Indian Journal of Cancer
Home  ICS  Feedback Subscribe Top cited articles Login 
Users Online :6261
Small font sizeDefault font sizeIncrease font size
Navigate here
Resource links
 »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
 »  Article in PDF (2,948 KB)
 »  Citation Manager
 »  Access Statistics
 »  Reader Comments
 »  Email Alert *
 »  Add to My List *
* Registration required (free)  

  In this article
 »  Abstract
 » Introduction
 » Conclusion
 »  References
 »  Article Tables

 Article Access Statistics
    PDF Downloaded746    
    Comments [Add]    
    Cited by others 12    

Recommend this journal


  Table of Contents  
Year : 2013  |  Volume : 50  |  Issue : 2  |  Page : 142-148

Metronomic therapy: Chemotherapy revisited

Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication27-Aug-2013

Correspondence Address:
K Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0019-509X.117027

Rights and Permissions

 » Abstract 

Cytotoxic antiproliferative chemotherapeutic agents are the mainstay of treatment in cancers. Chemotherapy is usually administered every 2-3 weeks. Along with acute toxicity and long-term effects of cumulative doses, this strategy potentially allows regrowth of the tumor in the interval period and leads to the emergence of resistant populations of tumor cells. Moreover, even with intense chemotherapy, the outcome is stagnating for most of the tumors. There has been recent interest in the use of chemotherapy in fractionated doses which is far below the maximum tolerated dose. This is called metronomic scheduling of chemotherapy. Here, we review the biology and evidence for metronomic chemotherapy.

Keywords: Chemotherapy, metronomics, economics

How to cite this article:
Noronha V, Krishna M V, Patil V, Joshi A, Banavali S D, Prabhash K. Metronomic therapy: Chemotherapy revisited. Indian J Cancer 2013;50:142-8

How to cite this URL:
Noronha V, Krishna M V, Patil V, Joshi A, Banavali S D, Prabhash K. Metronomic therapy: Chemotherapy revisited. Indian J Cancer [serial online] 2013 [cited 2022 Nov 29];50:142-8. Available from:

 » Introduction Top

Cytotoxic antiproliferative chemotherapeutic agents are the mainstay of treatment in cancers. Based on the model of log-dose survival growth curves, multiple drugs administered from one to a few days is the standard model for chemotherapy. [1] This approach entails administering the drugs at doses close to the maximum tolerated dose (MTD) with a time interval ranging between two and four weeks to allow for the recovery of the normal tissues, mainly the bone marrow progenitors. Along with acute toxicity and long-term effects of cumulative doses, this strategy potentially allows regrowth of the tumor in the interval period and leads to the emergence of resistant populations of tumor cells. Moreover, even with intense chemotherapy leading to upward of 3-log reduction in the tumor mass, there is only partial regression and the subsequent potential of relapse. [2]

Over the past few decades, there has been an unprecedented increase in our knowledge of the underlying molecular pathways and mechanisms of resistance to conventional chemotherapy. First, the tumor cells in solid neoplasms are a heterogeneous group with differing cell kinetics and angiogenic and metastatic potential. [3] These differences can be ascribed to single-nucleotide polymorphisms in the tumor cells. [4] Hence, successful chemotherapy should include multiple agents capable of acting on different targets. Second, tumor cells acquire resistance to chemotherapy, secondary to their inherent genomic instability. [5] Third, metastases are the commonest reason for relapse of tumor and tumor-related death and paradoxically, conventional chemotherapy is significantly less effective against metastases compared to the primary. [6] Finally, there is a significant interaction between the tumor and the surrounding microenvironment with cross-talk between the stroma and the neoplastic cells. [7] Consequently, any successful therapy against the tumor and metastases must target the stroma and the homeostatic controlling factors.


Over the past 40 years, since Judah Folkman's pioneering work, tumor angiogenesis is being recognized as a key driver of cancer growth and an important target for chemotherapy. [8] Angiogenesis is essential for the growth of both the primary tumor and the metastases. [7] Endothelial cells proliferate in response to known stimuli and can be inhibited by natural antiangiogenic molecules. [9] Significantly, tumor endothelial cells are qualitatively different from the normal endothelial cells. Intratumoral endothelial cells, compared to endothelial cells in normal quiescent tissues, proliferate rapidly and hence are more susceptible to cytotoxic agents. [6],[10],[11] Paradoxically, conventional chemotherapy schedules, due to their long treatment-free gaps, allow a small proportion of the endothelial cells to survive and maintain angiogenesis. Hence, normal dose-intensive chemotherapy has a less-than-complete effect on metastases and tumor relapses.

Angiogenesis as target of therapy

Considering the dependence of tumors on vasculature and endothelium, antiangiogenic drugs should have a significant effect on the growth of cancer. Theoretically, the drugs that target the angiogenic pathways damage the tumor cells by the induction of hypoxia and nutrient starvation. Experimental studies have shown that tumor angiogenesis could be better inhibited by frequent and low-dose cytotoxic agents than standard-dose chemotherapy. Klement et al., demonstrated that continuous low-dose vinblastine combined with anti-VEGF antibody (VEGF: Vascular endothelial growth factor) caused a significantly greater regression of xenograft tumors as a result of reduced tumor vascularity and angiogenesis. [12] Browder et al. showed similarly that metronomic antiangiogenic scheduling of cyclophosphamide (CTX) was three times more effective against drug-resistant Lewis lung carcinoma and EMT-6 (EMT: Epithelial to mesenchymal transition) breast carcinoma cell lines. Significantly, a more sustained endothelial apoptosis was shown in the tumor xenografts exposed to the metronomic schedule of treatment. [13] Other studies by O'Leary et al., using camptothecin analogues in mouse corneal model and Clements et al., using camptothecin and topotecan demonstrated a significant antiangiogenic effect when a metronomic scheduling was used. [14],[15] Further preclinical studies by Vacca et al. and Presta et al., supported the antiangiogenic effect of low-dose chemotherapy in preclinical models. [16],[17] Hanahan et al. coined the term 'metronomic' for this type of therapy-chronic administration of chemotherapeutic agents at relatively low, minimally toxic doses, and with no prolonged drug-free breaks. [18] This strategy of metronomic chemotherapy has been utilized in multiple studies with varying degrees of success.

Angiogenesis inhibitors in combination with metronomic chemotherapy

Targeted angiogenesis inhibitors are more selective than metronomic schedules of drugs alone. Theoretically, a combination of the two might be more efficacious than either agent alone. Proof of the concept was provided by several well-conducted preclinical studies. Selective antibodies to VEGF and selective cyclooxygenase-2 (COX-2) inhibitors are the agents commonly studied. Browder et al. showed that a combination of metronomic CTX and angiogenesis inhibitor TNP-470 led to the eradication of drug-resistant cell tumors in mice. [19] The primary mechanism in this study was postulated to be initial apoptosis of endothelial cells followed by apoptosis of tumor cells.

Other mechanisms of action

Apart from antiangiogeneis, recent research has cast light on the other mechanisms of action of metronomic chemotherapy including innate immunity, regulatory T cells (Tregs), tumor dormancy, and effects on the stroma and microenvironment.

Hanahan and Weinberg have defined six hallmark criteria in the tumorigenic process: Growth signal self-sufficiency, resistance to growth-inhibitory signals, resistance to apoptosis, limitless growth potential, sustained angiogenesis, and metastasizing potential. [20] In addition, the role of immunity has become increasingly prominent over the past few years and it has been suggested to be the seventh hallmark of cancer. [21]


Adaptive and innate immunity have an important role to play in cancer, with escape from immunosurveillance being one of the mechanisms of the growth of cancer. Conversely, an active immune system is essential for the optimal actions of chemotherapy agents. [22] Moreover, radiotherapy and certain cytotoxic drugs have an immunostimulatory effect that impair residual cancer cells and inhibit metastases. The increased incidence of cancers in immunodeficient and transplant patients is just one indicator of the importance of the immune system.

Cancer cells escape immunosurveillance by immunoselection (selection of nonimmunogenic tumor cell variants), also known as immunoediting or immunosubversion (active suppression of the immune response. [23]

Tanaka et al., showed that a few chemotherapeutic agents including vinblastine, paclitaxel, and etoposide can induce dendritic cell maturation in nontoxic concentration. The significance in metronomic chemotherapy is still to be elucidated. [24]


Tregs are CD4 + CD25 + lymphocytes, enriched with FoxP3, glucocorticoid-induced tumor necrosis factor (TNF) receptor, and cytotoxic T lymphocyte-associated antigen 4 that inhibit antitumor immune response by inhibiting both tumor-specific (CD4+ and CD8 + T cells) and nonspecific natural killer (NK) cells. [25] Tregs have been shown to be increased in multiple cancers and the presence of these cells correlates with a poorer response to chemotherapy. An interesting observation was the efficacy of low-dose CTX in inhibiting Tregs and increasing the innate immune effect against cancer in preclinical mouse models. [26] Ghiringhelli et al., also demonstrated the specific activity of low-dose CTX against circulating Tregs and their immunosuppression in various human cancers. [27] Lower doses of CTX led to the restoration of the activity of immune-specific cytotoxic T cells and NK cell function. The conventional-dose CTX probably inhibits all cells of the immune system and hence lacks the Treg-specific action seen with metronomic therapy. These findings have been corroborated in multiple preclinical studies. The association of Tregs, cancer immunity, and metronomic therapy is one of the most active areas of current research.

Tumor dormancy

Tumor dormancy is a stage of the evolution of cancer during which residual cancer is present but at an asymptomatic level. Tumor dormancy that includes angiogenic dormancy, cellular dormancy, and dormancy of the immune system maybe a result of cell cycle arrest or dynamic equilibrium between apoptosis and proliferation. [28] One of the mechanisms of metronomic therapy is the inhibition of angiogenesis and immune system which might result in tumor dormancy. Another intriguing possibility is the effect of the tumor itself in inducing immunity. Just as a small amount of antigen is required for immune stimulation, control and not eradication of tumor may lead to continued immunosurveillance. Although no studies have as yet demonstrated direct effects of metronomic chemotherapy in inducing cellular dormancy, this represents an attractive explanation for the efficacy of metronomic therapy.

4D effect

Andre et al., have postulated a 'drug-driven dependency/deprivation' or a four-dimensional (4D) phenomenon to explain the success of therapies utilizing intermittent drug interruptions. In a nutshell, the authors hypothesize that tumor cells become dependent on the chemotherapy agents during long exposure, and sudden cessation or replacement of therapy might lead to cell death. [29] This theory might account for the success of regimens where multiple drugs are used with differing periods of administration.

Clinical studies

Although there is a huge wealth of preclinical and theoretical data on metronomic therapy, the translation from the laboratory to the bedside has met with mixed results. Most of the trials are in advanced cancers and have resulted in increased progression-free survival and time to progression. Unfortunately, in real terms, the difference has been in the range of a few months only.

Metronomic chemotherapy in metastatic breast cancers

There are several studies based on metronomic principles in metastatic breast cancer. Orlando et al., published the results of two successive prospective trials conducted over seven years. [30] The treatment protocol was oral methotrexate (MTX) 2.5 mg twice daily on days 1 and 2 and oral CTX daily. Patients achieving clinical benefit [complete remission (CR), partial remission (PR), or stabilization of disease (SD)] for at least 12 months were included in the analysis. A total of 153 patients with a median follow-up of 23 months received the protocol, of whom, 48 received the chemotherapy as the first line. Five patients demonstrated CR and 25 had PR. Median time to progression for patients with prolonged clinical benefit was 21 months (range: 12-37 + months). After multivariate analysis, endocrine responsiveness and the achievement of an objective response correlated significantly with the achievement of prolonged clinical benefit.

Colleoni et al., evaluated the benefit of adding thalidomide to the above combination. [31] All patients with advanced breast cancer received oral CTX and MTX with or without thalidomide. In 171 patients, the overall response was 16.4% (28/171). Clinical benefit rate (CR + PR + SD at least 24 weeks) in this study was 41.5%. There was a statistically significant reduction in the serum VEGF levels with both the combinations. The addition of thalidomide did not add any benefit to oral chemotherapy.

The effect of the addition of anti-VEGF agent with chemotherapy is theoretically appealing as discussed above. The role of bevacizumab (10 mg/kg) with metronomic capecitabine (500 mg thrice daily) and CTX (50 mg once a day) was evaluated by Dellapasqua et al. [32] In 46 evaluable patients, there was a clinical benefit rate of 68% with a median time to progression of 42 weeks. The authors also studied the role of circulating endothelial cells and concluded that they may serve as surrogate markers for the efficacy of metronomic therapy.

HER2/neu (HER2: Human epidermal growth factor receptor 2) is an important prognostic and predictive marker in breast cancer that is linked to angiogenesis. The antibody to HER2, trastuzumab in a dose of 6 mg/kg, was evaluated in combination with metronomic MTX and CTX in metastatic breast cancer in 22 patients. [33] The clinical benefit rate was 47% and the median time to progression was six months.

Metronomic therapy is potentially useful in situations where traditional chemotherapy is too toxic or unfeasible. One hundred and fourteen elderly nonmetastatic hormone receptor-positive patients were treated with letrozole with or without oral metronomic CTX as primary therapy. [34] The treatment arm with CTX had better overall response rates, though the trial was not specifically designed to test the difference in the two arms.

A recent study evaluated oral uracil and tegafur compared to classic CTX, MTX, and fluorouracil (CMF) as adjuvant therapy in operated, node-negative breast cancer and found comparable efficacy with better quality of life and lesser toxicity for the oral regimen. [35]

There are several other studies in breast cancer evaluating various metronomic schedules and drugs. [36] Although almost all trials show promise, there is as yet, no definitely superior protocol.

Lung cancer

The combination of weekly docetaxel (25 mg/m 2 on days 1, 8, and 15 in a 28-day cycle) and oral trofosfamide was given as second-line therapy in 21 patients. [37] The overall response rate was 19%, median overall survival was 6.9 months, and the median progression-free survival 2.9 months. The regimen was well tolerated. Salvage weekly chemotherapy in relapsed lung cancer induced CR or PR in all 14 patients in one study. [38] Median survival was more than 30 months in this study, confirming the role of metronomic therapy in this setting. Different molecules like temozolomide have been evaluated in metastatic lung cancer with mixed results. [39] Although the response rates are satisfactory, long-term survivors are the exception than the rule.

Other solid malignancies

Metronomic chemotherapy has been evaluated in recurrent ovarian tumors, malignant melanomas, vascular tumors, renal cell cancers, prostate cancers, multiple myeloma, Hodgkin's disease, non-Hodgkin's lymphoma, mantle cell lymphoma, and other advanced cancers. [40],[41],[42],[43],[44],[45],[46],[47],[48],[49] As can be seen from [Table 1], oral CTX is present in almost all the regimens. It is combined with antiangiogenic agents like bevacizumab, immunomodulators like thalidomide, COX-2-selective inhibitors like rofecoxib, and peroxisome proliferator-associated receptor-gamma agonists like pioglitazone. Metronomic therapy was used in mostly metastatic, relapsed, and refractory patients. There is a distinct and clinically relevant response in this group of patients. The more pertinent finding is prolonged response and CR achieved in some patients, indicating that metronomic therapy might be selectively effective in certain patients. It is essential to develop techniques to identify these patients and incorporate metronomic principles to existing chemotherapy protocols. The metronomic agents were well tolerated with few grade 3 or 4 toxicities and could be administered over a long time in responding patients. Moreover, as many of the drugs are used as oral formulations, patient compliance and acceptance are significantly better than conventional chemotherapy.
Table 1: Oral CTX is present in regimens

Click here to view

Other agents that have been extensively tested include vinblastine, cisplatin, paclitaxel, and anthracyclines. All the trials show definite benefit with metronomic schedules; however, the exact dose, protocol, and mechanism of action have to be defined.

Pediatric patients

There is a higher incidence of successful cure among cancers in children. However, 25% of pediatric cancers are still incurable and are the focus of research. Metronomic schedules offer hope for longer term disease control with lesser toxicity and better disease control. Sterba et al., defined the COMBAT (COMBAT: combined oral maintenance biodifferentiating and antiangiogenic therapy) protocol consisting of metronomic schedules of celecoxib, (13cis)-retinoic acid, etoposide, and temozolomide given for a total of one year. [50] The protocol was used in 22 patients and resulted in clinical benefit (disease stabilization or response) in 9 of 14 assessable patients. The regimen was well tolerated with minimal side effects. The efficacy of metronomic therapy in a heavily pretreated cohort was shown in a study in recurrent and relapsed patients. [51] Twenty patients were treated with celecoxib and thalidomide with alternating etoposide and CTX for six months; 40% of the patients completed six months of therapy, whereas 25% of the patients continued to be progression-free at 123 weeks. Similarly, other trials showed clinical benefit with minimal toxicity in recurrent tumors. [52],[53]

Head and neck cancer

Head and neck cancer is a major problem in India. Metronomic chemotherapy has been tried in head and neck cancer with promising results. [54],[55] It appears that the time is right for the metronomic approach in oncology. [56]

Risks of metronomic therapy

Metronomic schedules have been extensively evaluated in trials across all age groups and types of cancers. Significantly, despite the patient population often being heavily pretreated, there have been no significant grade 3 and 4 toxicities. However, the long-term effect of prolonged exposure of drugs might lead to cumulative drug concentrations that exceed the safe limit. Cumulative effects of chemotherapy agents like etoposide are known to be associated with secondary leukemias. [57] A significant risk lies in using metronomic therapy in children where angiogenesis plays an important role in physiological growth. The effect of exposure to long-term chemotherapy on normal endothelial and vascular tissues is unknown.

 » Conclusion Top

Metronomic therapy represents 'out-of-the-box' thinking and utilizes existing drugs in different schedules to prolong survival. Backed by a wealth of preclinical data, metronomic schedules in the present day have shown promise in advanced cancers across all age groups and types. The challenge lies in proper selection of patients and in integrating metronomic schedules in adjuvant and possibly neoadjuvant therapy. Metronomic therapy has the potential to revolutionize treatment strategy, and large, well-designed studies are the need of the hour. Though the final chapter in the story of metronomic therapy is still a long way in the future, we can look ahead with optimism and hope.

 » References Top

1.Skipper HE, Schabel FM Jr, Mellett LB, Montgomery JA, Wilkoff LJ, Lloyd HH, et al. Implications of biochemical, cytokinetic, pharmacologic, and toxicologic relationships in the design of optimal therapeutic schedules. Cancer Chemother Rep 1970;54:431-50.  Back to cited text no. 1
2.Denekamp J, Daºu A, Waites A. Vasculature and microenvironmental gradients: The missing links in novel approaches to cancer therapy? Adv Enzyme Regul 1998;38:281-99.  Back to cited text no. 2
3.Bell C, Frost P, Kerbel RS. Cytogenetic heterogeneity of genetically marked and metastatically competent "dominant" tumor cell clones. Cancer Genet Cytogenet 1991;54:153-61.  Back to cited text no. 3
4.Liggett SB. Pharmacogenetic applications of the Human Genome project. Nat Med 2001;7:281-3.  Back to cited text no. 4
5.Gately S, Kerbel R. Antiangiogenic scheduling of lower dose cancer chemotherapy. Cancer J 2001;7:427-36.  Back to cited text no. 5
6.Kerbel RS. Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents. Bioessays 1991;13:31-6.  Back to cited text no. 6
7.Liotta LA, Kohn EC. The microenvironment of the tumour-host interface. Nature 2001;411:375-9.  Back to cited text no. 7
8.Folkman J. Tumor angiogenesis: Therapeutic implications. N Engl J Med 1971;285:1182-6.  Back to cited text no. 8
9.Gasparini G. Metronomic scheduling: The future of chemotherapy? Lancet Oncol 2001;2:733-40.  Back to cited text no. 9
10.Denekamp J. Vascular attack as a therapeutic strategy for cancer. Cancer Metastasis Rev 1990;9:267-82.  Back to cited text no. 10
11.Denekamp J. The tumour microcirculation as a target in cancer therapy: A clearer perspective. Eur J Clin Invest 1999;29:733-6.  Back to cited text no. 11
12.Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 2000;105:R15-24.  Back to cited text no. 12
13.Browder T, Butterfield CE, Kräling BM, Shi B, Marshall B, O'Reilly MS, et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 2000;60:1878-86.  Back to cited text no. 13
14.O'Leary JJ, Shapiro RL, Ren CJ, Chuang N, Cohen HW, Potmesil M. Antiangiogenic effects of camptothecin analogues 9-amino-20(S)-camptothecin, topotecan, and CPT-11 studied in the mouse cornea model. Clin Cancer Res 1999;5:181-7.  Back to cited text no. 14
15.Clements MK, Jones CB, Cumming M, Daoud SS. Antiangiogenic potential of camptothecin and topotecan. Cancer Chemother Pharmacol 1999;44:411-6.  Back to cited text no. 15
16.Vacca A, Iurlaro M, Ribatti D, Minischetti M, Nico B, Ria R, et al. Antiangiogenesis is produced by nontoxic doses of vinblastine. Blood 1999;94:4143-55.  Back to cited text no. 16
17.Presta M, Rusnati M, Belleri M, Morbidelli L, Ziche M, Ribatti D. Purine analogue 6-methylmercaptopurine riboside inhibits early and late phases of the angiogenesis process. Cancer Res 1999;59:2417-24.  Back to cited text no. 17
18.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.  Back to cited text no. 18
19.Browder T, Butterfield CE, Kräling BM, Shi B, Marshall B, O'Reilly MS, et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 2000;60:1878-86.  Back to cited text no. 19
20.Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57-70.  Back to cited text no. 20
21.Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: From immunosurveillance to tumor escape. Nat Immunol 2002;3:991-8.  Back to cited text no. 21
22.Tesniere A, Apetoh L, Ghiringhelli F, Joza N, Panaretakis T, Kepp O, et al. Immunogenic cancer cell death: A key-lock paradigm. Curr Opin Immunol 2008;20:504-11.  Back to cited text no. 22
23.Zitvogel L, Apetoh L, Ghiringhelli F, André F, Tesniere A, Kroemer G. The anticancer immune response: Indispensable for therapeutic success? J Clin Invest 2008;118:1991-2001.  Back to cited text no. 23
24.Tanaka H, Matsushima H, Mizumoto N, Takashima A. Classification of chemotherapeutic agents based on their differential in vitro effects on dendritic cells. Cancer Res 2009;69:6978-86.  Back to cited text no. 24
25.Kosmaczewska A, Ciszak L, Potoczek S, Frydecka I. The significance of Treg cells in defective tumor immunity. Arch Immunol Ther Exp 2008;56:181-91.  Back to cited text no. 25
26.Ghiringhelli F, Larmonier N, Schmitt E, Parcellier A, Cathelin D, Garrido C, et al. CD4+CD25+regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol 2004;34:336-44.  Back to cited text no. 26
27.Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother 2007;56:641-8.  Back to cited text no. 27
28.Aguirre-Ghiso JA. Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 2007;7:834-46.  Back to cited text no. 28
29.André N, Pasquier E. Response to 'Intermittent androgen blockade should be regarded as standard therapy in prostate cancer'. Nat Clin Pract Oncol 2009;6:E1.  Back to cited text no. 29
30.Orlando L, Cardillo A, Rocca A, Balduzzi A, Ghisini R, Peruzzotti G, et al. Prolonged clinical benefit with metronomic chemotherapy in patients with metastatic breast cancer. Anticancer Drugs 2006;17:961-7.  Back to cited text no. 30
31.Colleoni M, Orlando L, Sanna G, Rocca A, Maisonneuve P, Peruzzotti G, et al. Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: Antitumor activity and biological effects. Ann Oncol 2006;17:232-8.  Back to cited text no. 31
32.Dellapasqua S, Bertolini F, Bagnardi V, Campagnoli E, Scarano E, Torrisi R, et al. Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer. J Clin Oncol 2008;26:4899-905.  Back to cited text no. 32
33.Orlando L, Cardillo A, Ghisini R, Rocca A, Balduzzi A, Torrisi R, et al. Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer. BMC Cancer 2006;6:225.  Back to cited text no. 33
34.Bottini A, Generali D, Brizzi MP, Fox SB, Bersiga A, Bonardi S, et al. Randomized phase II trial of letrozole and letrozole plus low-dose metronomic oral cyclophosphamide as primary systemic treatment in elderly breast cancer patients. J Clin Oncol 2006;24:3623-8.  Back to cited text no. 34
35.Watanabe T, Sano M, Takashima S, Kitaya T, Tokuda Y, Yoshimoto M, et al. Oral uracil and tegafur compared with classic cyclophosphamide, methotrexate, fluorouracil as postoperative chemotherapy in patients with node-negative, high-risk breast cancer: National Surgical Adjuvant Study for Breast Cancer 01 Trial. J Clin Oncol 2009;27:1368-74.  Back to cited text no. 35
36.Wong NS, Buckman RA, Clemons M, Verma S, Dent S, Trudeau ME, et al. Phase I/II trial of metronomic chemotherapy with daily dalteparin and cyclophosphamide, twice-weekly methotrexate, and daily prednisone as therapy for metastatic breast cancer using vascular endothelial growth factor and soluble vascular endothelial growth factor receptor levels as markers of response. J Clin Oncol 2010;28:723-30.  Back to cited text no. 36
37.Görn M, Habermann CR, Anige M, Thöm I, Schuch G, Andritzky B, et al. A pilot study of docetaxel and trofosfamide as second-line andlsquo; metronomicandrsquo; chemotherapy in the treatment of metastatic non-small cell lung cancer (NSCLC). Onkologie 2008;31:185-9.  Back to cited text no. 37
38.Nick C. Metronomic chemotherapy in patients with advanced non-small-cell lung cancer associated with long-term survival. Clin Lung Cancer 2008;9:290.  Back to cited text no. 38
39.Kouroussis C, Vamvakas L, Vardakis N, Kotsakis A, Kalykaki A, Kalbakis K, et al. Continuous administration of daily low-dose temozolomide in pretreated patients with advanced non-small cell lung cancer: A phase II study. Oncology 2009;76:112-7.  Back to cited text no. 39
40.Garcia AA, Hirte H, Fleming G, Yang D, Tsao-Wei DD, Roman L, et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: A trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol 2008;26:76-82.  Back to cited text no. 40
41.Vogt T, Hafner C, Bross K, Bataille F, Jauch K, Berand A, et al. Antiangiogenetic therapy with pioglitazone, rofecoxib, and metronomic trofosfamide in patients with advanced malignant vascular tumors. Cancer 2003;98:2251-6.  Back to cited text no. 41
42.Spieth K, Kaufmann R, Gille J. Metronomic oral low-dose treosulfan chemotherapy combined with cyclooxygenase-2 inhibitor in pretreated advanced melanoma: A pilot study. Cancer Chemother Pharmacol 2003;52:377-82.  Back to cited text no. 42
43.Steinbild S, Arends J, Medinger M, Häring B, Frost A, Drevs J, et al. Metronomic antiangiogenic therapy with capecitabine and celecoxib in advanced tumor patients-results of a phase II study. Onkologie 2007;30:629-35.  Back to cited text no. 43
44.Briasoulis E, Pappas P, Puozzo C, Tolis C, Fountzilas G, Dafni U, et al. Dose-ranging study of metronomic oral vinorelbine in patients with advanced refractory cancer. Clin Cancer Res 2009;15:6454-61.  Back to cited text no. 44
45.Findlay M, Sharples K, Riley GA, Simpson A, Ackland S, Hall K, et al. Capecitabine and oral cyclophosphamide: A novel oral treatment combination for advanced cancer. Asia-Pacific J Clin Oncol 2007;3:99-105.  Back to cited text no. 45
46.Ruan J, Martin P, Coleman M, Furman RR, Cheung K, Faye A, et al. Durable responses with the metronomic rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide regimen in elderly patients with recurrent mantle cell lymphoma. Cancer 2010;116:2655-64.  Back to cited text no. 46
47.Coleman M, Martin P, Ruan J, Furman R, Niesvizky R, Elstrom R, et al. Prednisone, etoposide, procarbazine, and cyclophosphamide (PEP‐C) oral combination chemotherapy regimen for recurring/refractory lymphoma: Low‐dose metronomic, multidrug therapy. Cancer 2008;112:2228-32.  Back to cited text no. 47
48.Young SD, Whissell M, Noble JCS, Cano PO, Lopez PG, Germond CJ. Phase II clinical trial results involving treatment with low-dose daily oral cyclophosphamide, weekly vinblastine, and rofecoxib in patients with advanced solid tumors. Clin Cancer Res 2006;12:3092-8.  Back to cited text no. 48
49.Hovenga S, Daenen SM, de Wolf JT, van Imhoff GW, Kluin-Nelemans HC, Sluiter WJ, et al. Combined thalidomide and cyclophosphamide treatment for refractory or relapsed multiple myeloma patients: A prospective phase II study. Ann Hematol 2004;84:311-6.  Back to cited text no. 49
50.Sterba J, Valik D, Mudry P, Kepak T, Pavelka Z, Bajciova V, et al. Combined biodifferentiating and antiangiogenic oral metronomic therapy is feasible and effective in relapsed solid tumors in children: Single-center pilot study. Onkologie 2006;29:308-13.  Back to cited text no. 50
51.Kieran MW, Turner CD, Rubin JB, Chi SN, Zimmerman MA, Chordas C, et al. A feasibility trial of antiangiogenic (metronomic) chemotherapy in pediatric patients with recurrent or progressive cancer. J Pediatr Hematol Oncol 2005;27:573-81.  Back to cited text no. 51
52.André N, Rome A, Coze C, Padovani L, Pasquier E, Camoin L, et al. Metronomic etoposide/cyclophosphamide/celecoxib regimen given to children and adolescents with refractory cancer: A preliminary monocentric study. Clin Ther 2008;30:1336-40.  Back to cited text no. 52
53.Stempak D, Gammon J, Halton J, Moghrabi A, Koren G, Baruchel S. A pilot pharmacokinetic and antiangiogenic biomarker study of celecoxib and low-dose metronomic vinblastine or cyclophosphamide in pediatric recurrent solid tumors. J Pediatr Hematol Oncol 2006;28:720-8.  Back to cited text no. 53
54.Patil V, Noronha V, Krishna V, Joshi A, Prabhash K. Oral metronomic chemotherapy in recurrent, metastatic and locally advanced head and neck cancers. Clin Oncol 2013;25:388.  Back to cited text no. 54
55.Patil V, Noronha V, Dcruz AK, Banavali SD, Prabhash K. Metronomic chemotherapy in advanced oral cancers. J Cancer Res Ther 2012;8:106-10.  Back to cited text no. 55
56.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:e239-48.  Back to cited text no. 56
57.Le Deley MC, Leblanc T, Shamsaldin A, Raquin MA, Lacour B, Sommelet D, et al. Risk of secondary leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: A case-control study by the Société Française d'Oncologie Pédiatrique. J Clin Oncol 2003;21:1074-81  Back to cited text no. 57


  [Table 1]

This article has been cited by
1 Oral metronomic chemotherapy after definitive chemoradiation in esophageal squamous cell carcinoma: a randomized clinical trial
V. Noronha, V. M. Patil, N. S. Menon, A. Joshi, S. Goud, S. More, S. Kannan, A. Pawar, D. Nakti, A. Yadav, S. Shah, A. Mahajan, A. Janu, R. Kumar, A. Tibdewal, N. Mummudi, J. P. Agarwal, S. D. Banavali, K. Prabhash
Esophagus. 2022;
[Pubmed] | [DOI]
2 Young-Onset Pancreatobiliary Cancers—Whereto from Here?
Savio George Barreto
Indian Journal of Surgery. 2022;
[Pubmed] | [DOI]
3 A Mechanistic Review of Methotrexate and Celecoxib as a Potential Metronomic Chemotherapy for Oral Squamous Cell Carcinoma.
Mehta Vedant Kamal, Mahadev Rao, Rama Rao Damerla, Ananth Pai, Krishan Sharan, Akhil Palod, Preethi S. Shetty, Nawaz Usman, Naveena AN Kumar
Cancer Investigation. 2022; : 1
[Pubmed] | [DOI]
4 Achievements and challenges in the use of metronomics for the treatment of breast cancer
O. Graciela Scharovsky, María José Rico, Leandro E. Mainetti, Herman A. Perroud, Viviana R. Rozados
Biochemical Pharmacology. 2020; 175: 113909
[Pubmed] | [DOI]
5 Phase I/II Study of Palliative Triple Metronomic Chemotherapy in Platinum-Refractory/Early-Failure Oral Cancer
Vijay M. Patil, Vanita Noronha, Amit Joshi, Sachin Dhumal, Manoj Mahimkar, Atanu Bhattacharjee, Vikram Gota, Manish Pandey, Nandini Menon, Abhishek Mahajan, Nilesh Sable, Suman Kumar, Kavita Nawale, Sadaf Mukadam, Bhavin Solanki, Sudeep Das, Vijai Simha, George Abraham, Arun Chandrasekharan, Vikas Talreja, Hollis DSouza, Sujay Srinivas, Lakhan Kashyap, Shripad Banavali, Kumar Prabhash
Journal of Clinical Oncology. 2019; 37(32): 3032
[Pubmed] | [DOI]
6 A Commentary: Herbal Medicine Offers Great Potential in Support of Metronomic Cancer Therapy
Clara Bik-San Lau,Chun-Kwok Wong,Ping-Chung Leung
Journal of Cancer Therapy. 2017; 08(02): 86
[Pubmed] | [DOI]
7 Potential role of metronomic chemotherapy in the treatment of esophageal and gastroesophageal cancer
Vanita Noronha,Vijay M. Patil,Amit Joshi,Anuradha Chougule,Shripad Banavali,Kumar Prabhash
Cancer Letters. 2017; 400: 267
[Pubmed] | [DOI]
8 Cyclophosphamide and Bortezomib With Prednisone or Dexamethasone for the Treatment of Relapsed and Refractory Multiple Myeloma
Donna E. Reece,Young Trieu,Esther Masih-Khan,Eshetu G. Atenafu,Christine Chen,Anca Prica,Rodger Tiedemann,Suzanne Trudel,Vishal Kukreti
Clinical Lymphoma Myeloma and Leukemia. 2016; 16(7): 387
[Pubmed] | [DOI]
9 Metronomic cyclophosphamide eradicates large implanted GL261 gliomas by activating antitumor Cd8+T-cell responses and immune memory
Junjie Wu,David J Waxman
OncoImmunology. 2015; 4(4): e1005521
[Pubmed] | [DOI]
10 Phase I-II trial of oral cyclophosphamide, prednisone and lenalidomide for the treatment of patients with relapsed and refractory multiple myeloma
Donna E. Reece,Esther Masih-Khan,Eshetu G. Atenafu,Victor H. Jimenez-Zepeda,Peter Anglin,Christine Chen,Vishal Kukreti,Joseph R. Mikhael,Suzanne Trudel
British Journal of Haematology. 2014; : n/a
[Pubmed] | [DOI]
11 Metronomic cyclophosphamide schedule-dependence of innate immune cell recruitment and tumor regression in an implanted glioma model
Junjie Wu,David J. Waxman
Cancer Letters. 2014; 353(2): 272
[Pubmed] | [DOI]
12 New insights into metronomic chemotherapy-induced immunoregulation
Yi-Bin Hao,Shan-Yong Yi,Jing Ruan,Ling Zhao,Ke-Jun Nan
Cancer Letters. 2014; 354(2): 220
[Pubmed] | [DOI]


Print this article  Email this article


  Site Map | What's new | Copyright and Disclaimer | Privacy Notice
  Online since 1st April '07
  © 2007 - Indian Journal of Cancer | Published by Wolters Kluwer - Medknow