|Year : 2023 | Volume
| Issue : 1 | Page : 7-12
Metronomic chemotherapy in cancer: A ray of hope
Yashashri Chandrakant Shetty, Yashoda Ramachandra Aithal
Department of Pharmacology and Therapeutics, Seth G. S. Medical College and K. E. M. Hospital, Mumbai, Maharashtra, India
|Date of Submission||21-Dec-2022|
|Date of Decision||14-Feb-2023|
|Date of Acceptance||15-Feb-2023|
|Date of Web Publication||26-Apr-2023|
Yashoda Ramachandra Aithal
Department of Pharmacology and Therapeutics, Seth G. S. Medical College and K. E. M. Hospital, Main College Building, Parel, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Despite the high incidence of cancer and its related mortality, our knowledge regarding optimal treatment is limited necessitating the researchers to find an alternate therapy. Metronomic chemotherapy (MCT) is the potential new modality for cancer therapy. A dearth of studies on MCT has encouraged us to conduct a systematic review to observe the clinical trials conducted globally using MCT for various types of cancer. The primary objective was to assess the utilization of MCT in various cancers and drug regimens utilized. The secondary objective was to evaluate the objective, study design, patient demographics, country, and the outcome of the study. Materials and Methods: A literature search extracted the clinical trials using MCT from two electronic databases PubMed and clinicaltrial.Gov with an appropriate search term. Included articles were analyzed using descriptive statistics. Results: Two hundred and forty-five out of two hundred and eighty-seven articles retrieved met the inclusion criteria. The most studied cancers were breast (26.1%) and central nervous system (13.9%). Cyclophosphamide (46.1%) and capecitabine (18.8%) were the frequently used chemotherapeutic drugs. The rationale for drug selection was antiangiogenesis mostly (47.3%). Most of the studies were phase II clinical trials (56.3%). About 23.7% of trials were conducted in the United States of America, and 38.8% of the trials were carried out in a multicentric setup. Majority trials had tumor assessment as its endpoints (49.4%), and 35.1% of trials had open-label and nonrandomization methods. Conclusion: MCT was used commonly in breast cancer with cyclophosphamide and capecitabine being frequently used drug and tumor assessment being the most frequent endpoint utilized. MCT was employed due to its antiangiogenic properties in majority of the trials. Phase II and nonrandomized, single-arm, and open-labeled studies were the most observed study design.
Keywords: Angiogenesis, clinical trial, conventional chemotherapy, metronomic
|How to cite this article:|
Shetty YC, Aithal YR. Metronomic chemotherapy in cancer: A ray of hope. Oncol J India 2023;7:7-12
| Introduction|| |
Cancer is the leading cause of death worldwide. Despite considerable advances in therapy, various challenges do exist. According to the Global Cancer Observatory (GLOBOCAN) approximately 19.3 million new cancer cases and about 10 million cancer deaths have occurred in 2020 globally.
The use of conventional chemotherapy (CT) drugs is a mixed blessing. They act by inhibiting the growth of cells and preventing the abnormal proliferation. It is based on the maximum tolerated dose of a drug and continued for several cycles. However, the challenges associated are grievous including the increased toxicity, failure to maintain the sustained response, low specificity for cancer cells due to its nonspecific targeting effect., Hence, to the curb the harsh side effects of the CT, the metronomic CT (MCT) was introduced by Hanahan et al. in the early 2000s as an emerging alternate. It is the chronic administration of low doses CT achieving a sustained and prolonged active plasma levels of the drugs with favorable tolerability given regularly without extended rest periods. The concept of angiogenesis in tumor growth and metastasis changed the perspective of cancer therapy, pioneering research in this field. Later, several trials were conducted to evaluate the safety and efficacy of MCT in various cancers. These trials also highlighted the multitargeted mode of action emphasizing its role in cancer therapy.
However, the literature search revealed that a very few systematic reviews were conducted analyzing the MCT. Therefore, the present study aimed to assess the current knowledge on the clinical trials conducted globally using MCT for various types of cancer. The present systematic review describes the pattern of utilization of MCT drug regimens in various types of cancers in several clinical trial design and also describes the study objectives, patient profile, country where trials were conducted, and outcome endpoints. We aim to add crucial evidence with respect to this topic and help in better understanding.
| Materials and Methods|| |
The study was exempted from review by the institutional ethics committee (IEC [III] OUT/229/2021). An extensive, systematic literature search was carried out to identify all the published articles on “MCT” in PubMed and clinicaltrial.Gov with the search terms of “Metronomic AND (Cancer OR Tumor OR Neoplasm)” with a further filter criterion of “Clinical trial.” In clinicaltrial.Gov. articles with search terms “Metronomic” and “Cancer” were used. We retrieved all the articles published up to November 2021. The reviewing process was carried out in compliance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and by two investigators independently. The studies satisfying the inclusion criteria were considered for further analysis. A manual search of the cited references was done to eliminate the duplicates. The study investigators came to a common consensus before considering an article as relevant. The exclusion criteria included animal studies and unavailable full-text articles. Data collected were analyzed using Microsoft Excel-365 and represented in numbers and frequency. [Figure 1] describes the algorithm of database search and article inclusion.
| Results|| |
We identified 287 published articles with the specified search terms from PubMed and Clinicaltrial.Gov. Forty-two articles which were preclinical studies, and/or unavailable full-text articles were excluded from the analysis. Hence, a total of 245 papers were reviewed as potentially relevant articles.
Metronomic trials and cancers
We identified the most common cancers where the MCT was tried and the results are illustrated in [Figure 2].
|Figure 2: Metronomic trials and cancer types. CNS: Central nervous system|
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MCT was commonly used in breast cancer. Out of the 64 breast cancer trials which employed MCT and 43.7% (28/64) trials were on metastatic or advanced breast cancer. The exact stage of the cancer was not mentioned in 14.1% (9/64) studies. The second most common cancer trials with MCT were on central nervous system (CNS) neoplasm constituting of 13.9% (34/245) which included the glioblastoma and astrocytoma. The cancers categorized as “others” included those in bone cancers and melanoma. Non-small cell lung cancers also used MCT which was mentioned in 8.2% (20/245) of clinical trials.
Metronomic drug regimen
Cyclophosphamide and capecitabine were on top of the list in being extensively utilized in various cancers in their metronomic doses. The detailed drug utilization in the metronomic doses is shown in [Figure 3]. 71.7% (81/113) of the trials used cyclophosphamide in an oral dosing regimen with 50 mg/m2 once daily.
Most trials preferred the oral route 82.9% (203/245) for the drug administration. Other common routes of drug administration were intravenous, subcutaneous, and intramuscular. On further analysis, we noted that in 47.3% (116/245) trials and chemotherapeutic agents were given alone in metronomic doses. However, in 33.9% (83/245) trials, combined doses of CT with MCT were used. Radiotherapy was utilized in 2.0% (5/245) trials, and hormonal therapy was utilized in 3.7% (9/245) trials for a better treatment response.
Rationale for utilizing the regimen
The studies were thoroughly evaluated to understand the biological rationale for the utilization of metronomic doses of drugs. The commonly stated mechanisms in the published literature were the antiangiogenic mechanism by inhibiting growth factors and apoptosis of the tumor vascular endothelium in 47.3% (116/245) trials. Other rationale mentioned were cell division arrest in 15.9% (39/245), immunosuppression in 11.4% (28/245), and antiproliferative effects by gene regulation in 4.1% (10/245) of the included articles. The authors stated multiple mechanisms for the drug used in MCT. However, no rationale was mentioned in 27.3% (67/245) trials.
Study design characteristics
Out of all the trials included, 56.3% (138/245) trials were conducted as a phase 2 trial. While, 19.2% (47/245) of the trial were phase 1 and followed by 3.7% (9/245) phase 3 trials. There was a single trial conducted as a phase 0 trial. The trial phase was unclear or missing in 20.4% (50/245) trials. [Figure 4] depicts the most common study designs employed by the trials using metronomic regimens. About 35.1% (86/245) of the trials were nonrandomized, open-labeled trial. The study design was incompletely specified, with missing data regarding the method of blinding or control in 23.3% (57/245).
Endpoints assessed in metronomic trials
Analyzing the endpoints of the trials was one of the important objectives of this systematic review. The various primary endpoints employed in trials have been described in [Figure 5]. The tumor assessment markers enlisted were time to progression (TTP), progression-free survival (PFS), objective response rate (ORR), and disease-free survival. Less than one-third of the trials 31.8% (78/245) had used more than two secondary endpoints. About 29.4% (72/245) of studies had not considered any secondary endpoint. The most commonly employed secondary endpoints were tumor assessment markers, safety, tolerability endpoints, and biomarkers. Some studies which used tumor assessment markers as primary endpoints had blood fluid markers as secondary endpoints.
|Figure 5: Primary endpoints in metronomic trials. PK: Pharmacokinetics, PD: Pharmacodynamic, MTD: Maximum tolerated dose, DLT: Dose limiting toxicity|
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Place of conduct
Approximately, one quarter 23.7% (58/245) of the trials with MCT the regimen were conducted in the United States of America (USA), and followed by Italy 16.3% (40/245). India conducted just 2.4% (6/245) trials with the metronomic regimen. Out of 245 trials, 38.8% (95/245) trials enrolled participants from multicentric sites followed by 34.7% (85/245) trials from single centers. About 26.5% (65/245) of the included articles had not mentioned the number of sites enrolling the participants.
Patient demographic data were inconsistently reported in 20.8% (51/245) trials. Majority of the trials 73.5% (180/245) included the adult population (≥18 years). Around 5.7% (14/245) trials included the population <18 years comprising patients of CNS neoplasm and various other refractory cancers. About 13.1% (32/245) trials included only men; 28.2% (69/245) trials were exclusively conducted in women. Trials with both gender as their inclusion represented 58.8% (144/245) of all the studies.
| Discussion|| |
Over the years, innovative techniques in neoplastic cancer have evolved with a focus to develop a safe and efficient therapy. MCT is the frequent administration of antineoplastic drugs at very low doses without long drug-free periods. Several drugs and regimens have been exploited due to its unique mechanisms in various cancers.
According to our research, breast cancer was the most frequently observed cancer where MCT was employed. This might be substantiated by the estimated global incidence of 2.3 million cases in 2020. The mortality with breast cancer is approximately 685, 000 with a large geographical variations noted across the countries and world regions. Breast cancer still remains an unmet need owing to the economic burden and course of the disease. Conventionally used CT includes cytotoxic agents such as docetaxel/cyclophosphamide/adriamycin or hormonal therapies such as tamoxifen/aromatase inhibitors. However, the exhaustive list of toxicities associated with the drugs remains a challenge, suggesting the need for an alternative.
Simsek et al. quoted breast cancer as the biggest tracks for the “metronomic march.” A combination regimen of cyclophosphamide with capecitabine/methotrexate or vinorelbine was the most used in breast cancer. Wildiers et al. tested the combination of cyclophosphamide 50 mg daily with trastuzumab and pertuzumab (metronomic group), or trastuzumab and pertuzumab alone. The estimated PFS at 6 months in the metronomic group was 73·4% (56.6–84.6) with hazard ratio 0·65 (95% confidence interval [CI]: 0.37–1.12) versus 46.2% in the other group. Furthermore, the median PFS was 12.7 months in the metronomic group in contrast to 5.6 months. An additional 7 months of median PFS was offered to the patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. A Japanese Phase II study evaluating the ORR, PFS, and safety with capecitabine 828 mg/m2 twice daily with cyclophosphamide 33 mg/m2 twice daily showed an ORR of 44.4%, median PFS 12.3 months (95% CI: 8.9–18.9) with minimal toxicity.
Following the breast cancer, MCT was frequently utilized in CNS tumors like glioblastoma. We observed the consistent use of metronomic temozolomide in most CNS trials. A phase II study with sorafenib plus daily low-dose temozolomide for relapsed glioblastoma revealed that the combination was feasible and safe with a manageable toxicity profile, 6 months PFS 26%, overall survival of 7.4 months, and emphasizing the advantages of MCT.
Majority of the trials 82.9% (203/245) advocated the drugs orally, whereas in 5.7% (14/245) drugs were administered intravenously. In about 59.2% (145/245) trials, a single-dose regimen was considered while the rest had a diverse combination schedule. Metronomic-based CT-hormonal scheme was explored in trials. A multicenter phase II trial of neoadjuvant letrozole plus low-dose cyclophosphamide 50 mg once daily in postmenopausal patients with estrogen receptor positive breast cancer was conducted to evaluate clinical response rate (CRR). The CRR was 67.5% which was greater than the prespecified cutoff of 65%, reassuring the benefits of MCT. A study by Muthusamy et al. revealed a similar trend of observations where the MCT consisted mainly the drugs such as cyclophosphamide (27/50) and methotrexate (10/50). Furthermore, a total of 18 drugs were used as a single drug and combined regimen were seen in 50 trials. However, the study reviewed only 50 CT trials.
The main role of the MCT was derived from its antiangiogenesis property as quoted in 47.3% of trials (116/245). A detailed analysis showed that various aspects inducing the antiangiogenic property was, namely, by inhibition of growth factors such as vascular endothelial growth factor, inhibition of tyrosine kinase or thrombospondin-1, and hypoxia-inducible factor-1a, apoptosis of endothelial progenitor cells of tumor vasculature. Tumor endothelial cells are a chief target for the antiangiogenetic property. Furthermore, endothelial progenitor cells play a vital role in tumor vasculogenesis. Tumor action through modifying the host immunity is yet another important factor. Regulatory T cell hampers the cytotoxic response and thus maintains the tumor immune tolerance. A systematic review by Simsek et al. mentioned the similar mechanism of action of the drugs utilized in the metronomic scheme. The above-mentioned actions of the drugs make it vital to be utilized as a MCT drug.
Repurposing drugs in oncology project has encouraged the use of anti-cancer drugs such as nonsteroidal anti-inflammatory drugs (celecoxib/rofecoxib/etoricoxib), statins (pioglitazone) in oncotherapy due to the evidence of its antiangiogenic and antiproliferative potential. Patients of malignant vascular tumors were administered with a combination of pioglitazone, rofecoxib with trofosfamide. Out of the six patients, two showed complete response, and one showed partial response and the rest achieved stable disease. PFS was 7.7 months with mild adverse effects, therefore emerging as a new alternate.
It was evident from our study that majority of the trials were being conducted in developed countries such as the USA, Italy, and France. According to the Indian Council of Medical Research, approximately 1.45 million cases of cancer were diagnosed in 2016 in India and the projection for 20 years suggested that the cancer prevalence would double. Despite the growing cancer burden in India, just 2% of the metronomic trials were carried out specifically for the tumors of head and neck, and breast. A discrepancy in the percentage of patients presenting to a health-care facility is attributed to the lack of awareness in the population and the health-care workers, inadequate screening programs, poor diagnostic facilities, long distances to travel to reach a tertiary cancer center, limited finances, and stigma associated with the diagnosis. Six Indian trials were conducted in different tertiary cancer centers such as Tata Memorial Hospital, Mumbai and AIIMS, New Delhi, which throws light on the disparity in the art of diagnostic workup and treatment protocols of metropolitan cities and cancer centers of small towns. However, these trials showed credible clinical results. Three Indian trials were funded by various pharmaceutical industries while the others were by the government and institute collaboration. The major constraints for the conduct of metronomic researches could be ascribed to the lack of funding and expertise, insufficient infrastructure, stringent national regulations, and guidelines. A collaborative approach of government, healthcare system, pharmaceutical industries, and foreign agencies (non-governmental organizations and national institutes of health) focusing on Indian cancers would likely be the key to success. In the USA, majority trials were Government funded or pharmaceutical sponsored reflective of efforts to understand the healthcare system.
Majority of the reported data were extracted from phase II trials. An upsurge in nonrandomized, open label, single-arm study design was observed in MCT trials. This era encourages the researchers to conduct randomized trials, however, Baey and Le Deley have stated that the “non-randomized single-arm trials” using a Frequentist approach remain the most used trial design in oncology. However, over the years, growing attention has been seen with the use of randomized phase II trials with standard control arm to create a better evidence of safety and efficacy than by comparison to historical controls. This offers a protection against possible selection bias. However, the advantages may be outweighed by the limitations of including a large number of patients to observe a comparable difference in outcome.
A single multicentric phase 0 trial was conducted in Spain on hormone receptor positive/HER2-negative breast cancer with CT-hormonal scheme of oral vinorelbine with letrozole. It was concluded from the study that short-term MCT was well tolerated, feasible, and possessed an antiproliferative effect. Phase 0 offered a clinical platform for rapid, efficient testing of anticancer agents, and new combinations. Although the studies indicate the safety of administration, further efforts are needed to confirm the efficacy. Excellent phase III studies are recommended to add to the experience of MCT. Lien et al.'s study also mentioned a majority phase II trials being conducted representing that MCT is active and can be safely administered.
The clinical experience with MCT shows a 66.1% (162/245) favorable outcome where the primary and secondary endpoints were met.
This was one of the few systematic reviews conducted in India analyzing the utilization of CT drugs in a metronomic regimen for various cancers. This study gives the perspective of alternatives to be used in the metastatic settings. However, the study had a limitation of missing out relevant articles as it was a web-based study. We did not capture the data from the unpublished or unregistered trials, skewing our results.
| Conclusion|| |
Our analysis showcases the success of MCT, as an emerging alternate. As evidenced from our review, MCT was often employed in breast cancer, CNS tumors with a favorable clinical experience. Majority trials utilized cyclophosphamide and capecitabine. We noticed that most trials were phase II with their primary and secondary objectives being met, indicating the safety of MCT. A large contrariety was observed in trials being conducted in developed versus developing nations. Amid increasing concerns, the utilization of the MCT was disproportionate in various cancers, failing to be recognized as a mainstream therapy option. With improved disease understanding, infrastructure, monetary benefits, we can overcome the dearth of utilization of MCT in clinical trials as well as in the practice. MCT is indeed a ray of hope for future of oncotherapy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al.
Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-49.
Pucci C, Martinelli C, Ciofani G. Innovative approaches for cancer treatment: Current perspectives and new challenges. Ecancermedicalscience 2019;13:961.
Amjad MT, Chidharla A, Kasi A. Cancer chemotherapy. In: StatPearls. StatPearls Publishing; 2022.
Hanahan D, Bergers G, Bergsland E. Less is more, regularly: Metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 2000;105:1045-7.
Scharovsky OG, Mainetti LE, Rozados VR. Metronomic chemotherapy: Changing the paradigm that more is better. Curr Oncol 2009;16:7-15.
Maiti R. Metronomic chemotherapy. J Pharmacol Pharmacother 2014;5:186-92.
] [Full text]
Arnold M, Morgan E, Rumgay H, Mafra A, Singh D, Laversanne M, et al.
Current and future burden of breast cancer: Global statistics for 2020 and 2040. Breast 2022;66:15-23.
Waks AG, Winer EP. Breast cancer treatment: A review. JAMA 2019;321:288-300.
Simsek C, Esin E, Yalcin S. Metronomic chemotherapy: A systematic review of the literature and clinical experience. J Oncol 2019;2019:5483791.
Wildiers H, Tryfonidis K, Dal Lago L, Vuylsteke P, Curigliano G, Waters S, et al.
Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2-positive metastatic breast cancer (EORTC 75111-10114): An open-label, randomised, phase 2 trial from the Elderly Task Force/Breast Cancer Group. Lancet Oncol 2018;19:323-36.
Yoshimoto M, Takao S, Hirata M, Okamoto Y, Yamashita S, Kawaguchi Y, et al.
Metronomic oral combination chemotherapy with capecitabine and cyclophosphamide: A phase II study in patients with HER2-negative metastatic breast cancer. Cancer Chemother Pharmacol 2012;70:331-8.
Zustovich F, Landi L, Lombardi G, Porta C, Galli L, Fontana A, et al.
Sorafenib plus daily low-dose temozolomide for relapsed glioblastoma: A phase II study. Anticancer Res 2013;33:3487-94.
Ueno T, Masuda N, Kamigaki S, Morimoto T, Akiyama F, Kurosumi M, et al
. A multicenter phase II trial of neoadjuvant letrozole plus low-dose cyclophosphamide in postmenopausal patients with estrogen receptor-positive breast cancer (JBCRG-07): Therapeutic efficacy and clinical implications of circulating endothelial cells. Cancer Med 2018;7:2442-51.
Muthusamy P, Chary KV, Nalini GK. Metronomic chemotherapy: Seems prowess to battle against cancer in current scenario. J Clin Diagn Res 2016;10:C09-13.
Pantziarka P, Bouche G, Meheus L, Sukhatme V, Sukhatme VP. Repurposing drugs in oncology (ReDO)-cimetidine as an anti-cancer agent. Ecancermedicalscience 2014;8:485.
Vogt T, Hafner C, Bross K, Bataille F, Jauch KW, Berand A, et al.
Antiangiogenetic therapy with pioglitazone, rofecoxib, and metronomic trofosfamide in patients with advanced malignant vascular tumors. Cancer 2003;98:2251-6.
National Centre for Disease Informatics and Research, National Cancer Registry Programme, Indian Council of Medical Research: Three Year Report of Population Based and Hospital Cancer Registries; 2012-14. Available from: http://www.ncdindia.org
. [Last accessed on 2020 Dec 20].
Singh M, Prasad CP, Singh TD, Kumar L. Cancer research in India: Challenges and opportunities. Indian J Med Res 2018;148:362-5.
] [Full text]
Sullivan R, Badwe RA, Rath GK, Pramesh CS, Shanta V, Digumarti R, et al.
Cancer research in India: National priorities, global results. Lancet Oncol 2014;15:e213-22.
Baey C, Le Deley MC. Effect of a misspecification of response rates on type I and type II errors, in a phase II Simon design. Eur J Cancer 2011;47:1647-52.
Rubinstein LV, Korn EL, Freidlin B, Hunsberger S, Ivy SP, Smith MA. Design issues of randomized phase II trials and a proposal for phase II screening trials. J Clin Oncol 2005;23:7199-206.
Adamo B, Bellet M, Paré L, Pascual T, Vidal M, Pérez Fidalgo JA, et al.
Oral metronomic vinorelbine combined with endocrine therapy in hormone receptor-positive HER2-negative breast cancer: SOLTI-1501 VENTANA window of opportunity trial. Breast Cancer Res 2019;21:108.
Lien K, Georgsdottir S, Sivanathan L, Chan K, Emmenegger U. Low-dose metronomic chemotherapy: A systematic literature analysis. Eur J Cancer 2013;49:3387-95.
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