Nanoformulations-Based Metronomic Chemotherapy: Mechanism, Challenges, Recent Advances, and Future Perspectives
Abstract
:1. Introduction
1.1. Methodology
1.2. Conventional Chemotherapy and Its Limitation
2. Metronomic Chemotherapy
2.1. Mechanism of Action
2.1.1. Angiogenesis Inhibition
2.1.2. Triggering of Immunity
2.1.3. Initiation of Tumor Dormancy
2.2. Chemotherapeutic Difference: Conventional and Metronomic
2.3. Nanoformulations-Based MCT in Pre-Clinical Setting
2.4. MCT in Clinical Practice
2.4.1. Breast Cancer
2.4.2. Non-Small Cell Lung Carcinoma
2.4.3. Colorectal Cancer
2.4.4. Prostate Cancer
2.4.5. Gastroesophageal Cancer
2.4.6. Pancreatic Cancer
2.5. MCT as Maintenance Therapy
2.6. MCT as Targeted Therapy
3. Recent Advances and Challenges
4. Future Perspectives
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef] [PubMed]
- Panth, N.; Manandhar, B.; Paudel, K.R. Anticancer Activity of Punica granatum (Pomegranate): A Review. Phytother. Res. 2017, 31, 568–578. [Google Scholar] [CrossRef] [PubMed]
- Allemani, C.; Matsuda, T.; Di Carlo, V.; Harewood, R.; Matz, M.; Nikšić, M.; Bonaventure, A.; Valkov, M.; Johnson, C.J.; Estève, J.; et al. Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): Analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet 2018, 391, 1023–1075. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gurney, J.; Stanley, J.; McLeod, M.; Koea, J.; Jackson, C.; Sarfati, D. Disparities in Cancer-Specific Survival Between Māori and Non-Māori New Zealanders, 2007–2016. JCO Glob. Oncol. 2020, 6, 766–774. [Google Scholar] [CrossRef] [PubMed]
- DeVita, V.T., Jr.; Chu, E. A history of cancer chemotherapy. Cancer Res. 2008, 68, 8643–8653. [Google Scholar] [CrossRef] [Green Version]
- Pangeni, R.; Choi, J.U.; Panthi, V.K.; Byun, Y.; Park, J.W. Enhanced oral absorption of pemetrexed by ion-pairing complex formation with deoxycholic acid derivative and multiple nanoemulsion formulations: Preparation, characterization, and in vivo oral bioavailability and anticancer effect. Int. J. Nanomed. 2018, 13, 3329–3351. [Google Scholar] [CrossRef] [Green Version]
- Wysocki, P.J.; Lobacz, M.; Potocki, P.; Kwinta, L.; Michalowska-Kaczmarczyk, A.; Slowik, A.; Konopka, K.; Buda-Nowak, A. Metronomic Chemotherapy Based on Topotecan or Topotecan and Cyclophosphamide Combination (CyTo) in Advanced, Pretreated Ovarian Cancer. Cancers 2023, 15, 1067. [Google Scholar] [CrossRef]
- Buda-Nowak, A.; Kwinta, L.; Potocki, P.; Michalowska-Kaczmarczyk, A.; Slowik, A.; Konopka, K.; Streb, J.; Koniewski, M.; Wysocki, P.J. Metronomic Chemo-Endocrine Therapy (FulVEC) as a Salvage Treatment for Patients with Advanced, Treatment-Refractory ER+/HER2-Breast Cancer-A Retrospective Analysis of Consecutive Patients Data. J. Clin. Med. 2023, 12, 1350. [Google Scholar] [CrossRef]
- Senapati, S.; Mahanta, A.K.; Kumar, S.; Maiti, P. Controlled drug delivery vehicles for cancer treatment and their performance. Signal Transduct. Target. Ther. 2018, 3, 7. [Google Scholar] [CrossRef] [Green Version]
- Scharovsky, O.G.; Mainetti, L.E.; Rozados, V.R. Metronomic chemotherapy: Changing the paradigm that more is better. Curr. Oncol. 2009, 16, 7–15. [Google Scholar] [CrossRef] [Green Version]
- Liu, J.; He, M.; Wang, Z.; Li, Q.; Xu, B. Current Research Status of Metronomic Chemotherapy in Combination Treatment of Breast Cancer. Oncol. Res. Treat. 2022, 45, 681–692. [Google Scholar] [CrossRef]
- Maeda, H.; Wu, J.; Sawa, T.; Matsumura, Y.; Hori, K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: A review. J. Control. Release 2000, 65, 271–284. [Google Scholar] [CrossRef]
- Koo, H.; Huh, M.S.; Sun, I.C.; Yuk, S.H.; Choi, K.; Kim, K.; Kwon, I.C. In vivo targeted delivery of nanoparticles for theranosis. Acc. Chem. Res. 2011, 44, 1018–1028. [Google Scholar] [CrossRef]
- Li, Y.; Maciel, D.; Rodrigues, J.; Shi, X.; Tomas, H. Biodegradable Polymer Nanogels for Drug/Nucleic Acid Delivery. Chem. Rev. 2015, 115, 8564–8608. [Google Scholar] [CrossRef]
- Li, M.; Zhao, G.; Su, W.K.; Shuai, Q. Enzyme-Responsive Nanoparticles for Anti-tumor Drug Delivery. Front. Chem. 2020, 8, 647. [Google Scholar] [CrossRef] [PubMed]
- Ding, M.; Zhang, Y.; Li, J.; Pu, K. Bioenzyme-based nanomedicines for enhanced cancer therapy. Nano Converg. 2022, 9, 7. [Google Scholar] [CrossRef] [PubMed]
- Chang, T.M.S. ARTIFICIAL CELL evolves into nanomedicine, biotherapeutics, blood substitutes, drug delivery, enzyme/gene therapy, cancer therapy, cell/stem cell therapy, nanoparticles, liposomes, bioencapsulation, replicating synthetic cells, cell encapsulation/scaffold, biosorbent/immunosorbent haemoperfusion/plasmapheresis, regenerative medicine, encapsulated microbe, nanobiotechnology, nanotechnology. Artif. Cells Nanomed. Biotechnol. 2019, 47, 997–1013. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Munzone, E.; Colleoni, M. Clinical overview of metronomic chemotherapy in breast cancer. Nat. Rev. Clin. Oncol. 2015, 12, 631–644. [Google Scholar] [CrossRef] [PubMed]
- Banys-Paluchowski, M.; Ruckhaberle, E.; Schutz, F.; Krawczyk, N.; Fehm, T. Metronomic Chemotherapy for Primary Non-Metastatic Breast Cancer-a Systematic Review of the Literature. Geburtshilfe Frauenheilkd. 2017, 77, 142–148. [Google Scholar] [CrossRef] [Green Version]
- Malik, P.S.; Raina, V.; Andre, N. Metronomics as maintenance treatment in oncology: Time for chemo-switch. Front. Oncol. 2014, 4, 76. [Google Scholar] [CrossRef] [Green Version]
- She, L.; Tian, K.; Han, J.; Zuo, W.; Wang, Z.; Zhang, N. Cost-effectiveness analysis of metronomic capecitabine as adjuvant chemotherapy in locoregionally advanced nasopharyngeal carcinoma. Front. Oncol. 2022, 12, 904372. [Google Scholar] [CrossRef] [PubMed]
- Frei, E., 3rd; Canellos, G.P. Dose: A critical factor in cancer chemotherapy. Am. J. Med. 1980, 69, 585–594. [Google Scholar] [CrossRef] [PubMed]
- Hanna, N.; Einhorn, L.H. Testicular cancer: A reflection on 50 years of discovery. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2014, 32, 3085–3092. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- May, T.; Goldstein, D.P.; Berkowitz, R.S. Current chemotherapeutic management of patients with gestational trophoblastic neoplasia. Chemother. Res. Pract. 2011, 2011, 806256. [Google Scholar] [CrossRef]
- Pangeni, R.; Panthi, V.K.; Yoon, I.S.; Park, J.W. Preparation, Characterization, and In Vivo Evaluation of an Oral Multiple Nanoemulsive System for Co-Delivery of Pemetrexed and Quercetin. Pharmaceutics 2018, 10, 158. [Google Scholar] [CrossRef] [Green Version]
- Wang, X.; Zhang, H.; Chen, X. Drug resistance and combating drug resistance in cancer. Cancer Drug Resist. 2019, 2, 141–160. [Google Scholar] [CrossRef] [Green Version]
- Phi, L.T.H.; Sari, I.N.; Yang, Y.G.; Lee, S.H.; Jun, N.; Kim, K.S.; Lee, Y.K. Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment. Stem Cells Int. 2018, 2018, 5416923. [Google Scholar] [CrossRef] [Green Version]
- Peetla, C.; Vijayaraghavalu, S.; Labhasetwar, V. Biophysics of cell membrane lipids in cancer drug resistance: Implications for drug transport and drug delivery with nanoparticles. Adv. Drug Deliv. Rev. 2013, 65, 1686–1698. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hanahan, D.; Bergers, G.; Bergsland, E. Less is more, regularly: Metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J. Clin. Investig. 2000, 105, 1045–1047. [Google Scholar] [CrossRef]
- Maiti, R. Metronomic chemotherapy. J. Pharmacol. Pharmacother. 2014, 5, 186–192. [Google Scholar] [CrossRef] [Green Version]
- Cazzaniga, M.E.; Cordani, N.; Capici, S.; Cogliati, V.; Riva, F.; Cerrito, M.G. Metronomic Chemotherapy. Cancers 2021, 13, 2236. [Google Scholar] [CrossRef]
- Banchi, M.; Fini, E.; Crucitta, S.; Bocci, G. Metronomic Chemotherapy in Pediatric Oncology: From Preclinical Evidence to Clinical Studies. J. Clin. Med. 2022, 11, 6254. [Google Scholar] [CrossRef]
- Bocci, G.; Nicolaou, K.C.; Kerbel, R.S. Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs. Cancer Res. 2002, 62, 6938–6943. [Google Scholar]
- Zitvogel, L.; Apetoh, L.; Ghiringhelli, F.; Kroemer, G. Immunological aspects of cancer chemotherapy. Nat. Rev. Immunol. 2008, 8, 59–73. [Google Scholar] [CrossRef] [PubMed]
- Kono, K.; Kawaida, H.; Takahashi, A.; Sugai, H.; Mimura, K.; Miyagawa, N.; Omata, H.; Fujii, H. CD4(+)CD25high regulatory T cells increase with tumor stage in patients with gastric and esophageal cancers. Cancer Immunol. Immunother. 2006, 55, 1064–1071. [Google Scholar] [CrossRef] [PubMed]
- Lutsiak, M.E.; Semnani, R.T.; De Pascalis, R.; Kashmiri, S.V.; Schlom, J.; Sabzevari, H. Inhibition of CD4(+)25 +T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 2005, 105, 2862–2868. [Google Scholar] [CrossRef]
- Bergers, G.; Benjamin, L.E. Tumorigenesis and the angiogenic switch. Nat. Rev. Cancer 2003, 3, 401–410. [Google Scholar] [CrossRef]
- Bahl, A.; Bakhshi, S. Metronomic chemotherapy in progressive pediatric malignancies: Old drugs in new package. Indian J. Pediatr. 2012, 79, 1617–1622. [Google Scholar] [CrossRef] [PubMed]
- Weitman, S.D.; Glatstein, E.; Kamen, B.A. Back to the basics: The importance of concentration x time in oncology. J. Clin. Oncol. 1993, 11, 820–821. [Google Scholar] [CrossRef]
- Lien, K.; Georgsdottir, S.; Sivanathan, L.; Chan, K.; Emmenegger, U. Low-dose metronomic chemotherapy: A systematic literature analysis. Eur. J. Cancer 2013, 49, 3387–3395. [Google Scholar] [CrossRef]
- Simsek, C.; Esin, E.; Yalcin, S. Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience. J. Oncol. 2019, 2019, 5483791. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pasquier, E.; Andre, N.; Braguer, D. Targeting microtubules to inhibit angiogenesis and disrupt tumour vasculature: Implications for cancer treatment. Curr. Cancer Drug Targets 2007, 7, 566–581. [Google Scholar] [CrossRef] [PubMed]
- Kemp, J.A.; Kwon, Y.J. Cancer nanotechnology: Current status and perspectives. Nano Converg. 2021, 8, 34. [Google Scholar] [CrossRef] [PubMed]
- Rasool, M.; Malik, A.; Waquar, S.; Arooj, M.; Zahid, S.; Asif, M.; Shaheen, S.; Hussain, A.; Ullah, H.; Gan, S.H. New challenges in the use of nanomedicine in cancer therapy. Bioengineered 2022, 13, 759–773. [Google Scholar] [CrossRef] [PubMed]
- Kerbel, R.; Folkman, J. Clinical translation of angiogenesis inhibitors. Nat. Rev. Cancer 2002, 2, 727–739. [Google Scholar] [CrossRef]
- Folkman, J. Tumor angiogenesis: Therapeutic implications. N. Engl. J. Med. 1971, 285, 1182–1186. [Google Scholar] [CrossRef]
- Miller, K.D.; Sweeney, C.J.; Sledge, G.W., Jr. Redefining the target: Chemotherapeutics as antiangiogenics. J. Clin. Oncol. 2001, 19, 1195–1206. [Google Scholar] [CrossRef]
- Browder, T.; Butterfield, C.E.; Kraling, B.M.; Shi, B.; Marshall, B.; O’Reilly, M.S.; Folkman, J. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 2000, 60, 1878–1886. [Google Scholar] [PubMed]
- Klement, G.; Baruchel, S.; Rak, J.; Man, S.; Clark, K.; Hicklin, D.J.; Bohlen, P.; Kerbel, R.S. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J. Clin. Investig. 2000, 105, R15–R24. [Google Scholar] [CrossRef] [Green Version]
- Maharjan, R.; Choi, J.U.; Kweon, S.; Pangeni, R.; Lee, N.K.; Park, S.J.; Chang, K.Y.; Park, J.W.; Byun, Y. A novel oral metronomic chemotherapy provokes tumor specific immunity resulting in colon cancer eradication in combination with anti-PD-1 therapy. Biomaterials 2022, 281, 121334. [Google Scholar] [CrossRef]
- Maharjan, R.; Subedi, L.; Pangeni, R.; Jha, S.K.; Kang, S.H.; Chang, K.Y.; Byun, Y.; Choi, J.U.; Park, J.W. Metronomic delivery of orally available pemetrexed-incorporated colloidal dispersions for boosting tumor-specific immunity. Drug Deliv. 2021, 28, 2313–2328. [Google Scholar] [CrossRef]
- Choi, J.U.; Maharjan, R.; Pangeni, R.; Jha, S.K.; Lee, N.K.; Kweon, S.; Lee, H.K.; Chang, K.Y.; Choi, Y.K.; Park, J.W.; et al. Modulating tumor immunity by metronomic dosing of oxaliplatin incorporated in multiple oral nanoemulsion. J. Control. Release 2020, 322, 13–30. [Google Scholar] [CrossRef]
- Jha, S.K.; Chung, J.Y.; Pangeni, R.; Choi, H.S.; Subedi, L.; Kweon, S.; Choi, J.U.; Byun, Y.; Kim, Y.H.; Park, J.W. Enhanced antitumor efficacy of bile acid-lipid complex-anchored docetaxel nanoemulsion via oral metronomic scheduling. J. Control. Release 2020, 328, 368–394. [Google Scholar] [CrossRef]
- Pangeni, R.; Subedi, L.; Jha, S.K.; Kweon, S.; Kang, S.H.; Chang, K.Y.; Choi, J.U.; Byun, Y.; Park, J.W. Improvements in the Oral Absorption and Anticancer Efficacy of an Oxaliplatin-Loaded Solid Formulation: Pharmacokinetic Properties in Rats and Nonhuman Primates and the Effects of Oral Metronomic Dosing on Colorectal Cancer. Int. J. Nanomed. 2020, 15, 7719–7743. [Google Scholar] [CrossRef] [PubMed]
- Cai, X.J.; Wang, Z.; Cao, J.W.; Ni, J.J.; Xu, Y.Y.; Yao, J.; Xu, H.; Liu, F.; Yang, G.Y. Anti-angiogenic and anti-tumor effects of metronomic use of novel liposomal zoledronic acid depletes tumor-associated macrophages in triple negative breast cancer. Oncotarget 2017, 8, 84248–84257. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jyoti, A.; Fugit, K.D.; Sethi, P.; McGarry, R.C.; Anderson, B.D.; Upreti, M. An in vitro assessment of liposomal topotecan simulating metronomic chemotherapy in combination with radiation in tumor-endothelial spheroids. Sci. Rep. 2015, 5, 15236. [Google Scholar] [CrossRef] [Green Version]
- Cai, X.J.; Fei, W.D.; Xu, Y.Y.; Xu, H.; Yang, G.Y.; Cao, J.W.; Ni, J.J.; Wang, Z. Combination of metronomic administration and target delivery strategies to improve the anti-angiogenic and anti-tumor effects of triptolide. Drug Deliv. Transl. Res. 2020, 10, 93–107. [Google Scholar] [CrossRef] [PubMed]
- Fei, T.; Yang, L.-J.; Mo, X.-H.; Wang, X.-L.; Jun, G. Metronomic paclitaxel-loaded mPEG–PLA nanoparticles show enhanced anti-tumor efficacy compared to maximum tolerated dose administration. J. Nanoparticle Res. 2014, 16, 2706. [Google Scholar] [CrossRef]
- Doi, Y.; Okada, T.; Matsumoto, H.; Ichihara, M.; Ishida, T.; Kiwada, H. Combination therapy of metronomic S-1 dosing with oxaliplatin-containing polyethylene glycol-coated liposome improves antitumor activity in a murine colorectal tumor model. Cancer Sci. 2010, 101, 2470–2475. [Google Scholar] [CrossRef]
- Hoelzer, D.; Leiske, M.N.; Hartlieb, M.; Bus, T.; Pretzel, D.; Hoeppener, S.; Kempe, K.; Thierbach, R.; Schubert, U.S. Tumor targeting with pH-responsive poly(2-oxazoline)-based nanogels for metronomic doxorubicin treatment. Oncotarget 2018, 9, 22316–22331. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wichmann, V.; Eigeliene, N.; Saarenheimo, J.; Jekunen, A. Recent clinical evidence on metronomic dosing in controlled clinical trials: A systematic literature review. Acta Oncol. 2020, 59, 775–785. [Google Scholar] [CrossRef] [PubMed]
- Taguchi, T.; Nakayama, T.; Masuda, N.; Yoshidome, K.; Akagi, K.; Nishida, Y.; Yoshikawa, Y.; Ogino, N.; Abe, C.; Sakamoto, J.; et al. Study of low-dose capecitabine monotherapy for metastatic breast cancer. Chemotherapy 2010, 56, 166–170. [Google Scholar] [CrossRef] [PubMed]
- Fedele, P.; Marino, A.; Orlando, L.; Schiavone, P.; Nacci, A.; Sponziello, F.; Rizzo, P.; Calvani, N.; Mazzoni, E.; Cinefra, M.; et al. Efficacy and safety of low-dose metronomic chemotherapy with capecitabine in heavily pretreated patients with metastatic breast cancer. Eur. J. Cancer 2012, 48, 24–29. [Google Scholar] [CrossRef] [PubMed]
- De Iuliis, F.; Salerno, G.; Taglieri, L.; Lanza, R.; Scarpa, S. On and off metronomic oral vinorelbine in elderly women with advanced breast cancer. Tumori 2015, 101, 30–35. [Google Scholar] [CrossRef]
- Malyla, V.; Paudel, K.R.; Shukla, S.D.; Donovan, C.; Wadhwa, R.; Pickles, S.; Chimankar, V.; Sahu, P.; Bielefeldt-Ohmann, H.; Bebawy, M.; et al. Recent advances in experimental animal models of lung cancer. Future Med. Chem. 2020, 12, 567–570. [Google Scholar] [CrossRef]
- Paudel, K.R.; Panth, N.; Pangeni, R.; Awasthi, R.; Chawla, V.; Mehta, M.; Tambuwala, M.M.; Hansbro, P.M. Targeting lung cancer using advanced drug delivery systems. In Targeting Chronic Inflammatory Lung Diseases Using Advanced Drug Delivery Systems; Elsevier: Amsterdam, The Netherlands, 2020; pp. 493–516. [Google Scholar]
- Wadhwa, R.; Paudel, K.R.; Shukla, S.; Shastri, M.; Gupta, G.; Devkota, H.P.; Chellappan, D.K.; Hansbro, P.M.; Dua, K. Epigenetic Therapy as a Potential Approach for Targeting Oxidative Stress–Induced Non-Small-Cell Lung Cancer. In Handbook of Oxidative Stress in Cancer: Mechanistic Aspects; Springer: Singapore, 2020; pp. 1545–1560. [Google Scholar]
- Camerini, A.; Banna, G.L.; Cinieri, S.; Pezzuto, A.; Mencoboni, M.; Rosetti, F.; Figueiredo, A.; Rizzo, P.; Ricci, A.; Langenhoven, L.; et al. Metronomic oral vinorelbine for the treatment of advanced non-small cell lung cancer: A multicenter international retrospective analysis. Clin. Transl. Oncol. 2019, 21, 790–795. [Google Scholar] [CrossRef]
- Banna, G.L.; Camerini, A.; Bronte, G.; Anile, G.; Addeo, A.; Rundo, F.; Zanghi, G.; Lal, R.; Libra, M. Oral Metronomic Vinorelbine in Advanced Non-small Cell Lung Cancer Patients Unfit for Chemotherapy. Anticancer Res. 2018, 38, 3689–3697. [Google Scholar] [CrossRef]
- Gorn, M.; Habermann, C.R.; Anige, M.; Thom, I.; Schuch, G.; Andritzky, B.; Brandl, S.; Burkholder, I.; Edler, L.; Hossfeld, D.K.; et al. A pilot study of docetaxel and trofosfamide as second-line ‘metronomic’ chemotherapy in the treatment of metastatic non-small cell lung cancer (NSCLC). Onkologie 2008, 31, 185–189. [Google Scholar] [CrossRef]
- Kakolyris, S.; Samonis, G.; Koukourakis, M.; Vlachonicolis, I.; Chalkiadakis, G.; Kalbakis, K.; Souglakos, I.; Agelaki, S.; Toloudis, P.; Georgoulias, V. Treatment of non-small-cell lung cancer with prolonged oral etoposide. Am. J. Clin. Oncol. 1998, 21, 505–508. [Google Scholar] [CrossRef]
- Jones, B.S.; Jerome, M.S.; Miley, D.; Jackson, B.E.; DeShazo, M.R.; Reddy, V.V.; Singh, K.P.; Brown, O.C.; Robert, F. Pilot phase II study of metronomic chemotherapy in combination with bevacizumab in patients with advanced non-squamous non-small cell lung cancer. Lung Cancer 2017, 106, 125–130. [Google Scholar] [CrossRef] [Green Version]
- Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin. 2020, 70, 7–30. [Google Scholar] [CrossRef] [PubMed]
- Lokich, J. Capecitabine: Fixed daily dose and continuous (noncyclic) dosing schedule. Cancer Investig. 2004, 22, 713–717. [Google Scholar] [CrossRef] [PubMed]
- Romiti, A.; Falcone, R.; Roberto, M.; Marchetti, P. Current achievements and future perspectives of metronomic chemotherapy. Investig. New Drugs 2017, 35, 359–374. [Google Scholar] [CrossRef] [PubMed]
- Simkens, L.H.; van Tinteren, H.; May, A.; ten Tije, A.J.; Creemers, G.J.; Loosveld, O.J.; de Jongh, F.E.; Erdkamp, F.L.; Erjavec, Z.; van der Torren, A.M.; et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): A phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet 2015, 385, 1843–1852. [Google Scholar] [CrossRef]
- Andre, N.; Banavali, S.; Snihur, Y.; Pasquier, E. Has the time come for metronomics in low-income and middle-income countries? Lancet Oncol. 2013, 14, e239–e248. [Google Scholar] [CrossRef]
- Calvani, N.; Morelli, F.; Naglieri, E.; Gnoni, A.; Chiuri, V.E.; Orlando, L.; Fedele, P.; Cinieri, S. Metronomic chemotherapy with cyclophosphamide plus low dose of corticosteroids in advanced castration-resistant prostate cancer across the era of taxanes and new hormonal drugs. Med. Oncol. 2019, 36, 80. [Google Scholar] [CrossRef]
- Maulard-Durdux, C.; Dufour, B.; Hennequin, C.; Chretien, Y.; Delanian, S.; Housset, M. Phase II study of the oral cyclophosphamide and oral etoposide combination in hormone-refractory prostate carcinoma patients. Cancer 1996, 77, 1144–1148. [Google Scholar] [CrossRef]
- Noronha, V.; Patil, V.M.; Joshi, A.; Chougule, A.; Banavali, S.; Prabhash, K. Potential role of metronomic chemotherapy in the treatment of esophageal and gastroesophageal cancer. Cancer Lett. 2017, 400, 267–275. [Google Scholar] [CrossRef] [PubMed]
- Bobek, V.; Matkowski, R.; Gurlich, R.; Grabowski, K.; Szelachowska, J.; Lischke, R.; Schutzner, J.; Harustiak, T.; Pazdro, A.; Rzechonek, A.; et al. Cultivation of circulating tumor cells in esophageal cancer. Folia Histochem. Cytobiol. 2014, 52, 171–177. [Google Scholar] [CrossRef] [Green Version]
- He, S.; Shen, J.; Hong, L.; Niu, L.; Niu, D. Capecitabine “metronomic” chemotherapy for palliative treatment of elderly patients with advanced gastric cancer after fluoropyrimidine-based chemotherapy. Med. Oncol. 2012, 29, 100–106. [Google Scholar] [CrossRef]
- El Darsa, H.; El Sayed, R.; Abdel-Rahman, O. What is the real value of metronomic chemotherapy in the treatment of gastrointestinal cancer? Expert Opin. Pharmacother. 2021, 22, 2297–2302. [Google Scholar] [CrossRef]
- Roberto, M.; Romiti, A.; Onesti, C.E.; D’Antonio, C.; Milano, A.; Falcone, R.; Barucca, V.; Palombi, L.; Righini, R.; Marchetti, P. A metronomic schedule as salvage chemotherapy for upper gastrointestinal tract cancer. Anticancer Drugs 2016, 27, 106–111. [Google Scholar] [CrossRef] [PubMed]
- Romiti, A.; Falcone, R.; Roberto, M.; Marchetti, P. Tackling pancreatic cancer with metronomic chemotherapy. Cancer Lett. 2017, 394, 88–95. [Google Scholar] [CrossRef] [PubMed]
- Isacoff, W.H.; Reber, H.A.; Bedford, R.; Hoos, W.; Rahib, L.; Upfill-Brown, A.; Donahue, T.; Hines, O.J. Low-Dose Continuous 5-Fluorouracil Combined with Leucovorin, nab-Paclitaxel, Oxaliplatin, and Bevacizumab for Patients with Advanced Pancreatic Cancer: A Retrospective Analysis. Target. Oncol. 2018, 13, 461–468. [Google Scholar] [CrossRef] [Green Version]
- Xu, X.; Li, R.; Zhu, P.; Zhang, P.; Chen, J.; Lin, Y.; Chen, Y. Clinical efficacy and safety of maintenance therapy for advanced non-small cell lung cancer: A retrospective real-world study. World J. Surg. Oncol. 2021, 19, 231. [Google Scholar] [CrossRef] [PubMed]
- Platania, M.; Pasini, F.; Porcu, L.; Boeri, M.; Verderame, F.; Modena, Y.; Del Conte, A.; Nichetti, F.; Garassino, M.C.; Martinetti, A.; et al. Oral maintenance metronomic vinorelbine versus best supportive care in advanced non-small-cell lung cancer after platinum-based chemotherapy: The MA.NI.LA. multicenter, randomized, controlled, phase II trial. Lung Cancer 2019, 132, 17–23. [Google Scholar] [CrossRef] [PubMed]
- Liu, Y.; Gu, F.; Liang, J.; Dai, X.; Wan, C.; Hong, X.; Zhang, K.; Liu, L. The efficacy and toxicity profile of metronomic chemotherapy for metastatic breast cancer: A meta-analysis. PLoS ONE 2017, 12, e0173693. [Google Scholar] [CrossRef] [Green Version]
- Colleoni, M.; Gray, K.P.; Gelber, S.; Lang, I.; Thurlimann, B.; Gianni, L.; Abdi, E.A.; Gomez, H.L.; Linderholm, B.K.; Puglisi, F.; et al. Low-Dose Oral Cyclophosphamide and Methotrexate Maintenance for Hormone Receptor-Negative Early Breast Cancer: International Breast Cancer Study Group Trial 22-00. J. Clin. Oncol. 2016, 34, 3400–3408. [Google Scholar] [CrossRef]
- Shawky, H.; Galal, S. Preliminary results of capecitabine metronomic chemotherapy in operable triple-negative breast cancer after standard adjuvant therapy--a single-arm phase II study. J. Egypt. Natl. Cancer Inst. 2014, 26, 195–202. [Google Scholar] [CrossRef] [Green Version]
- Li, J.B.; Lin, Z.C.; Wong, M.C.S.; Wang, H.H.X.; Li, M.; Li, S. A cost-effectiveness analysis of capecitabine maintenance therapy versus routine follow-up for early-stage triple-negative breast cancer patients after standard treatment from a perspective of Chinese society. BMC Med. 2022, 20, 320. [Google Scholar] [CrossRef]
- Aurilio, G.; Munzone, E.; Botteri, E.; Sciandivasci, A.; Adamoli, L.; Minchella, I.; Esposito, A.; Cullura, D.; Curigliano, G.; Colleoni, M.; et al. Oral metronomic cyclophosphamide and methotrexate plus fulvestrant in advanced breast cancer patients: A mono-institutional case-cohort report. Breast J. 2012, 18, 470–474. [Google Scholar] [CrossRef] [PubMed]
- Young, S.D.; Lafrenie, R.M.; Clemons, M.J. Phase ii trial of a metronomic schedule of docetaxel and capecitabine with concurrent celecoxib in patients with prior anthracycline exposure for metastatic breast cancer. Curr. Oncol. 2012, 19, e75–e83. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Addeo, R.; Sgambato, A.; Cennamo, G.; Montella, L.; Faiola, V.; Abbruzzese, A.; Capasso, E.; Leo, L.; Botti, G.; Caraglia, M.; et al. Low-dose metronomic oral administration of vinorelbine in the first-line treatment of elderly patients with metastatic breast cancer. Clin. Breast Cancer 2010, 10, 301–306. [Google Scholar] [CrossRef] [PubMed]
- Lebeau, B.; Chouaid, C.; Baud, M.; Masanes, M.J.; Febvre, M. Oral second- and third-line lomustine-etoposide-cyclophosphamide chemotherapy for small cell lung cancer. Lung Cancer 2010, 67, 188–193. [Google Scholar] [CrossRef] [PubMed]
- Klein, R.; Wielage, R.; Muehlenbein, C.; Liepa, A.M.; Babineaux, S.; Lawson, A.; Schwartzberg, L. Cost-effectiveness of pemetrexed as first-line maintenance therapy for advanced nonsquamous non-small cell lung cancer. J. Thorac. Oncol. 2010, 5, 1263–1272. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Torre, L.A.; Bray, F.; Siegel, R.L.; Ferlay, J.; Lortet-Tieulent, J.; Jemal, A. Global cancer statistics, 2012. CA Cancer J. Clin. 2015, 65, 87–108. [Google Scholar] [CrossRef] [Green Version]
- Bocci, G.; Kerbel, R.S. Pharmacokinetics of metronomic chemotherapy: A neglected but crucial aspect. Nat. Rev. Clin. Oncol. 2016, 13, 659–673. [Google Scholar] [CrossRef]
- Kareva, I. Understanding Cancer from a Systems Biology Point of View: From Observation to Theory and Back; Academic Press: Cambridge, MA, USA, 2018. [Google Scholar]
- Stanway, S.; Lodge, M.; Sullivan, R.; Diprose, K.; Young, A.M.; Crisp, N.; Lewis, P.; Eden, T.; Aggarwal, A.; Nadin, A.; et al. The UK’s contribution to cancer control in low-income and middle-income countries. Lancet Oncol. 2021, 22, e410–e418. [Google Scholar] [CrossRef]
Parameters | Conventional Chemotherapy | MCT | References |
---|---|---|---|
Dose | Designed to deliver at MTD | Below than MTD | [38] |
Dosing frequency | Specified intervals (weekly, fortnightly, three-weekly) | Daily, every alternate day, weekly | [30] |
Plasma concentration | Fluctuated | Sustained | [30,42] |
Target cells | Proliferating tumor cells | Endothelial cells (in the progressing vasculature of the tumor) | [33] |
Aim of administration | To treat cancer directly by hampering or destroying speedily dividing cancer cells | To achieve cancer control by focusing on angiogenesis | [30] |
Toxicity | Toxicity is a main concern due to drugs used as MTD | No remarkable toxic side effects as achievement of sustained low drug level in blood | [38] |
Efficacy | More successful in the primary tumor in comparison with metastasis | Advanced cancer | [30] |
Cancer Types | Metronomic Chemotherapy | Findings | Reference |
---|---|---|---|
Breast cancer | Capecitabine: 825 mg/m2 twice daily for 21 out of 28 days. | The overall survival and median progression-free survival were 24.8 and 6.9 months, respectively. This study exhibited that CPB was better tolerated and efficacious in this schedule. | [62] |
Vinorelbine: 70 mg/m2 thrice a week in 34 elderly patients, followed by one week break. | The regimen was adequately tolerated (grade 3 neutropenia 6%), and overall survival and median progression-free survival were 15.9 and 7.7 months, respectively. | [63] | |
Combinational oral administration of cyclophosphamide and methotrexate delivered at a low dose to 63 patients. | The overall clinical benefit rate and overall objective response rate were 32% and 19%, respectively. | [64] | |
Non-small cell lung cancer | Vinorelbine via oral route at 50 mg, 40 mg, and 30 mg three times a week as a first, second, or subsequent line. | Vinorelbine demonstrated activity of disease stabilization for a longer period with an overall disease control rate and response rate of 61.9% and 17.8%, respectively. | [68] |
Weekly schedule of 25 mg/m2 docetaxel and 50 mg trofosfamide once daily in 62 patients of IV NSCLC | The median overall survival, overall response, and progression-free survival were 9.6 months, 19%, and 2.9 months, respectively. | [70] | |
Etoposide: 100 mg oral was given to NSCLC patients. | The corresponding figures for stable disease and partial response were 34% and 28%, respectively, in addition to median overall survival of 9 months and six months to progression. | [71] | |
Colorectal cancer | The uninterrupted constant dosage regimen of irinotecan or fluorouracil (1500 mg or 2000 mg daily) with or without other treatments. | A minor toxicity profile and none of the patients treated with a metronomic schedule of capecitabine experienced any grade of side effects. | [74] |
Metronomic regimen of capecitabine at a daily dose of 1500 mg. | Median OS and disease control rate of 8 months and 26%, respectively. | [75] | |
Prostate Cancer | Cyclophosphamide 50 mg orally once a day as a metronomic regimen with corticosteroids (oral delivery of dexamethasone; 1 mg/day or prednisolone; 10 mg/day). | Cyclophosphamide resulted in a moderately low rate of prostate-specific antigen responses (16%). Moreover, corresponding figures for overall survival and progression-free survival were 8.1 and 4 months, respectively. | [78] |
In another study, CPM 100 mg with etoposide 50 mg (14/21 days) was examined in 20 hormone refractory sufferers. | The overall response was reported to be 35%. | [79] | |
Gastro-esophageal cancer | Capecitabine 1500 mg once a day continuously. | They revealed therapeutic safety with partial response and stable disease in 1 and 6 patients, respectively. | [83] |
Capecitabine 100 mg/d, d1-28/35. | Median time to progression, median overall survival, and response rate were 3.6 months, 7.6 months, and 20.9%, respectively. The toxicity profile was achieved within the acceptable limit with lesser than 10% grade 3 and no grade 4 toxicities. | [84] | |
Pancreas cancer | A weekly low-dose metronomic regimen of nab-paclitaxel (60 mg/m2) and oxaliplatin (50 mg/m2) in addition to continuous infusion of 5FU (180 mg/m2/d). | This metronomic regimen proved to be efficacious and safe in which RR, OS, and DCR were 49%, 19 months, and 81%, respectively. | [86] |
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Panthi, V.K.; Dua, K.; Singh, S.K.; Gupta, G.; Hansbro, P.M.; Paudel, K.R. Nanoformulations-Based Metronomic Chemotherapy: Mechanism, Challenges, Recent Advances, and Future Perspectives. Pharmaceutics 2023, 15, 1192. https://doi.org/10.3390/pharmaceutics15041192
Panthi VK, Dua K, Singh SK, Gupta G, Hansbro PM, Paudel KR. Nanoformulations-Based Metronomic Chemotherapy: Mechanism, Challenges, Recent Advances, and Future Perspectives. Pharmaceutics. 2023; 15(4):1192. https://doi.org/10.3390/pharmaceutics15041192
Chicago/Turabian StylePanthi, Vijay Kumar, Kamal Dua, Sachin Kumar Singh, Gaurav Gupta, Philip M. Hansbro, and Keshav Raj Paudel. 2023. "Nanoformulations-Based Metronomic Chemotherapy: Mechanism, Challenges, Recent Advances, and Future Perspectives" Pharmaceutics 15, no. 4: 1192. https://doi.org/10.3390/pharmaceutics15041192
APA StylePanthi, V. K., Dua, K., Singh, S. K., Gupta, G., Hansbro, P. M., & Paudel, K. R. (2023). Nanoformulations-Based Metronomic Chemotherapy: Mechanism, Challenges, Recent Advances, and Future Perspectives. Pharmaceutics, 15(4), 1192. https://doi.org/10.3390/pharmaceutics15041192