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SYMPOSIUM FOR METRONOMICS AND ECONOMICS- REVIEW ARTICLE
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
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.117027

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 » 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 2021 May 19];50:142-8. Available from: https://www.indianjcancer.com/text.asp?2013/50/2/142/117027



 » 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.

Angiogenesis

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]

Immunity

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

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.

 
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