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Metronomic chemotherapy: A relook at its basis and rationale
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Cancer Letters xxx (2016) 1e6
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Cancer Letters journal homepage: www.elsevier.com/locate/canlet
Mini-review Q4 Q3
Metronomic chemotherapy: A relook at its basis and rationale Tanujaa Rajasekaran a, Quan-Sing Ng a, Daniel Shao-Weng Tan a, Wan-Teck Lim a, Mei-Kim Ang a, Chee-Keong Toh a, Balram Chowbay b, Ravindran Kanesvaran a, Eng-Huat Tan a, * a b
Q1
Division of Medical Oncology, National Cancer Centre, Singapore Divsion of Medical Sciences, Laboratory of Clinical Pharmacology, National Cancer Centre, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history: Received 27 October 2016 Received in revised form 7 December 2016 Accepted 9 December 2016
Metronomic administration of chemotherapy has long been recognized as having a different biological effect from maximal tolerated dose (MTD) administration. Preclinical studies have demonstrated these differences quite elegantly and many clinical trials have also demonstrated reproducible activity albeit small, in varied solid malignancies even in patients who were heavily pretreated. However, the concept of metronomic chemotherapy has been plagued by lack of a clear definition resulting in the published literature that is rather varied and confusing. There is a need for a definition that is mechanism(s)-based allowing metronomics to be distinguished from standard MTD concept. With significant advances made in understanding cancer biology and biotechnology, it is now possible to attain that goal. What is needed is both a concerted effort and adequate funding to work towards it. This is the only way for the oncology community to determine how metronomic chemotherapy fits in the overall cancer management schema. © 2016 Published by Elsevier Ireland Ltd.
Keywords: Metronomic chemotherapy Cancer Definition of metronomic chemotherapy Biomarkers
Introduction Concepts of cancer therapy have evolved significantly over the decades leading to major strides in survival, even in patients with incurable stages of the disease. It is well established that successful outcome of therapy does not solely depend on taking on the cancer cells, but the microenvironment surrounding them that sustains and shields them from potential damage and death. The battle against cancer started in the 1970's with the use of cytotoxics that are administered at or close to maximal tolerated dose (MTD), typically given in combination regimens comprising agents with non-overlapping toxicities [1,2]. The MTD approach aims to disrupt the mitotic processes of the cancer cells that are typically in overdrive that renders them more sensitive to these drugs than normal quiescent cells. But this strategy is rarely successful in cancers of a complex makeup and it is well established that such cancers make use of the microenvironment to survive. * Corresponding author. National Cancer Centre Singapore, 11, Hospital Drive, 169610, Singapore. Fax: þ65 62272759. E-mail addresses: [email protected] (T. Rajasekaran), ng.quan. [email protected] (Q.-S. Ng), [email protected] (D.S.-W. Tan), [email protected] (W.-T. Lim), [email protected] (M.-K. Ang), [email protected] (C.-K. Toh), [email protected] (B. Chowbay), [email protected] (R. Kanesvaran), tan.eng. [email protected] (E.-H. Tan).
Two important concepts of cancer therapy have emerged progressively over a long period of time to target the microenvironment [3]: vascular supply of tumor cells that provide the essential nutrients and the immune cell milieu that has learnt to “live” with the destructive force of the cancer cells. The call by Judah Folkman [4] to target the blood supply of cancer cells in 1971 led to a 30-year journey before the first antiangiogenic drug called bevacizumab was approved in breast and colorectal cancers. Although the survival benefit conferred was at best modest, the achievement can be considered a landmark as the concept of targeting supporting structures like blood supply was clinically validated. The development of immunotherapy initially was met with more disappointments than successes. However about 2 years ago immune checkpoint inhibitors were proven to confer significant survival benefit in treatment-refractory complex cancers such as melanomas and renal cancers. Certain cytotoxics when given in a continuous or more frequent manner without extended rest periods have been found to exert a therapeutic effect on the tumor microenvironment. For instance, it can result in a significant anti-angiogenic effect [5,6]. This strategy came about on a hypothesis that endothelial cell recovery can occur during treatment-free period of conventional scheduling and this could support regrowth of tumor cells and thereby increase the risk
http://dx.doi.org/10.1016/j.canlet.2016.12.013 0304-3835/© 2016 Published by Elsevier Ireland Ltd.
Please cite this article in press as: T. Rajasekaran, et al., Metronomic chemotherapy: A relook at its basis and rationale, Cancer Letters (2016), http://dx.doi.org/10.1016/j.canlet.2016.12.013
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of emergence of drug-resistant tumor cells [7,8]. A closely spaced or continuous administration of cytotoxics akin to the uninterrupted ticking of a metronome as coined by Hanahan was hypothesized to selectively target the proliferating endothelial cells of cancer and spare the quiescent mature endothelial cells of healthy tissues [9]. Moreover avoidance of mutation and development of resistance is possible, as the proliferating endothelial cells are the main targets, which are genetically more stable. This schedule would necessitate a lower dose of cytotoxics to allow frequent administration. Both Folkman's and Kerbel's group have proven this concept elegantly with their in-vitro and in-vivo experiments [5,6]. Chemotherapy may also have potentially useful partnership with immunotherapy in cancer treatment [10]. Several cytotoxics have been shown in preclinical studies to overcome the tumor immunosuppressive environment in several ways [11,12]. In fact the immunomodulatory properties of cyclophosphamide have been known since 1974 when it was shown to reduce T-cell suppressive activity [13]. It is likely that the cytotoxic and immunomodulatory doses of chemotherapy agents would be different and it is also likely that not all chemotherapy drugs have the same immunomodulatory effects on the tumor microenvironment. Metronomic dosing of chemotherapeutic agents may be able to restore the immune response to a certain degree albeit not fully. It is certainly an attractive mechanism worthy of further exploitation. A recent meta-analysis of metronomic chemotherapy involving 80 Phase I/II trials, of mainly pre-treated patients with advanced/ metastatic breast (26.25%) and prostate (11.25%) cancer showed a response rate of 26% and a mean disease control rate of 56%. Grade 3/4 adverse events as expected were rare (anemia 8%, fatigue 13%) [14]. Hence metronomic chemotherapy appears to be both clinically beneficial and safe. What is metronomic chemotherapy? While Hanahan used the analogy of the metronome to describe the closely spaced administration of chemotherapy, there is no universally accepted definition [15]. The oft used definition is schedule-based and refers to a chronic administration of chemotherapy at low, minimally toxic doses on uninterrupted close intervals [16]. Klement and Kamen offered an alternative definition of metronomic chemotherapy as the minimum biologically effective dose of a chemotherapeutic agent, which given at regular dosing regimen with no prolonged drug free interval leads to anti-tumor activity [17]. However, both definitions failed to focus on the alternative mechanisms of action of such schedules, which is the most important distinguishing feature of such an administration. Such a definition would need a robust and reproducible way to measure the anti-angiogenic and immune-related effects of metronomic administration and therein lies the limitation of such a definition. A mechanistic definition is critical to distinguish such a schedule from MTD administration, which we have come to appreciate has a very different biological effect. A mechanistic definition would streamline the literature now abundant with reports of clinical effects of so-called metronomic schedules but some with toxicity profiles that seemed to be more in line with MTD schedules. If a purported metronomic schedule published in the literature reported significant degree of grade 3 or 4 toxicities that necessitated frequent interruptions, there is a need to question whether any efficacy of treatment that resulted is truly a metronomic effect and not a MTD effect. It would benefit the medical and research literati if a more accurate definition be consistently applied in the published literature that we can better appreciate how metronomic chemotherapy can fit into overall scheme of cancer management.
Are there biomarkers available to guide metronomic dosing? The importance of biomarkers to guide drug development, which should also include drug repurposing or repositioning have been dealt with in excellent reviews [18,19]. Biomarkers to indicate achievement of pharmacodynamic effects are important to determine the optimal metronomic dose (OMD) of cytotoxics. While MTD determination is easily established with routine laboratory tests and clinical assessments, OMD determination faces significant challenges. Amongst the many reported mechanisms of anti-cancer actions of metronomic chemotherapy, two main pharmacodynamic parameters of interest in metronomic chemotherapy are probably worthy of further exploration as biomarkers, namely antiangiogenic and immune effects. These are arguably the most extensively studied in therapies specific for angiogenesis and immune modulation, albeit not translated into routine clinical use due to lack of validation. Though they are not sufficiently sensitive, specific or reproducible to predict response or survival outcome in routine clinical setting, they may still be useful in the research setting to help derive useful data regarding the metronomic activity of cytotoxic agents of interest to guide the appropriate metronomic dosing. Many potential biomarkers were studied to demonstrate inhibition of targets of angiogenesis when evaluating anti-angiogenic drugs. They include circulating blood biomarkers (cytokines such as VEGF, angiopoetin or thrombospondin-1/2 and circulating endothelial cells), immunohistochemistry (e.g. VEGF and TSP-2), functional imaging (e.g. DCE-MRI, or DCE-CT) and even singlenucleotide polymorphisms (e.g. VEGF, IL6, IL8, etc) [20e26]. Though changes may occur in tandem with treatment administration, neither the baseline levels nor changes have been shown to consistently correlate with response or survival outcome. Functional imaging (e.g. DCE-MRI) has been explored quite extensively in several small studies. DCE-MRI is an established technique for evaluation of tumor vasculature and has been utilized in early phase clinical trials of vascular targeting drugs [19,24e26]. DCE-MRI is a technique in which a paramagnetic low molecular weight contrast agent is injected intravenously and monitored, with multiple images over a period of minutes, as it enters the tumor blood vessels and subsequently passes into the extravascular and extracellular space. Vascular parameters can be assessed by T1weighted and T2-weighted sequences. Quantitative parameters of tumor vascularity derived using DCE-MRI include blood flow, permeability-surface area product, fractional intravascular volume and fractional interstitial volume. However functional imaging is limited by the fact that only one or two representative lesions from one tumor site can be selected for measurement and it is needful therefore to assume that changes in levels in the selected lesion reflect similar changes in other unmeasured lesions during antiangiogenic treatment. Therefore functional imaging fails to take into account the possible heterogeneity in behavior of the disseminated lesions. This trait may account for the inability of functional imaging to predict for benefit consistently in clinical studies [27]. Metronomic chemotherapy has been reported to affect tumor immune biology in several ways. However, like immune checkpoint inhibitors, it does not uniformly affect tumor immune biology within or across tumor types. As such there is a need to characterize comprehensively the effect of metronomic dosing of cytotoxics on the immunosuppressive and immune stimulatory components that define the inflammatory state of the tumor microenvironment. The significant advances made in the field of high throughput technologies can allow a deeper interrogation of the antibody responses, as well as the magnitude, cytotoxic function and T cell receptor repertoire of T lymphocytes than what has been done in
Please cite this article in press as: T. Rajasekaran, et al., Metronomic chemotherapy: A relook at its basis and rationale, Cancer Letters (2016), http://dx.doi.org/10.1016/j.canlet.2016.12.013
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the area of metronomic chemotherapy thus far. It will be possible to obtain a more in-depth understanding if the effects of metronomic chemotherapy are correlated with the mutation antigen profile, the gene signature and epigenetic modification of tumor, in addition to the immune cells [28]. This can also lead to a more informed manner of combining metronomic chemotherapy with the immune checkpoint inhibitors, which has already taken oncology practice to a whole new level. This would of course necessitate a carefully designed study that involves procurement of blood and tumor biospecimens during the course of therapy with metronomic chemotherapy. It is likely that the often conflicting and confusing literature in this topic of predictive biomarkers is due to variable and nonuniform way of evaluation in terms of choice of the types of biomarker(s), the laboratory procedures, and the classification of the patients relative to the biomarker [29]. While changes in levels or measurement of some of the available biomarkers were documented fairly reproducibly to indicate target action, they are still not robust enough for clinical utility [27]. Hence at this juncture, a mechanistic definition for metronomic chemotherapy though ideal, cannot be realized with the current technology. However with the rapid advances and improvement in biological understanding and laboratory technology, it may be feasible in the near future to define the OMD of cytotoxics based on a mechanistic approach that can be applied to the population at large. The Pharmaceutical Research and Manufacturers of America defines “Proof of concept” (POC) as the earliest point in the drug development process at which the weight of evidence suggests that it is “reasonably likely” that the key attributes for success are present and the key causes of failure are absent. Zhao et al. paraphrased this definition further as “the point at which investment in large and costly dose-finding and subsequent phase III studies is justified” [30,31]. It is arguable based on the definition whether the metronomic chemotherapy concept has attained “POC” status based on the clinical trials conducted to date. Perhaps it is now appropriate to move on to potential surrogate biomarkers given the lack of validated anti-angiogenic and immune modulation biomarkers to guide metronomic chemotherapy development. Advances in molecular diagnostics such as droplet digital PCR and next generation sequencing have made possible real-time assessment of tumor burden through the assessment of mutation burden in cell-free DNA from patients on therapy [32,33]. Reducing the tumor burden is the ultimate goal of any cancer therapy regardless the target. Hence this form of tumor biomarker that measures tumor burden if proven to be robust and reproducible may be able to overcome the obstacles faced when measuring the targets of angiogenesis and immune modulation. The crucial role that pharmacokinetics play in metronomic chemotherapy development should be brought up at this juncture. Both pharmacodynamics and pharmacokinetics biomarkers are inseparable partners if we desire to move the status of metronomics from empiricism to a more precise and informed applied science [34]. It is also important that the sample size of future studies need to be sufficiently large to allow identification of the appropriate patients to target for this therapeutic approach. This is lacking in studies conducted to date. The small studies with incorporation of biomarkers lack the power of the sample size to zero-in on the best biomarkers to bring forward, and the big randomized studies lack the inclusion of biomarkers to help validate the potential biomarker candidates. What are the clinical evidence that metronomic chemotherapy works? Slow advances have been made in area of metronomic chemotherapy unlike the relative rapid development of genome targeted
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therapies such as EGFR or ALK inhibitors or the immune checkpoint inhibitors which are guided largely by biomarker development. Evaluation of the literature for efficacy of metronomic chemotherapy is also hampered by the empiricism of its definition. For lack of a better way other than reliance on the empirical definition proposed by Klement and Kamen [17], the following points ought to be borne in mind when a published study is reviewed: 1) is the dose administered frequently enough that endothelial cell recovery can reasonably be thwarted? 2) is the level of grade 3e4 toxicities low enough to keep dose interruptions to a negligible level? In order to be “clean” in evaluating its clinical merits, we confined our discussion to studies done with single agent cytotoxics described as given in a metronomic fashion. There have been multiple studies published using metronomic chemotherapy alone. Majority are phase 1 and 2 studies [35e54]. For brevity's sake, we confine our discussion to vinorelbine, capecitabine and cyclophosphamide, which are the most commonly used metronomic agents due to the availability of oral formulation. Table 1 summarizes the main points regarding these studies. Most of the studies did not carry out pharmacokinetics evaluation and the grade 3 or 4 toxicities reported in some of these studies do indicate that the dose selected may not be in the metronomic range for a proportion of the patients. The optimal dose of metronomic vinorelbine was established to be a 50 mg orally thrice a week [35,36]. The metronomic dose of vinorelbine was derived using the modified phase 1 MTD approach which leads one to question if the dose of 50 mg thrice a week is really “metronomic” for a subset of patients of smaller stature [35]. Perhaps an adaptive trial design may be more appropriate for metronomic dose finding of cytotoxics [55]. Although Briasoulis et al. demonstrated a generally favorable safety profile with this dose in their studies including a randomized phase 2 study of a mixed group of solid tumors, about 11e18% of the patients in each arm developed grade 3e4 neutropenia with no statistical significance between the 30 or 40 or 50 mg thrice weekly doses. The limited pharmacokinetic study which reflected a dose proportional increase of steady state concentrations was noted but did not reach statistical significance. Kontopodis et al. reported the activity of metronomic oral vinorelbine 50 mg thrice weekly in 46 heavily pretreated non-small cell lung cancer and found a response rate of 10.9% and 19.6% achieved disease stabilization [37]. The median time to progression (TTP) was 2.2 months, median overall survival of 9.4 months and the 1-year survival rate of 30.1% was attained. However grade 3e4 toxicities was quite significant at this dose with Grade 3e4 neutropenia observed in 23.9%, febrile neutropenia in 10.9% and grade 3 fatigue in 10.9%. An ongoing randomized phase 2 trial comparing metronomic schedule versus the standard MTD schedule of oral vinorelbine is currently recruiting in Europe [41]. Capecitabine with its broad spectrum of activity and oral formulation is one of the most extensively studied metronomic agent. However, there are few single agent metronomic capecitabine studies reported and none had pharmacokinetics built in [42e44]. The dose schedule is variable amongst the studies though activity even in the setting of prior therapies was reproducible (Table 1). Stockler et al. assigned 323 patients with advanced breast cancer to standard capecitabine, daily metronomic capecitabine and the classic Bonadonna CMF regimen [45]. The capecitabine arms showed improved survival and better tolerability and there was no difference in efficacy and tolerability between the standard and metronomic capecitabine arm. However it is of note that the toxicity profile and dose reduction rate were equal between the metronomic and standard capecitabine arms, which begs the question as to whether the dose selected for the metronomic arm is truly in the metronomic range. Pharmacodynamic and pharmacokinetic correlates were not conducted in this study.
Please cite this article in press as: T. Rajasekaran, et al., Metronomic chemotherapy: A relook at its basis and rationale, Cancer Letters (2016), http://dx.doi.org/10.1016/j.canlet.2016.12.013
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Table 1 Studies of metronomic schedule with single agent cytotoxics. Author (ref)
N
Cytotoxic/dose
Prior treatment
Disease site
ORR (%)
CBR (%)
Grade 3e4 toxicities
Briasoulis [40]
73
Yes
Mixed
5
20
Neutropenia 11e18%
Kontopodis [41]
46
VRL at 30 mg, 40 mg, 50 mg thrice weekly VRL 50 mg thrice weekly
Yes
NSCLC
11
30
No
Breast
38
68%
No No Yes
Prostate NSCLC Gastric
35 (PSA) 18.6 21
NA 58 51
Neutropenia 24% Febrile neutropenia 11% Neutropenia 9% Febrile neutropenia 6% none none Neutropenia 9%
Yes No (59) Yes (31 sora) No
Breast HCC Breast
24 5 (naïve) 0 (prior sora) 20
62 56 (naïve) 32 (pior sora) 50
2
VRL 70 mg/m thrice weekly for 3 out of 4 weeks VRL 30 mg thrice weekly VRL 50 mg thrice weekly Cape 1000 mg/m2 daily 4 out of 5 wk Cape 1500 mg daily Cape 1000 mg daily
Addeo [42]
34
DiDesidaro [43] Camerini [44] He [46]
41 43 45
Fedele [47] Brandi [48]
60 90
Stockler [49]
107
Cape 650 mg/m2 twice daily continuously
Nicolini [50]
7
Yes
Prostate
25
62.5
Glode [51] Lord [52]
34 58
CTX 100e150 mg alternately daily CTX 50 mg daily CTX 50 mg/m2 daily
Yes (13 patients) Yes
Prostate Prostate
79 (PSA) 34.5
85 (PSA) Not reported
Penel [53] Nelius [54] Ladoire [55]
44 17 23
CTX 50 mg twice daily CTX 50 mg daily CTX 50 mg daily
Yes Yes Yes
Mixed Prostate Prostate
0 23.5 (PSA) 26 (PSA)
11.4 53 (PSA) 48 (PSA)
Mir [56]
26
CTX 100 mg twice daily
Yes
Sarcoma
27
69
Gebbia [57] Ferrandina [58]
22 54
CTX 50 mg daily CTX 50 mg daily
Yes Yes
Breast Ovarian
14 20.4
55 40.7
Hand/Foot 5% Not reported Thrombocytopenia 3% Anemia 3% Neutropenia 0.9% Hand/Foot 16% Neutropenia (grade 2 or 3) 100% Not reported Neutropenia 1.7% Anemia 1.7% None None Neutropenia 4% Anemia 8% Lymphopenia 26% Anemia 7.7% Thrombocytopenia 7.7% Lymphopenia 80.7% Leukopenia 5% Anemia 2% Asthenia 2%
N ¼ sample size; VRL ¼ vinorelbine oral; Cape ¼ capecitabine; CTX ¼ cyclophosphamide; sora ¼ sorafenib; ORR ¼ overall response rate; CBR ¼ Clinical benefit rate; NSCLC ¼ non-small cell lung cancer; HCC ¼ hepatocellular carcinoma; PSA ¼ prostate-specific antigen.
Similarly, studies on metronomic cyclophosphamide are confined largely to small studies mainly conducted in prostate cancer [46e54]. Majority of the patients were heavily pretreated and activity was demonstrated reproducibly in these studies. Due to lack of pharmacodynamics and pharmacokinetics data, the optimal dose of metronomic cyclophosphamide is unknown with most studies utilizing 50 mg daily dosing. This dose is well tolerated with negligible grade 3e4 toxicities and demonstrable activity albeit small (Table 1). Metronomic chemotherapy in the adjuvant setting Metronomic chemotherapy in the adjuvant setting was shown in two large randomized trials in breast and lung cancer patients [56,57]. A randomized trial in 900 patients with completely resected pathological stage I adenocarcinoma of the lung, reported a significantly increased 2-year survival (88% versus 85%) with uraciletegafur at 200 mg/m2 as maintenance for 2 years compared with the control group receiving no treatment [56]. The rate of treatment compliance was fairly good with 80 percent at 6 months, 74 percent at 12 months, 69 percent at 18 months and 61 percent at 24 months. The toxicity profile especially the myelotoxicity rate is reported to be very low, which is consistent with the expected profile of metronomic dosing. In the adjuvant breast trial involving 733 patients with node-negative disease, uracil-tegafur administered for 2 years was shown to be non-inferior in efficacy when compared to standard CMF meeting the study end-point [57]. The quality of life measurement was superior in the uracil-tegafur arm though the grade 3e4 non-hematological toxicity rate was higher in the study arm. The seemingly higher toxicity profile in this study
compared to the lung study may be attributed to the higher dose of uracil-tegafur used (300 mg/m2). However the compliance rate of 63.6% at 2 years was comparable to the lung study. Re-purposing cytotoxics from mtd to metronomics There are advantages in pursuing the metronomic approach of administering cytotoxics. Firstly, there is enough cumulative evidence from pre-clinical and clinical studies that metronomic cytotoxics work differently from MTD approach. Secondly oncologists are familiar with the MTD toxicity profile of these drugs. And finally, these drugs are easily available at low cost or in generic forms and the cost of re-developing these drugs is less likely to put a further strain on healthcare systems throughout the world [58]. However, metronomic chemotherapy would not benefit every patient as is clear from the clinical data gathered to date. There is still a need to identify the right context and the right patient group to benefit from metronomic chemotherapy whether in mono- or combination therapy. Time and commitment from the oncology community are required to determine the role that metronomic chemotherapy play in clinical practice. Funding for this research is unlikely to come from the pharmaceutical industry. Therefore the government and any healthcare-related non-profit organization would have to step in to commit research dollars into this major undertaking. Conclusion and future development Metronomic treatment as an alternative strategy is of sufficient interest to pursue but suffers from the lack of resources with
Please cite this article in press as: T. Rajasekaran, et al., Metronomic chemotherapy: A relook at its basis and rationale, Cancer Letters (2016), http://dx.doi.org/10.1016/j.canlet.2016.12.013
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respect to research and development. Its multi targeted nature, potential to be combined with targeted therapies and immunotherapies, low cost and convenience of oral administration makes it a very appealing strategy for clinicians. The complex mechanisms of action of metronomic cytotoxics used either as monotherapy or in combination needs to be well understood to define the best drugs to use according to the tumor type, patient population and clinical setting. Acknowledgement Translational & Clinical Research, the National Medical Research Council, Singapore (NMRC/TCR/007-NCC/2013); National Cancer Centre Core Block grant (NRNCFCG16157) and Centre Grant Programme (NRNMRCG13157). We are also grateful to the Trailblazer Foundation Ltd. and Singapore Millenium Foundation for their instrumental support to the Lung Cancer Consortium Singapore (NRFTB11122). Conflict of interest None. References [1] H.E. Skipper, F.M. Schabel Jr., L.B. Mellett, et al., Implications of biochemical, cytokinetic, pharmacologic, and toxicologic relationships in the design of optimal therapeutic schedules, Cancer Chemother. Rep. 54 (1970) 431e450. [2] J.J. Kim, I.F. Tannock, Repopulation of cancer cells during therapy: an important cause of treatment failure, Nat. Rev. Cancer 5 (2005) 516e525. [3] M.J. Bissell, W.C. Hines, Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression, Nat. Med. 17 (2011) 320e329. [4] J. Folkman, Tumor angiogenesis: therapeutic implications, N. Engl. J. Med. 285 (1971), 1182e1161. [5] T. Browder, C.E. Butterfield, B.M. Kr€ aling, et al., Anti-angiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer, Cancer Res. 60 (2000) 1878e1886. [6] G. Klement, S. Baruchel, J. Rak, et al., Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity, J. Clin. Invest. 105 (2000) R15eR24. [7] F. Bertolini, S. Paul, P. Mancuso, et al., Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells, Cancer Res. 63 (2003) 4342e4346. [8] Y. Shaked, U. Emmenegger, S. Man, et al., Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum anti-angiogenic activity, Blood 106 (2005) 3058e3061. [9] D. Hanahan, G. Bergers, E. Bergsland, Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice, J. Clin. Invest. 105 (2007) 1045. [10] R.A. Lake, B.W. Robinson, Immunotherapy and chemotherapy d a practical partnership, Nat. Rev. Cancer 5 (2005) 397e405. [11] Y.B. Hao, S.Y. Yi, J. Ruan, et al., New insights into metronomic chemotherapyinduced immunoregulation, Cancer Lett. 354 (2014) 220e226. [12] Y. Shaked, E. Pham, S. Hariharan, et al., Evidence implicating immunological host effects in the efficacy of metronomic low-dose chemotherapy, Cancer Res. 76 (2016) 5983e5993. [13] L. Polak, J.L. Turk, Reversal of immunological tolerance by cyclophosphamide through inhibition of suppressor cell activity, Nature 249 (1974) 654e656. [14] K. Lien, S. Georgsdottir, L. Sivanathan, et al., Low-dose metronomic chemotherapy: a systematic literature analysis, Eur. J. Cancer 16 (2013) 3387e3395. [15] E. Munzone, M. Colleoni, Clinical overview of metronomic chemotherapy in breast cancer, Nat. Rev. Clin. Oncol. 12 (2015) 631e644. , Metronomic chemotherapy: new ratio[16] E. Pasquier, M. Kavallaris, N. Andre nale for new directions, Nat. Rev. Clin. Oncol. 7 (2010) 455e465. [17] G.L. Klement, B.A. Kamen, Nontoxic, fiscally responsible, future of oncology: could it be beginning in the third world? J. Paediatr. Haematol. Oncol. 33 (2011) 1e3. [18] P. Workman, E.O. Aboagye, Y.L. Chung, et al., Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing clinical trials of innovative therapies, J. Natl. Cancer Inst. 98 (2006) 580e598. [19] J.P. O'Connor, E.O. Aboagye, J.E. Adams, et al., Imaging biomarker roadmap for cancer studies, Nat. Rev. Clin. Oncol. (2016) 162. [20] G. Cramarossa, E.K. Lee, L. Sivanathan, et al., A systematic literature analysis of correlative studies in low-dose metronomic chemotherapy trials, Biomark. Med. 8 (2014) 893e911.
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Kouvatseas, et al., Dose selection trial of metronomic oral vinorelbine monotherapy in patients with metastatic cancer: a Hellenic Cooperative Oncology Group clinical translational study, BMC Cancer 13 (2013) 263. [37] E. Kontopodis, D. Hatzidaki, I. Varthalitis, et al., A phase II study of metronomic oral vinorelbine administered in the second line and beyond in non-small cell lung cancer (NSCLC): a phase II study of the Hellenic Oncology Research Group, J. Chemother. 25 (2013) 49e55. [38] R. Addeo, A. Sgambato, G. Cennamo, et al., Low-dose metronomic oral administration of vinorelbine in the first-line treatment of elderly patients with metastatic breast cancer, Clin. Breast Cancer 10 (2010) 301e306. [39] T. Di Desidero, L. Derosa, L. Galli, et al., Clinical, pharmacodynamic and pharmacokinetic results of a prospective phase II study on oral metronomic vinorelbine and dexamethasone in castration-resistant prostate cancer patients, Invest. New Drugs 34 (2016) 760e770. [40] A. Camerini, C. Puccetti, S. Donati, et al., Metronomic oral vinorelbine as firstline treatment in elderly patients with advanced non-small cell lung cancer: results of a phase II trial (MOVE trial), BMC Cancer 15 (2015) 359. [41] https://www.clinicaltrialsregister.eu/ctr-search/search?query¼vinorelbineþ tartrate. [42] S. He, J. Shen, L. Hong, Capecitabine “metronomic” chemotherapy for palliative treatment of elderly patients with advanced gastric cancer after fluoropyrimidine-based chemotherapy, Med. Oncol. 29 (2009) 100e106. [43] P. Fedele, A. Marino, L. Orlando, et al., Efficacy and safety of low-dose metronomic chemotherapy with capecitabine in heavily pretreated patients with metastatic breast cancer, Eur. J. Cancer 48 (2012) 24e49. [44] G. Brandi, F. De Rosa, V. Agostini, et al., Metronomic capecitabine in advanced hepatocellular carcinoma patients: a phase II study, Oncologist 18 (2013) 1256e1257. [45] M.R. Stockler, V.J. Harvey, P.A. 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Contents lists available at ScienceDirect
Cancer Letters journal homepage: www.elsevier.com/locate/canlet
Mini-review Q4 Q3
Metronomic chemotherapy: A relook at its basis and rationale Tanujaa Rajasekaran a, Quan-Sing Ng a, Daniel Shao-Weng Tan a, Wan-Teck Lim a, Mei-Kim Ang a, Chee-Keong Toh a, Balram Chowbay b, Ravindran Kanesvaran a, Eng-Huat Tan a, * a b
Q1
Division of Medical Oncology, National Cancer Centre, Singapore Divsion of Medical Sciences, Laboratory of Clinical Pharmacology, National Cancer Centre, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history: Received 27 October 2016 Received in revised form 7 December 2016 Accepted 9 December 2016
Metronomic administration of chemotherapy has long been recognized as having a different biological effect from maximal tolerated dose (MTD) administration. Preclinical studies have demonstrated these differences quite elegantly and many clinical trials have also demonstrated reproducible activity albeit small, in varied solid malignancies even in patients who were heavily pretreated. However, the concept of metronomic chemotherapy has been plagued by lack of a clear definition resulting in the published literature that is rather varied and confusing. There is a need for a definition that is mechanism(s)-based allowing metronomics to be distinguished from standard MTD concept. With significant advances made in understanding cancer biology and biotechnology, it is now possible to attain that goal. What is needed is both a concerted effort and adequate funding to work towards it. This is the only way for the oncology community to determine how metronomic chemotherapy fits in the overall cancer management schema. © 2016 Published by Elsevier Ireland Ltd.
Keywords: Metronomic chemotherapy Cancer Definition of metronomic chemotherapy Biomarkers
Introduction Concepts of cancer therapy have evolved significantly over the decades leading to major strides in survival, even in patients with incurable stages of the disease. It is well established that successful outcome of therapy does not solely depend on taking on the cancer cells, but the microenvironment surrounding them that sustains and shields them from potential damage and death. The battle against cancer started in the 1970's with the use of cytotoxics that are administered at or close to maximal tolerated dose (MTD), typically given in combination regimens comprising agents with non-overlapping toxicities [1,2]. The MTD approach aims to disrupt the mitotic processes of the cancer cells that are typically in overdrive that renders them more sensitive to these drugs than normal quiescent cells. But this strategy is rarely successful in cancers of a complex makeup and it is well established that such cancers make use of the microenvironment to survive. * Corresponding author. National Cancer Centre Singapore, 11, Hospital Drive, 169610, Singapore. Fax: þ65 62272759. E-mail addresses: [email protected] (T. Rajasekaran), ng.quan. [email protected] (Q.-S. Ng), [email protected] (D.S.-W. Tan), [email protected] (W.-T. Lim), [email protected] (M.-K. Ang), [email protected] (C.-K. Toh), [email protected] (B. Chowbay), [email protected] (R. Kanesvaran), tan.eng. [email protected] (E.-H. Tan).
Two important concepts of cancer therapy have emerged progressively over a long period of time to target the microenvironment [3]: vascular supply of tumor cells that provide the essential nutrients and the immune cell milieu that has learnt to “live” with the destructive force of the cancer cells. The call by Judah Folkman [4] to target the blood supply of cancer cells in 1971 led to a 30-year journey before the first antiangiogenic drug called bevacizumab was approved in breast and colorectal cancers. Although the survival benefit conferred was at best modest, the achievement can be considered a landmark as the concept of targeting supporting structures like blood supply was clinically validated. The development of immunotherapy initially was met with more disappointments than successes. However about 2 years ago immune checkpoint inhibitors were proven to confer significant survival benefit in treatment-refractory complex cancers such as melanomas and renal cancers. Certain cytotoxics when given in a continuous or more frequent manner without extended rest periods have been found to exert a therapeutic effect on the tumor microenvironment. For instance, it can result in a significant anti-angiogenic effect [5,6]. This strategy came about on a hypothesis that endothelial cell recovery can occur during treatment-free period of conventional scheduling and this could support regrowth of tumor cells and thereby increase the risk
http://dx.doi.org/10.1016/j.canlet.2016.12.013 0304-3835/© 2016 Published by Elsevier Ireland Ltd.
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of emergence of drug-resistant tumor cells [7,8]. A closely spaced or continuous administration of cytotoxics akin to the uninterrupted ticking of a metronome as coined by Hanahan was hypothesized to selectively target the proliferating endothelial cells of cancer and spare the quiescent mature endothelial cells of healthy tissues [9]. Moreover avoidance of mutation and development of resistance is possible, as the proliferating endothelial cells are the main targets, which are genetically more stable. This schedule would necessitate a lower dose of cytotoxics to allow frequent administration. Both Folkman's and Kerbel's group have proven this concept elegantly with their in-vitro and in-vivo experiments [5,6]. Chemotherapy may also have potentially useful partnership with immunotherapy in cancer treatment [10]. Several cytotoxics have been shown in preclinical studies to overcome the tumor immunosuppressive environment in several ways [11,12]. In fact the immunomodulatory properties of cyclophosphamide have been known since 1974 when it was shown to reduce T-cell suppressive activity [13]. It is likely that the cytotoxic and immunomodulatory doses of chemotherapy agents would be different and it is also likely that not all chemotherapy drugs have the same immunomodulatory effects on the tumor microenvironment. Metronomic dosing of chemotherapeutic agents may be able to restore the immune response to a certain degree albeit not fully. It is certainly an attractive mechanism worthy of further exploitation. A recent meta-analysis of metronomic chemotherapy involving 80 Phase I/II trials, of mainly pre-treated patients with advanced/ metastatic breast (26.25%) and prostate (11.25%) cancer showed a response rate of 26% and a mean disease control rate of 56%. Grade 3/4 adverse events as expected were rare (anemia 8%, fatigue 13%) [14]. Hence metronomic chemotherapy appears to be both clinically beneficial and safe. What is metronomic chemotherapy? While Hanahan used the analogy of the metronome to describe the closely spaced administration of chemotherapy, there is no universally accepted definition [15]. The oft used definition is schedule-based and refers to a chronic administration of chemotherapy at low, minimally toxic doses on uninterrupted close intervals [16]. Klement and Kamen offered an alternative definition of metronomic chemotherapy as the minimum biologically effective dose of a chemotherapeutic agent, which given at regular dosing regimen with no prolonged drug free interval leads to anti-tumor activity [17]. However, both definitions failed to focus on the alternative mechanisms of action of such schedules, which is the most important distinguishing feature of such an administration. Such a definition would need a robust and reproducible way to measure the anti-angiogenic and immune-related effects of metronomic administration and therein lies the limitation of such a definition. A mechanistic definition is critical to distinguish such a schedule from MTD administration, which we have come to appreciate has a very different biological effect. A mechanistic definition would streamline the literature now abundant with reports of clinical effects of so-called metronomic schedules but some with toxicity profiles that seemed to be more in line with MTD schedules. If a purported metronomic schedule published in the literature reported significant degree of grade 3 or 4 toxicities that necessitated frequent interruptions, there is a need to question whether any efficacy of treatment that resulted is truly a metronomic effect and not a MTD effect. It would benefit the medical and research literati if a more accurate definition be consistently applied in the published literature that we can better appreciate how metronomic chemotherapy can fit into overall scheme of cancer management.
Are there biomarkers available to guide metronomic dosing? The importance of biomarkers to guide drug development, which should also include drug repurposing or repositioning have been dealt with in excellent reviews [18,19]. Biomarkers to indicate achievement of pharmacodynamic effects are important to determine the optimal metronomic dose (OMD) of cytotoxics. While MTD determination is easily established with routine laboratory tests and clinical assessments, OMD determination faces significant challenges. Amongst the many reported mechanisms of anti-cancer actions of metronomic chemotherapy, two main pharmacodynamic parameters of interest in metronomic chemotherapy are probably worthy of further exploration as biomarkers, namely antiangiogenic and immune effects. These are arguably the most extensively studied in therapies specific for angiogenesis and immune modulation, albeit not translated into routine clinical use due to lack of validation. Though they are not sufficiently sensitive, specific or reproducible to predict response or survival outcome in routine clinical setting, they may still be useful in the research setting to help derive useful data regarding the metronomic activity of cytotoxic agents of interest to guide the appropriate metronomic dosing. Many potential biomarkers were studied to demonstrate inhibition of targets of angiogenesis when evaluating anti-angiogenic drugs. They include circulating blood biomarkers (cytokines such as VEGF, angiopoetin or thrombospondin-1/2 and circulating endothelial cells), immunohistochemistry (e.g. VEGF and TSP-2), functional imaging (e.g. DCE-MRI, or DCE-CT) and even singlenucleotide polymorphisms (e.g. VEGF, IL6, IL8, etc) [20e26]. Though changes may occur in tandem with treatment administration, neither the baseline levels nor changes have been shown to consistently correlate with response or survival outcome. Functional imaging (e.g. DCE-MRI) has been explored quite extensively in several small studies. DCE-MRI is an established technique for evaluation of tumor vasculature and has been utilized in early phase clinical trials of vascular targeting drugs [19,24e26]. DCE-MRI is a technique in which a paramagnetic low molecular weight contrast agent is injected intravenously and monitored, with multiple images over a period of minutes, as it enters the tumor blood vessels and subsequently passes into the extravascular and extracellular space. Vascular parameters can be assessed by T1weighted and T2-weighted sequences. Quantitative parameters of tumor vascularity derived using DCE-MRI include blood flow, permeability-surface area product, fractional intravascular volume and fractional interstitial volume. However functional imaging is limited by the fact that only one or two representative lesions from one tumor site can be selected for measurement and it is needful therefore to assume that changes in levels in the selected lesion reflect similar changes in other unmeasured lesions during antiangiogenic treatment. Therefore functional imaging fails to take into account the possible heterogeneity in behavior of the disseminated lesions. This trait may account for the inability of functional imaging to predict for benefit consistently in clinical studies [27]. Metronomic chemotherapy has been reported to affect tumor immune biology in several ways. However, like immune checkpoint inhibitors, it does not uniformly affect tumor immune biology within or across tumor types. As such there is a need to characterize comprehensively the effect of metronomic dosing of cytotoxics on the immunosuppressive and immune stimulatory components that define the inflammatory state of the tumor microenvironment. The significant advances made in the field of high throughput technologies can allow a deeper interrogation of the antibody responses, as well as the magnitude, cytotoxic function and T cell receptor repertoire of T lymphocytes than what has been done in
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the area of metronomic chemotherapy thus far. It will be possible to obtain a more in-depth understanding if the effects of metronomic chemotherapy are correlated with the mutation antigen profile, the gene signature and epigenetic modification of tumor, in addition to the immune cells [28]. This can also lead to a more informed manner of combining metronomic chemotherapy with the immune checkpoint inhibitors, which has already taken oncology practice to a whole new level. This would of course necessitate a carefully designed study that involves procurement of blood and tumor biospecimens during the course of therapy with metronomic chemotherapy. It is likely that the often conflicting and confusing literature in this topic of predictive biomarkers is due to variable and nonuniform way of evaluation in terms of choice of the types of biomarker(s), the laboratory procedures, and the classification of the patients relative to the biomarker [29]. While changes in levels or measurement of some of the available biomarkers were documented fairly reproducibly to indicate target action, they are still not robust enough for clinical utility [27]. Hence at this juncture, a mechanistic definition for metronomic chemotherapy though ideal, cannot be realized with the current technology. However with the rapid advances and improvement in biological understanding and laboratory technology, it may be feasible in the near future to define the OMD of cytotoxics based on a mechanistic approach that can be applied to the population at large. The Pharmaceutical Research and Manufacturers of America defines “Proof of concept” (POC) as the earliest point in the drug development process at which the weight of evidence suggests that it is “reasonably likely” that the key attributes for success are present and the key causes of failure are absent. Zhao et al. paraphrased this definition further as “the point at which investment in large and costly dose-finding and subsequent phase III studies is justified” [30,31]. It is arguable based on the definition whether the metronomic chemotherapy concept has attained “POC” status based on the clinical trials conducted to date. Perhaps it is now appropriate to move on to potential surrogate biomarkers given the lack of validated anti-angiogenic and immune modulation biomarkers to guide metronomic chemotherapy development. Advances in molecular diagnostics such as droplet digital PCR and next generation sequencing have made possible real-time assessment of tumor burden through the assessment of mutation burden in cell-free DNA from patients on therapy [32,33]. Reducing the tumor burden is the ultimate goal of any cancer therapy regardless the target. Hence this form of tumor biomarker that measures tumor burden if proven to be robust and reproducible may be able to overcome the obstacles faced when measuring the targets of angiogenesis and immune modulation. The crucial role that pharmacokinetics play in metronomic chemotherapy development should be brought up at this juncture. Both pharmacodynamics and pharmacokinetics biomarkers are inseparable partners if we desire to move the status of metronomics from empiricism to a more precise and informed applied science [34]. It is also important that the sample size of future studies need to be sufficiently large to allow identification of the appropriate patients to target for this therapeutic approach. This is lacking in studies conducted to date. The small studies with incorporation of biomarkers lack the power of the sample size to zero-in on the best biomarkers to bring forward, and the big randomized studies lack the inclusion of biomarkers to help validate the potential biomarker candidates. What are the clinical evidence that metronomic chemotherapy works? Slow advances have been made in area of metronomic chemotherapy unlike the relative rapid development of genome targeted
3
therapies such as EGFR or ALK inhibitors or the immune checkpoint inhibitors which are guided largely by biomarker development. Evaluation of the literature for efficacy of metronomic chemotherapy is also hampered by the empiricism of its definition. For lack of a better way other than reliance on the empirical definition proposed by Klement and Kamen [17], the following points ought to be borne in mind when a published study is reviewed: 1) is the dose administered frequently enough that endothelial cell recovery can reasonably be thwarted? 2) is the level of grade 3e4 toxicities low enough to keep dose interruptions to a negligible level? In order to be “clean” in evaluating its clinical merits, we confined our discussion to studies done with single agent cytotoxics described as given in a metronomic fashion. There have been multiple studies published using metronomic chemotherapy alone. Majority are phase 1 and 2 studies [35e54]. For brevity's sake, we confine our discussion to vinorelbine, capecitabine and cyclophosphamide, which are the most commonly used metronomic agents due to the availability of oral formulation. Table 1 summarizes the main points regarding these studies. Most of the studies did not carry out pharmacokinetics evaluation and the grade 3 or 4 toxicities reported in some of these studies do indicate that the dose selected may not be in the metronomic range for a proportion of the patients. The optimal dose of metronomic vinorelbine was established to be a 50 mg orally thrice a week [35,36]. The metronomic dose of vinorelbine was derived using the modified phase 1 MTD approach which leads one to question if the dose of 50 mg thrice a week is really “metronomic” for a subset of patients of smaller stature [35]. Perhaps an adaptive trial design may be more appropriate for metronomic dose finding of cytotoxics [55]. Although Briasoulis et al. demonstrated a generally favorable safety profile with this dose in their studies including a randomized phase 2 study of a mixed group of solid tumors, about 11e18% of the patients in each arm developed grade 3e4 neutropenia with no statistical significance between the 30 or 40 or 50 mg thrice weekly doses. The limited pharmacokinetic study which reflected a dose proportional increase of steady state concentrations was noted but did not reach statistical significance. Kontopodis et al. reported the activity of metronomic oral vinorelbine 50 mg thrice weekly in 46 heavily pretreated non-small cell lung cancer and found a response rate of 10.9% and 19.6% achieved disease stabilization [37]. The median time to progression (TTP) was 2.2 months, median overall survival of 9.4 months and the 1-year survival rate of 30.1% was attained. However grade 3e4 toxicities was quite significant at this dose with Grade 3e4 neutropenia observed in 23.9%, febrile neutropenia in 10.9% and grade 3 fatigue in 10.9%. An ongoing randomized phase 2 trial comparing metronomic schedule versus the standard MTD schedule of oral vinorelbine is currently recruiting in Europe [41]. Capecitabine with its broad spectrum of activity and oral formulation is one of the most extensively studied metronomic agent. However, there are few single agent metronomic capecitabine studies reported and none had pharmacokinetics built in [42e44]. The dose schedule is variable amongst the studies though activity even in the setting of prior therapies was reproducible (Table 1). Stockler et al. assigned 323 patients with advanced breast cancer to standard capecitabine, daily metronomic capecitabine and the classic Bonadonna CMF regimen [45]. The capecitabine arms showed improved survival and better tolerability and there was no difference in efficacy and tolerability between the standard and metronomic capecitabine arm. However it is of note that the toxicity profile and dose reduction rate were equal between the metronomic and standard capecitabine arms, which begs the question as to whether the dose selected for the metronomic arm is truly in the metronomic range. Pharmacodynamic and pharmacokinetic correlates were not conducted in this study.
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Table 1 Studies of metronomic schedule with single agent cytotoxics. Author (ref)
N
Cytotoxic/dose
Prior treatment
Disease site
ORR (%)
CBR (%)
Grade 3e4 toxicities
Briasoulis [40]
73
Yes
Mixed
5
20
Neutropenia 11e18%
Kontopodis [41]
46
VRL at 30 mg, 40 mg, 50 mg thrice weekly VRL 50 mg thrice weekly
Yes
NSCLC
11
30
No
Breast
38
68%
No No Yes
Prostate NSCLC Gastric
35 (PSA) 18.6 21
NA 58 51
Neutropenia 24% Febrile neutropenia 11% Neutropenia 9% Febrile neutropenia 6% none none Neutropenia 9%
Yes No (59) Yes (31 sora) No
Breast HCC Breast
24 5 (naïve) 0 (prior sora) 20
62 56 (naïve) 32 (pior sora) 50
2
VRL 70 mg/m thrice weekly for 3 out of 4 weeks VRL 30 mg thrice weekly VRL 50 mg thrice weekly Cape 1000 mg/m2 daily 4 out of 5 wk Cape 1500 mg daily Cape 1000 mg daily
Addeo [42]
34
DiDesidaro [43] Camerini [44] He [46]
41 43 45
Fedele [47] Brandi [48]
60 90
Stockler [49]
107
Cape 650 mg/m2 twice daily continuously
Nicolini [50]
7
Yes
Prostate
25
62.5
Glode [51] Lord [52]
34 58
CTX 100e150 mg alternately daily CTX 50 mg daily CTX 50 mg/m2 daily
Yes (13 patients) Yes
Prostate Prostate
79 (PSA) 34.5
85 (PSA) Not reported
Penel [53] Nelius [54] Ladoire [55]
44 17 23
CTX 50 mg twice daily CTX 50 mg daily CTX 50 mg daily
Yes Yes Yes
Mixed Prostate Prostate
0 23.5 (PSA) 26 (PSA)
11.4 53 (PSA) 48 (PSA)
Mir [56]
26
CTX 100 mg twice daily
Yes
Sarcoma
27
69
Gebbia [57] Ferrandina [58]
22 54
CTX 50 mg daily CTX 50 mg daily
Yes Yes
Breast Ovarian
14 20.4
55 40.7
Hand/Foot 5% Not reported Thrombocytopenia 3% Anemia 3% Neutropenia 0.9% Hand/Foot 16% Neutropenia (grade 2 or 3) 100% Not reported Neutropenia 1.7% Anemia 1.7% None None Neutropenia 4% Anemia 8% Lymphopenia 26% Anemia 7.7% Thrombocytopenia 7.7% Lymphopenia 80.7% Leukopenia 5% Anemia 2% Asthenia 2%
N ¼ sample size; VRL ¼ vinorelbine oral; Cape ¼ capecitabine; CTX ¼ cyclophosphamide; sora ¼ sorafenib; ORR ¼ overall response rate; CBR ¼ Clinical benefit rate; NSCLC ¼ non-small cell lung cancer; HCC ¼ hepatocellular carcinoma; PSA ¼ prostate-specific antigen.
Similarly, studies on metronomic cyclophosphamide are confined largely to small studies mainly conducted in prostate cancer [46e54]. Majority of the patients were heavily pretreated and activity was demonstrated reproducibly in these studies. Due to lack of pharmacodynamics and pharmacokinetics data, the optimal dose of metronomic cyclophosphamide is unknown with most studies utilizing 50 mg daily dosing. This dose is well tolerated with negligible grade 3e4 toxicities and demonstrable activity albeit small (Table 1). Metronomic chemotherapy in the adjuvant setting Metronomic chemotherapy in the adjuvant setting was shown in two large randomized trials in breast and lung cancer patients [56,57]. A randomized trial in 900 patients with completely resected pathological stage I adenocarcinoma of the lung, reported a significantly increased 2-year survival (88% versus 85%) with uraciletegafur at 200 mg/m2 as maintenance for 2 years compared with the control group receiving no treatment [56]. The rate of treatment compliance was fairly good with 80 percent at 6 months, 74 percent at 12 months, 69 percent at 18 months and 61 percent at 24 months. The toxicity profile especially the myelotoxicity rate is reported to be very low, which is consistent with the expected profile of metronomic dosing. In the adjuvant breast trial involving 733 patients with node-negative disease, uracil-tegafur administered for 2 years was shown to be non-inferior in efficacy when compared to standard CMF meeting the study end-point [57]. The quality of life measurement was superior in the uracil-tegafur arm though the grade 3e4 non-hematological toxicity rate was higher in the study arm. The seemingly higher toxicity profile in this study
compared to the lung study may be attributed to the higher dose of uracil-tegafur used (300 mg/m2). However the compliance rate of 63.6% at 2 years was comparable to the lung study. Re-purposing cytotoxics from mtd to metronomics There are advantages in pursuing the metronomic approach of administering cytotoxics. Firstly, there is enough cumulative evidence from pre-clinical and clinical studies that metronomic cytotoxics work differently from MTD approach. Secondly oncologists are familiar with the MTD toxicity profile of these drugs. And finally, these drugs are easily available at low cost or in generic forms and the cost of re-developing these drugs is less likely to put a further strain on healthcare systems throughout the world [58]. However, metronomic chemotherapy would not benefit every patient as is clear from the clinical data gathered to date. There is still a need to identify the right context and the right patient group to benefit from metronomic chemotherapy whether in mono- or combination therapy. Time and commitment from the oncology community are required to determine the role that metronomic chemotherapy play in clinical practice. Funding for this research is unlikely to come from the pharmaceutical industry. Therefore the government and any healthcare-related non-profit organization would have to step in to commit research dollars into this major undertaking. Conclusion and future development Metronomic treatment as an alternative strategy is of sufficient interest to pursue but suffers from the lack of resources with
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respect to research and development. Its multi targeted nature, potential to be combined with targeted therapies and immunotherapies, low cost and convenience of oral administration makes it a very appealing strategy for clinicians. The complex mechanisms of action of metronomic cytotoxics used either as monotherapy or in combination needs to be well understood to define the best drugs to use according to the tumor type, patient population and clinical setting. Acknowledgement Translational & Clinical Research, the National Medical Research Council, Singapore (NMRC/TCR/007-NCC/2013); National Cancer Centre Core Block grant (NRNCFCG16157) and Centre Grant Programme (NRNMRCG13157). We are also grateful to the Trailblazer Foundation Ltd. and Singapore Millenium Foundation for their instrumental support to the Lung Cancer Consortium Singapore (NRFTB11122). Conflict of interest None. References [1] H.E. Skipper, F.M. Schabel Jr., L.B. Mellett, et al., Implications of biochemical, cytokinetic, pharmacologic, and toxicologic relationships in the design of optimal therapeutic schedules, Cancer Chemother. Rep. 54 (1970) 431e450. [2] J.J. Kim, I.F. Tannock, Repopulation of cancer cells during therapy: an important cause of treatment failure, Nat. Rev. Cancer 5 (2005) 516e525. [3] M.J. Bissell, W.C. Hines, Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression, Nat. Med. 17 (2011) 320e329. [4] J. Folkman, Tumor angiogenesis: therapeutic implications, N. Engl. J. Med. 285 (1971), 1182e1161. [5] T. Browder, C.E. Butterfield, B.M. Kr€ aling, et al., Anti-angiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer, Cancer Res. 60 (2000) 1878e1886. [6] G. Klement, S. Baruchel, J. Rak, et al., Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity, J. Clin. Invest. 105 (2000) R15eR24. [7] F. Bertolini, S. Paul, P. Mancuso, et al., Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells, Cancer Res. 63 (2003) 4342e4346. [8] Y. Shaked, U. Emmenegger, S. Man, et al., Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum anti-angiogenic activity, Blood 106 (2005) 3058e3061. [9] D. Hanahan, G. Bergers, E. Bergsland, Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice, J. Clin. Invest. 105 (2007) 1045. [10] R.A. Lake, B.W. Robinson, Immunotherapy and chemotherapy d a practical partnership, Nat. Rev. Cancer 5 (2005) 397e405. [11] Y.B. Hao, S.Y. Yi, J. Ruan, et al., New insights into metronomic chemotherapyinduced immunoregulation, Cancer Lett. 354 (2014) 220e226. [12] Y. Shaked, E. Pham, S. Hariharan, et al., Evidence implicating immunological host effects in the efficacy of metronomic low-dose chemotherapy, Cancer Res. 76 (2016) 5983e5993. [13] L. Polak, J.L. Turk, Reversal of immunological tolerance by cyclophosphamide through inhibition of suppressor cell activity, Nature 249 (1974) 654e656. [14] K. Lien, S. Georgsdottir, L. Sivanathan, et al., Low-dose metronomic chemotherapy: a systematic literature analysis, Eur. J. Cancer 16 (2013) 3387e3395. [15] E. Munzone, M. Colleoni, Clinical overview of metronomic chemotherapy in breast cancer, Nat. Rev. Clin. Oncol. 12 (2015) 631e644. , Metronomic chemotherapy: new ratio[16] E. Pasquier, M. Kavallaris, N. Andre nale for new directions, Nat. Rev. Clin. Oncol. 7 (2010) 455e465. [17] G.L. Klement, B.A. Kamen, Nontoxic, fiscally responsible, future of oncology: could it be beginning in the third world? J. Paediatr. Haematol. Oncol. 33 (2011) 1e3. [18] P. Workman, E.O. Aboagye, Y.L. Chung, et al., Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing clinical trials of innovative therapies, J. Natl. Cancer Inst. 98 (2006) 580e598. [19] J.P. O'Connor, E.O. Aboagye, J.E. Adams, et al., Imaging biomarker roadmap for cancer studies, Nat. Rev. Clin. Oncol. (2016) 162. [20] G. Cramarossa, E.K. Lee, L. Sivanathan, et al., A systematic literature analysis of correlative studies in low-dose metronomic chemotherapy trials, Biomark. Med. 8 (2014) 893e911.
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