 months (95% CI, 6.3-10.4) while it was 6.1 months (95% CI, 4.7-7.4), in Arm B (HR 0.63; 95% CI, 0.47–0.83; p=0.00011). The corresponding median PFS was 7.6 months (95% CI, 6.3-8.8) and 3.5 months (95% CI, 2.2-4.7) (HR, 2.79; 95% CI, 1.98-3.93; P<0.000). Significant differences in EORTC-C30 were found for the physical functioning domain between baseline and 1-month follow-up visit. PC chemotherapy combined with triple OMCT showed good tolerability, with common toxicities including fatigue (40.3%), and hyponatremia (25.4%), similar to the incidence observed with PC chemotherapy alone. Conclusions: This study demonstrates that the addition of triple OMCT to paclitaxel and carboplatin chemotherapy is an effective and safe treatment option for patients with advanced HNSCC in platinum-sensitive settings. This treatment option is particularly valuable in LMICs, where cetuximab and pembrolizumab are not feasible. Clinical trial information: CTRI/2022/10/046520 . [Table: see text]

Immune modulation of the liver metastatic colorectal cancer microenvironment via the oral CAPOX-mediated cGAS-STING pathway

We evaluated modulation of the immunosuppressive tumor microenvironment in both local and liver metastatic colorectal cancer (LMCC), focusing on tumor-associated macrophages, which are the predominant immunosuppressive cells in LMCC. We developed an orally administered metronomic chemotherapy regimen, oral CAPOX. This regimen combines capecitabine and a nano-micelle encapsulated, lysine-linked deoxycholate and oxaliplatin complex (OPt/LDC-NM). The treatment effectively modulated immune cells within the tumor microenvironment by activating the cGAS-STING pathway and inducing immunogenic cell death. This therapy modulated immune cells more effectively than did capecitabine monotherapy, the current standard maintenance chemotherapy for colorectal cancer. The macrophage-modifying effect of oral CAPOX was mediated via the cGAS-STING pathway. This is a newly identified mode of immune cell activation induced by metronomic chemotherapy. Moreover, oral CAPOX synergized with anti-PD-1 antibody (αPD-1) to enhance the T-cell–mediated antitumor immune response. In the CT26. CL25 subcutaneous model, combination therapy achieved a 91 % complete response rate with a confirmed memory effect against the tumor. This combination also altered the immunosuppressive tumor microenvironment in LMCC, which αPD-1 monotherapy could not achieve. Oral CAPOX and αPD-1 combination therapy outperformed the maximum tolerated dose for treating LMCC, suggesting metronomic therapy as a promising strategy.

To study the survival outcomes of uncommon recurrences among patients with cervical cancer compared with loco-regional and nodal recurrences at a tertiary care center in North East India – Bridging the knowledge gap in the existing literature.

BackgroundRecurrence rates of FIGO stage IB-IIA and IIB-IVA cervical cancer 28–64 respectively. There is a scarcity of data on the recurrence recurrence pattern for unusual sites and theirrecurrence pattern for unusual sites and its association with survival and prognosis. ObjectiveTo study overall survival in patients with distant metastasis compared to local and regional nodal metastasis. MethodsA retrospective study was done from 1/1/2017 to 30/12/22. Cervical cancer patients post primary treatments were included. Survival was analyzed with respect to 3 groups local, regional nodalconducted from 1/1/2017 to 30/12/22. Cervical cancer patients who had received primary post-primary treatments were included. Survival was analyzed with respect to three groups: local, regional nodal, and distant metastasis. Results225 patients had recurrences post-completion of primary treatment, of which 105 (46.6%)(46.6 %) had local, 46 (20.4%)(20.4 %) had regional nodal, and 74 (33.3%) had distant recurrences. The median time for recurrence in local, regional nodal, and atypical recurrences were 9, 9, and 13 months (p value - <0.05), respectively. Treatment included systemic chemotherapy 122 (54.2%), metronomic therapy 19 (8.4%), palliative radiotherapy 44 (19.5%), palliative surgery 8 (3.5%) and best supportive care 30 (13.3%) patients. Median Time to treatment-death of patients after recurrence in local, nodal and distant recurrences was 17.0 months, 18.0 months and 10.0 months respectively (p value - < 0.05). Overall Survival of patients after primary treatment with local, nodal and distant recurrences was 35.0 months, 47.0 months and 50.0 months respectively (p value <0.05). ConclusionLocal recurrence is most common, followed by regional, nodal, and distant recurrences. Overall survival post recurrence was lowest for distant recurrences and highest for local recurrences however overall survival after primary treatment completion was highest for distant recurrence due to the late presen; however, tation of distant recurrences.

Evaluation of Metronomic Therapy as a Low-Cost, Sustainable, Standard-of-Care Option in Desmoid Fibromatosis: Real-World Data From a Tertiary Care Center in India

PURPOSE Desmoid fibromatosis (DF) is a locally aggressive tumor with low mortality but significant morbidity. There is a lack of standard of care, and existing therapies are associated with significant barriers including access, cost, and toxicities. This study aimed to explore the efficacy and safety of the metronomic therapy (MT) in DF in a large, homogenous cohort from India. PATIENTS AND METHODS This study involved histologically confirmed DF cases treated with MT comprising vinblastine (6 mg) and methotrexate (15 mg) both once a week, and tamoxifen (40 mg/m2) in two divided doses once daily between 2002 and 2018. RESULTS There were 315 patients with a median age of 27 years; the commonest site was extremity (142 of 315; 45.0%). There were 159 (50.1%) male patients. Of the 123 (39.0%) prior treated patients, 119 had surgery. Of 315 patients, 263 (83.5%) received treatment at our institute (MT—151, 77—local treatment, 9—tyrosine kinase inhibitor, and 26 were observed). Among the MT cohort (n = 163, 61.2%), at a median follow-up of 36 (0.5-186) months, the 3-year progression-free and overall survival were 81.1% (95% CI, 74.3 to 88.4) and 99.2% (95% CI, 97.6 to 100), respectively. There were 35% partial responses. Ninety-two patients (56.4%) completed 1-year therapy, which was an independent prognosticator ( P &lt; .0001; hazard ratio, 0.177 [95% CI, 0.083 to 0.377]). MT was well tolerated. Predominant grade ≥3 toxicities were febrile neutropenia, 12 (7.4%) without any chemotoxicity-related death. The annual cost of MT was $130 US dollars. CONCLUSION The novel, low-cost MT qualifies as one of the effective, less toxic, sustainable, standard-of-care options for the treatment of DF with global reach and merits wide recognition.

Development of Thin-Film Light-Emitting Devices for Hyper Localized Photodynamic Therapy

In this study, we fabricated a thin-film light-emitting device to apply metronomic photodynamic therapy (PDT) in a weak light emitted by LED chips that showed the PDT effect at the cellular level. Thin-film light-emitting devices can operate an LED chip by the wireless power supply. This device has been developed by exploiting a flexible antenna coil made from Au nanoparticle ink printed on a 5-μm-thick poly(D, L-lactic acid) thin film. The weak light intensity of LED (10∼400 µW/cm2) can direct the cell death regions. Further quantification of mPDT at the cellular level as well as in vivo evaluation, will be carried out.

Proliferative verrucous leukoplakia/multifocal leukoplakia in patients with and without oral submucous fibrosis.

Oral submucous fibrosis (OSF) and proliferative verrucous leukoplakia (PVL) are established as oral potentially malignant disorders. Dual pathology of the two conditions is not commonly encountered in clinical practice. This study aims to present a case series of multifocal leukoplakia in patients with and without OSF to outline the clinical behavior and challenges in the management of this high-risk group in clinical practice. We retrospectively analyzed cases of six Indian patients (four with OSF) managed over a period of 5.5 to 13 years at the Government Dental College, Nagpur. Patient data consisting of age, gender, medical history, habits, clinical findings, and biopsy reports were recorded at the initial visit. During follow-up visits, the clinicopathological data were reassessed. When surgical intervention failed to arrest the disease or when surgery was contraindicated metronomic therapy with Folitrax 15 mg once a week and Celecoxib 100mg twice daily was initiated. All patients developed PVL after the initial pathology diagnosis of OSF or oral leukoplakia. Initial lesions were either homogenous or non-homogenous leukoplakia. All patients developed multiple recurrences, regional or systemic metastasis. Despite thorough interventions, the patients died of, or with the disease. The occurrence of two or more oral potentially malignant disorders poses challenges in patient management and possibly presents a higher risk of malignant transformation. More clinical trials are necessary to assess the benefits of metronomic therapy for patients diagnosed with aggressive PVL concurrently found with OSF.

The Rehabilitation Efficacy of the Novel Metronomic Breathing Technique for Gerontic Patients After Percutaneous Coronary Intervention for Acute Myocardial Infarction-A Pilot Study.

The respiratory rehabilitation technique is a crucial component of early cardiac recovery in geriatric patients with acute myocardial infarction (AMI). This study primarily investigated the effectiveness of a novel respiratory rehabilitation technique, metronomic breathing (MB), on geriatric patients after percutaneous coronary intervention for AMI and compliance with home-based rehabilitation compared to traditional respiratory rehabilitation. From June 2022 to March 2023, 75 acute myocardial infarction (AMI) patients admitted to the Shanghai Tenth People's Hospital Cardiovascular Department were consecutively enrolled. Ultimately, 46 patients completed the follow-up in this study-26 in the MB group and 20 in the control group-who underwent the novel MB technique and conventional abdominal breathing training. The primary endpoint of the study was left ventricular function measured by noninvasive hemodynamics three months after discharge. The secondary endpoints were compliance and quality of life after three months of home rehabilitation. After the intervention, several cardiac functional parameters (SV, SVI, CO, CI, LCW, and LCWI), myocardial contractility parameters (VI), and systemic vascular resistance parameters (SVR and SVRI) were significantly greater in the MB group than in the preintervention group (P < 0.05). Furthermore, post-treatment, the MB group exhibited greater SV, SVI, CO, CI, and VI; lower SVR, SVRI, and SBP; and a lower readmission rate three months later than did the control group. The SF-36 scores after three months of MB intervention, PE, BP, GH, VT, SF, RE, and MH, were all significantly greater than those before treatment (P < 0.05). Moreover, the MB group displayed greater compliance with home-based cardiac rehabilitation (P < 0.05). Compared to conventional respiratory rehabilitation training methods, short-term metronomic respiratory therapy is more effective for reducing systemic vascular resistance, enhancing left ventricular ejection function, enhancing quality of life, and increasing home-based rehabilitation compliance in geriatric patients following AMI with PCI.

Muscarinic Receptors as Targets for Metronomic Therapy in Ovarian Cancer

Aim: In this study, the effects of muscarinic acetylcholine receptor (mAChR) agonist carbachol on the proliferation of cisplatin-resistant (A2780cis) and cisplatin-free (SKOV-3) ovarian cancer cell line were for the first time investigated to further evaluate the potential therapeutic effect of metronomic chemotherapy.&#x0D; Material and Methods: The inhibitory effect of carbachol on cell proliferation was detected using the xCELLigence Real-Time Cell Analyzer (RTCA) dual plate (DP) system. A preliminary study was conducted to determine the dose of carbachol 100 µM, cisplatin 1 µM, and two combination studies were carried out with 100 µM carbachol + cisplatin 1 µM and 100 µM carbachol + 10 µM atropine, over cancer cells without drugs was used as the control group. The cell proliferation curve was monitored for 96 hours. The cell index value of inhibition in cell proliferation was automatically measured every hour for each well using RTCA 1.2.1 software.&#x0D; Results: Co-administration of carbachol with cisplatin caused a decrease in cell number in both A2780cis and SKOV-3 cell lines in a time-dependent manner (p

The effectiveness of stereotactic irradiation followed by metronomic MEMMAT therapy in children with oligometastatic recurrent medulloblastoma

Low survival rates in children with recurrent medulloblastoma (MB) necessitate the search for new therapeutic approaches as alternatives to the existing treatment standards. Favorable dosimetric characteristics of stereotactic radiation techniques justify the use of such treatments for local radiation control in children with oligometastatic recurrent MB. Given the constant risk of metastatic dissemination and in order to potentiate response to radiation therapy and improve progression-free survival, metronomic molecular-targeted antiangiogenic therapy (MEMMAT, Medulloblastoma European Multitarget Metronomic AntiAngiogenic Trial) can be considered in children with recurrent/progressive MB. Here, we report 2 clinical cases that demonstrate the effectiveness of the treatment approach involving stereotactic irradiation followed by the metronomic MEMMAT regimen for oligometastatic recurrent MB in pediatric patients. The patients’ parents gave consent to the use of their child's data, including photographs, for research purposes and in publications.

Tazemetostat in the therapy of pediatric INI1-negative malignant rhabdoid tumors

Rhabdoid tumors are aggressive tumors that may arise in the kidney, soft tissue, central nervous system, or other organs. They are defined by SMARCB1 (INI1) or SMARCA4 alterations. Often, very young children are affected, and the prognosis is dismal. Four patients with primary atypical teratoid rhabdoid tumor (AT/RT, a rhabdoid tumor in the central nervous system) were treated by resection and high dose chemotherapy. Tazemetostat was introduced after completion of chemotherapy. Three patients have achieved an event free survival of 32, 34, and 30 months respectively. One progressed and died. His overall survival was 20 months. One patient was treated for a relapsed atypical teratoid rhabdoid tumor. The treatment combined metronomic therapy, radiotherapy, tazemetostat and immunotherapy. This patient died of disease progression, with an overall survival of 37 months. One patient was treated for a rhabdoid tumor of the ovary. Tazemetostat was given as maintenance after resection, chemotherapy, and radiotherapy, concomitantly with immunotherapy. Her event free survival is 44 months. Only approximately 40% of patients with rhabdoid tumors achieve long-term survival. Nearly all relapses occur within two years from diagnosis. The event free survival of four of the six patients in our cohort has exceeded this timepoint. Tazemetostat has been mostly tested as a single agent in the relapsed setting. We present promising results when applied as maintenance or add on in the first line treatment.

Metronomic Chemotherapy in Oral Cancer: A Review.

Treatment of locally advanced oral cancer requires multidisciplinary care, including surgery, radiotherapy, and chemotherapy, which varies based on the stage of the disease, site of involvement, and surgical access. Oral cancer usually presents with an increased recurrence rate and potential for distant metastatic spread. It confers a poor prognosis with a 50% mortality rate after five years. Oral metronomic chemotherapy aims to achieve higher patient compliance due to its ease of administration, lower dosage, and lesser side effects than conventional IV regimens of platinum-based drugs. In this review, we have summarized the relevant literature to benefit the readers regarding the potential application of metronomic therapy in the management of oral cancer.

ANGI-10. METRONOMIC 5 DRUG ANTI-ANGIOGENESIS THERAPY FOR RECURRENT EPENDYMOMA

Abstract Low dose continuous (metronomic) anti-angiogenesis therapy is a treatment regimen currently under investigation for chemo-refractory tumors to target tumor vasculature. This effect has been shown to improve survival in primary brain tumors such as medulloblastoma. The Dana Farber Antiangiogenic Chemotherapy Phase II Trial and MEMMAT trial are investigations into outcomes of metronomic anti-angiogenesis therapy for children with recurrent ependymoma, among other primary brain tumors. We retrospectively report 9 pediatric patients diagnosed between the ages of 1 and 8 with surgery and radiation refractory posterior fossa ependymoma that were treated with 5 drug metronomic anti-angiogenesis therapy including celecoxib, thalidomide, fenofibrate, and alternating low dose etoposide and cyclophosphamide. For one patient, we added bevacizumab every other week. 7 patients had anaplastic presentation of ependymoma. All patients either had gross total resection or multiple subtotal resections. Tumor markers include GFAP, S100, EMA, OLIG 2, CD99, and Ki-67. Side effects were primarily hematologic but also included muscle pain, constipation, and dizziness, however treatment was tolerated well overall. The primary reason for stopping treatment early was progression of disease, no patients stopped therapy for side effects. There was no change in response to therapy based on tumor markers found. 2-year survival was 78% and 2-year progression free survival was 56%. 3/9 patients have no recurrent disease, two of these patients had anaplastic ependymoma and 1 presented with metastatic disease to the spine. We show improved outcomes with a minimal side effect profile for metronomic anti-angiogenesis therapy in pediatric patients with recurrent ependymoma refractory to surgical and radiation therapy.

Sustained Survival Benefit in Recurrent Medulloblastoma by a Metronomic Antiangiogenic Regimen

Medulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen. To evaluate the response rate of pediatric patients with medulloblastoma recurrence using an antiangiogenic metronomic combinatorial approach (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial [MEMMAT]). This phase 2, investigator-initiated, multicenter nonrandomized controlled trial assessed 40 patients with relapsed or refractory medulloblastoma without a ventriculoperitoneal shunt who were younger than 20 years at original diagnosis. Patients were enrolled between April 1, 2014, and March 31, 2021. Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose (metronomic) oral etoposide and cyclophosphamide, supplemented by intravenous bevacizumab and intraventricular therapy consisting of alternating etoposide and cytarabine. The primary end point was response after 6 months of antiangiogenic metronomic therapy. Secondary end points included progression-free survival (PFS), overall survival (OS), and quality of life. Adverse events were monitored to assess safety. Of the 40 patients (median [range] age at treatment start, 10 [4-17] years; 25 [62.5%] male) prospectively enrolled, 23 (57.5%) achieved disease control after 6 months of treatment, with a response detected in 18 patients (45.0%). Median OS was 25.5 months (range, 10.9-40.0 months), and median PFS was 8.5 months (range, 1.7-15.4 months). Mean (SD) PFS at both 3 and 5 years was 24.6% (7.9%), while mean (SD) OS at 3 and 5 years was 43.6% (8.5%) and 22.6% (8.8%), respectively. No significant differences in PFS or OS were evident based on molecular subgroup analysis or the number of prior recurrences. In patients demonstrating a response, mean (SD) overall 5-year PFS was 49.7% (14.3%), and for patients who remained progression free for the first 12 months of treatment, mean (SD) 5-year PFS was 66.7% (16.1%). Treatment was generally well tolerated. Grade 3 to 4 treatment-related adverse events included myelosuppression, infections, seizures, and headaches. One heavily pretreated patient with a third recurrence died of secondary acute myeloid leukemia. This feasible and well-tolerated MEMMAT combination regimen demonstrated promising activity in patients with previously irradiated recurrent medulloblastoma. Given these results, this predominantly oral, well-tolerated, and outpatient treatment warrants further evaluation. ClinicalTrials.gov Identifier: NCT01356290.

Gemcitabine effects on tumor microenvironment of pancreatic ductal adenocarcinoma: Special focus on resistance mechanisms and metronomic therapies

Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest malignancies, with dismal survival rates and extremely prevalent chemoresistance. Gemcitabine is one of the primary treatments used in treating PDACs, but its benefits are limited due to chemoresistance, which could be attributed to interactions between the tumor microenvironment (TME) and intracellular processes. In preclinical models, certain schedules of administration of gemcitabine modulate the TME in a manner that does not promote resistance. Metronomic therapy constitutes a promising strategy to overcome some barriers associated with current PDAC treatments. This review will focus on gemcitabine's mechanism in treating PDAC, combination therapies, gemcitabine's interactions with the TME, and gemcitabine in metronomic therapies.

Oral metronomic therapy of pancreatic cancer with gemcitabine and paclitaxel co-loaded in lecithin-based Self-Nanoemulsifying preconcentrate (LBSNEP)

This study aimed to evaluate gemcitabine (GEM)/paclitaxel (PTX) co-loaded into a lecithin-based self-nanoemulsifying preconcentrate (LBSNEP) orally administered in a metronomic therapeutic manner against pancreatic cancer. LBSNEP was developed and evaluated, composed of Caproyl 90, Tween80, lecithin, TPGS, and propyl glycol at a ratio of 20:20:30:5:25, resulting in a droplet diameter of approximately 180 nm. Cell viability studies on MIA PaCa-2 demonstrated a synergetic effect at a proportion of 1:2 between PTX and GEM. Additionally, LBSNEP and baicalein (BAI) were demonstrated to prevent GEM from being deaminated by cytidine deaminase. The combination of GEM, PTX, and BAI in the LBSNEP showed good dissolution in simulated gastric fluid. The pharmacokinetic study conducted on rats showed that co-administration of GEM, PTX, and BAI in the LBSNEP enhanced the respective relative oral bioavailability levels of GEM and PTX by 1.5- and 2-fold, respectively, compared to the solution group. The tumor inhibition study was conducted with metronomic therapy at a low daily dose compared to conventional therapy at a higher dose every 3 days. Results indicated that oral metronomic delivery of GEM/PTX/BAI LBSNEP could inhibit tumor growth during administration phase, and that there were similar tumor volumes compared to traditional chemotherapy at day 28 even if the dose of metronomic chemotherapy was 2.2-fold less than that of the latter. In conclusion, a self-nanoemulsifying drug-delivery system for the oral delivery of GEM, PTX, and BAI in a metronomic manner enhanced the therapeutic effect on pancreatic cancer, providing an alternative option for chemotherapy.

A self-powered wireless detachable drug/light injector for metronomic photodynamic therapy in cancer treatment

Cancer is a growing global health concern, and photodynamic therapy (PDT) has emerged as a promising technology with minimal side effects for cancer treatment. Miniaturized PDT devices that offer a flexible and convenient strategy for the low-dose delivery of light or drugs are needed to replace invasive optical fibers. Here, we present a self-powered, wireless, and detachable drug/light injector that conforms to the properties of metronomic PDT for cancer treatment. The device comprises a semi-invasive pedestal with a micro light emitting diode (μ-LED) and a syringe needle, and a detachable actuator that contains a drug reservoir, a thermally-driven pump, and a wireless control circuit. The two parts are magnetically attracted to each other, and the detachable actuator can be conveniently replaced or refilled with drugs. The device can be wirelessly controlled to deliver on-demand dosages of drugs and light into the tumor under the skin. Additionally, we further demonstrate that the device can in principle be partially self-powered using body motion energy upon connection to different piezoelectric nanogenerators. In-vitro and in-vivo experiments on mice have demonstrated the feasibility of the device's therapeutic regimen for implementing metronomic PDT. The average volume of tumors in the treatment group was reduced by 57.4 % compared to the control group. This device has potential applications in future clinical cancer treatment and can expand the scope of self-powered systems for biomedical engineering.

Phase 3 randomized study for evaluation of physician choice Rx and triple metronomic as second-line therapy in head and neck cancer (CRSF 2021-HN-001).

LBA6004 Background: There are multiple options of treatment in second-line therapy in locally advanced head and neck squamous cell carcinoma (LAHNSCC) with recurrent or metastatic disease. However triple metronomic chemotherapy is oral, affordable, and requires minimal resources. Hence in this study, we compared NCCN-recommended physician choice of standard systemic therapy versus triple metronomic therapy in the second-line treatment of head and neck cancer. Methods: This was a phase 3, multicentric (16 sites), randomized study with a superiority design that was approved by the institutional ethics committees and registered with CTRI (CTRI/2021/08/036002) conducted in India under the aegis of Cancer Research Statistics Foundation. The study recruited LAHNSCC with a recurrent and metastatic disease that either was platinum-refractory or was planned for second-line chemotherapy. The key inclusion criteria were: Age ≥18 years, ECOG PS 0-2, and the presence of normal hematological and biochemical parameters. These patients underwent 1:1 central stratified randomization (Stratification - site of disease &amp; ECOG PS) to either triple metronomic chemotherapy (methotrexate 9 mg/m2 PO weekly, celecoxib 200 mg PO twice daily and erlotinib 150 mg PO once daily) or physician choice therapy ( nivolumab or pembrolizumab or cetuximab or taxane or afatinib or 5-FU or capecitabine). The study drugs were administered either till disease progression or the development of intolerable side effects. The primary endpoint of the study is overall survival (OS). The secondary endpoints are adverse events (CTCAE version 5.0), progression-free survival (PFS), and quality of life (EORTC). The sample size required was 114. The OS and PFS were estimated using Kaplan-Meier method and were compared using the log-rank test. Cox proportional hazard model was constructed for the calculation of the hazard ratio. The adverse events were compared using Fisher's test. A p-value of 0.05 was considered significant. Results: At a median follow-up of 258 (95% CI 209-306) days.The median overall survival of the triple metronomic chemotherapy was 181 days (95%CI 142.7-219.2) versus 123 days (95%CI 94-152) in the physician choice therapy arm (P=.0.002). The corresponding hazard ratio of death was 0.58 (95%CI 0.33-0.79, P=0.003). The 6-month OS was 52.9% (95%CI 36.9-65.1) versus 14.8% (95%CI 6.4-26.4). The median progression-free survival was 120 days (95%CI 89.2-150.8) versus 70 days (95% CI 58.2-81.8) in metronomic chemotherapy and in the physician choice therapy arms respectively (P=0.000). The corresponding hazard ratio of progression was 0.5 (95%CI 0.33-0.74, P=0.001). Conclusions: In this phase 3 multicentric study, triple metronomic chemotherapy as second-line therapy had an overall survival and progression-free survival advantage over NCCN-recommended physician choice therapy. Clinical trial information: CTRI/2021/08/036002 .