The Most Attractive Hyderabad Call Girls Kothapet 𖠋 9332606886 𖠋 Will You Mis...
Metronomic Chemotherapy
1. Dr Sonali R. Karekar
PGY-2,
Dept. of Pharmacology &
Therapeutics,
Seth GSMC & KEMH.
Metronomic Chemotherapy
2. Flow Of Seminar
2
Background
What is Metronomic Chemotherapy?
Differences from Conventional Chemotherapy
Mechanism of action
Drugs used in Adults & Paediatrics
Optimal Biological Dose
Clinical trials
Toxicity
Resistance
Cost comparison
Limitations
Summary
3. Cancer
• Every year globally 8.2 million people die from cancer
• ICMR in 2016 said that the total number of new cancer
cases in India is likely to reach nearly 17.3 lakh by 2020
• Acc to a study, 7.5% of patient deaths occurred within 30
days of chemotherapy, were related to treatment rather
than disease progression
O’Brien MER, Borthwick A, Rigg A, et al. Mortality within 30 days of chemotherapy: a clinical
governance benchmarking issue for oncology patients. British Journal of Cancer.
2006;95(12):1632-1636. doi:10.1038/sj.bjc.6603498.
3
4. Current challenges to Maximum
Tolerated Dose (MTD)
Chemotherapy
Chemotherapy and Side effects
Collateral damage
Certain malignancies do not have a cure
Time interval between cycles - Emerging resistance
R. S. Kerbel,G. Klement, K. I. Pritchard, B. Kamen; Continuous low-dose anti-angiogenic/metronomic chemotherapy: from
the research laboratory into the oncology clinic. Annals of Oncology. 2002;31(1): 12–15. 4
Targeting endothelial cells present in a tumor’s growing
vasculature Potential Benefit
What would be the advantage of using
chemotherapeutics as possible angiogenesis inhibitors?
5. What would be the advantage of
using chemotherapeutics as possible
angiogenesis inhibitors?
• Massive and diverse genetic instabilities present in cancer
cells
• Targeting of a normal, terminally differentiated and
genetically stable endothelial cell presents the theoretical
possibility of avoiding, or at least delaying, the onset of
acquired drug resistance
• Might be more effective in metastasis
5
6. Pioneer of angiogenesis theory
• 1970s – Judah Folkman
• Tumor angiogenesis was recognized as a key driver of cancer
growth and an important target for chemotherapy.
6
7. Why not routine angiogenesis
inhibitors?
Shortcomings of anti-vascular tumor therapy:
(i) most tumors are inherently resistant to VEGFi and other
anti-vascular therapies used alone;
(ii) even when used in combinations that increase the initial
response rate, responsive tumors typically develop acquired
resistance within a few months; and
(iii)Adjuvant use of these agents did not increase cure rates
7
However, the frequent and sustained use of low doses
of conventional chemotherapeutics mimics the long-
term antiangiogenic activities of VEGFi.
8. Browder, et al. Antiangiogenic Scheduling of Chemotherapy Improves Efficacy against Experimental
Drug-resistant Cancer. Cancer research. 2000. 8
Concept of Metronomic Chemotherapy
In the year 2000, Browder et al. reported that :
• Cyclophosphamide given to tumor-bearing mice
• Maximum Tolerated Dose (MTD)
• Breaks at every 3 weeks
• Little therapeutic benefit
• Transient anti-angiogenic effect.
9. • Cyclophosphamide administered chronically once a week
without breaks
• At a lower dose (e.g. one third of the MTD)
• Repair process was compromised and anti-angiogenic
effects of the drug were not lost.
9
Concept of Metronomic Chemotherapy
This method of administrating chemotherapy
was named ‘anti-angiogenic chemotherapy’ by
Browder et al and ‘metronomic’ dosing by
Hanahan et al
10. What is Metronomic Chemotherapy?
Metronomic chemotherapy is the chronic administration
of chemotherapy at low, minimally toxic doses on a
frequent schedule of administration, with no prolonged
drug-free breaks.
André N, Banavali S, Snihur Y, Pasquier E. Has the time come for metronomics in low-income
and middle-income countries?. The Lancet Oncology. 2013;14(6):e239-e248. 10
12. Mechanism of action
Pasquier E, Kavallaris M,André N. Metronomic chemotherapy: new rationale for new
directions. Nature Reviews Clinical Oncology. 2010;7(8):455-465.
12
Stimulates immune response
Inhibits tumor angiogenesis
Treg cell
Tumor cell
13. 4 D Effect
Andre et al., have postulated a ‘drug-driven
dependency/ deprivation’ or a 4-dimensional
(4D) phenomenon
•Tumor cells become dependent on the
chemotherapy during long exposure
•Sudden cessation or replacement of therapy
might lead to cell death.
13
16. Conventional
Chemotherapy
Metronomic
Chemotherapy
Maximum tolerated
doses(MTD) used
Lower dose than MTD
Therapy at defined intervals
depending on recovery of bone
marrow. Eg: 3 weekly
Dosing frequency is
continuous. Eg: Weekly, daily,
alternate days
Rise and fall of plasma conc Sustained plasma conc
Targets proliferating tumor
cells
Targets endothelial cells of
vasculature of the tumour
Toxicity concern Less toxicity
16
17. The main characteristics of metronomic
chemotherapy are:
Frequent (dose-dense) administration of chemotherapy
without any interruptions
Using a biological optimized dose instead MTD
Preference for oral drugs
Low incidence of treatment related side-effects
Potential for delayed development of resistance.
17
18. Criteria of an anti-angiogenic
agent for MCT
• Strong differential cytotoxicity between cancer cells and
endothelial cells
• Changes of mechanistic effects (e.g., biomarker changes:IL-1
and 6, VEGF, VEGFR1 and 2, bFGF, MMP-2 and 9, vessel density
etc.)
• Inhibition of angiogenesis in-vivo and in-vitro (in-vivo models at
best only with spontaneous, slow growing tumors)
Maiti R. Metronomic chemotherapy. J Pharmacol Pharmacother 2014;5:186-92. 18
19. Which Patients Are
Candidates?
• Does not benefit every patient as is clear
from the clinical data gathered to date.
• Need to identify the right context and the
right patient group to benefit from
metronomic chemotherapy
19
20. The use of Metronomic Chemotherapy in the clinical practice
has been mainly limited to :
Palliative purposes in relapse/refractory diseases
and metastatic cases
20
When to use?
21. When to use?
•Particularly appropriate for maintenance strategies
•Can be delivered as a continuation of the induction
regimen, where one or two drugs already used in the
induction regimen are carried on as maintenance;
or
• As switch maintenance, where short periods of
conventional chemotherapy are followed by long courses of
non cross-resistant cytotoxic drugs.
21
22. Toxicity
• Generally well tolerated
• Most common toxic effects of this treatment are:
• Grade 1 nausea and/or vomiting,
• Grade 1 and 2 anemia, neutropenia, leucopenia and
lymphopenia as well as low-grade fatigue
• Cumulative effects can lead to secondary leukemia, or
myelodysplastic syndrome (MDS)
Gnoni A, Silvestris N, Licchetta A, Santini D, Scartozzi M, Ria R et al. Metronomic chemotherapy
from rationale to clinical studies: A dream or reality?. Critical Reviews in Oncology/Hematology.
2015;95(1):46-61.
22
23. Biomarkers for evaluation
• Shaked et al., have investigated some cellular pharmacodynamic
biomarkers :
(i) previous observations showing significant and sustained decline in
circulating VEGFR-2+ Endothelial Progenitor Cells (CEP);
(ii) preclinical validation of measuring levels of such cells as a surrogate
blood-based marker of angiogenesis
Maiti R. Metronomic chemotherapy. J Pharmacol Pharmacother 2014;5:186-92.
24. Biomarkers for evaluation
• Circulating blood biomarkers (cytokines such as VEGF,
thrombospondin-1/2 and circulating endothelial cells)
• Functional imaging (e.g. DCE-MRI, or DCE-CT - utilized in early
phase clinical trials)
T. Rajasekaran, et al., Metronomic chemotherapy: A relook at its basis and rationale. Cancer
Letters. 2016.
24
However, these biomarkers have not shown to
consistently correlate with response or
survival outcome.
25. Trials in Metronomic CT
• Metronomic doses are nearly 1/10th of MTD of conventional
chemotherapy – Toxicity not a concern
• Therefore the aims of phase 1 clinical trial is to obtain the
Optimum Biological Dose (OBD) of a drug
25
26. Study designs in Metronomic
trials
• Phase I standard '3+3' design to observe pre-defined DLT
Failed to detect the OBD.
• The OBD is determined based on the performance of desired
level of Surrogate Marker(SM).
• Single arm studies
• Majority of these are Phase I and Phase II studies, with small
patient numbers
• Often when standard of care has been exhausted.
26
28. Drugs used in Metronomic trials
•Totally 18 drugs were used as single drug and in combinations
•Most commonly employed drugs were cyclophosphamide,
methotrexate, capecitabine, bevacizumab, vinorelbine
•Cyclophosphamide and methotrexate were employed in
doses of 50mg once daily and 2.5mg twice daily respectively.
28
Metronomic Chemotherapy: Seems Prowess
to Battle against Cancer in Current Scenario
30. Metronomic CT inTNBC – Phase
III results
30
The mean OS for groups 1 37.3 months
Group 2 29.3 months
4-year OS were 74% for group 1 v/s 55% for group 2
33. Issues in metronomic trials
Lack of studies regarding pharmacokinetics and the
pharmacodynamic properties
To detect cumulative side effects
Long duration of trials– How long?
Metronomic chemotherapy studies should be adopted only
after strong preclinical data indicating –
Which drugs should be used, how long, and at which doses?
33
34. Metronomic Resistance
• Shares a number of mechanisms of resistance that are also
functional in VEGFi therapy
• Some mechanisms are –
Endothelial cell-driven resistance – Vascular remodeling
Drug efflux pump positive endothelial progenitor cells
Riesco-Martinez M, Parra K, Saluja R, Francia G, Emmenegger U. Resistance to metronomic
chemotherapy and ways to overcome it. Cancer Letters. 2017;400:311-318.
34
35. Cost Comparison
• According to a pharmacoeconomic evaluation by Bocci et al.
in metastatic breast cancer, metronomic regimen is a cost-
effective alternative to intravenous infusion chemotherapy
regimens
• Concluded that the MCT scheme could reduce health care
costs
Bocci G, Tuccori M, Emmenegger U, et al. Cyclophosphamide–methotrexate “metronomic”
chemotherapy for the palliative treatment of metastatic breast cancer. A comparative
pharmacoeconomic evaluation. Ann Oncol 2005;16:1243–52.
35
36. Drug repositioning
• Using drugs already approved for non-malignant diseases on
the basis of newly identified anticancer properties
• Data available on pharmacokinetics, bioavailability, toxicities
• Truncates drug development process
• Repurposing Drugs in Oncology (ReDO) project
André N, Banavali S, Snihur Y, Pasquier E. Has the time come for metronomics in low-income and
middle-income countries?. The Lancet Oncology. 2013;14(6):e239-e248.
36
37. Successful Drug repositioning
examples
• Celecoxib Anti-angiogenic
• Propranolol Immunomodulatory and anti-
angiogenic properties
• Valproic acid Histone deacetylase inhibitor
• Metformin AMP kinase and mTOR
inhibitor or epithelial–mesenchymal
transition inhibitor
• Itraconazole Sonic hedgehog inhibitor
• Nifurtimox inhibitor of tyrosine-related
kinase B
37
38. In vitro assays - Metformin and
Propranolol
Conventional
Chemotherapy
Metronomic
Chemotherapy
Cell Type IC50
Metformin
(µM)
IC50
Propranolol
(µM)
IC50
Metformin
(µM)
IC50
Propranolol
(µm)
4T1 5.87 5.20 0.16 0.10
MDA-
MB-231
5.90 7.91 0.27 0.21
MCF7 1.08 7.97 0.07 0.17
Rico M, Baglioni M, Bondarenko M, Laluce N, Rozados V, André N et al. Metformin and propranolol
combination prevents cancer progression and metastasis in different breast cancer models.
Oncotarget. 2016;8(2).
38
39. Limitations
• Most effective dose and schedule have yet to be defined
• May not benefit every patient as is clear from the clinical
data gathered to date
• Need to identify the right context and the right patient
group to benefit from metronomic chemotherapy
• Time lag between anti-tumor effect and a visible reduction
in tumor bulk may in some cases decrease the utility in
advanced disease
T. Rajasekaran, et al., Metronomic chemotherapy: A relook at its basis and rationale.
Cancer Letters .2016. 39
40. • There is a need to delineate patient subsets in which
metronomic will prove useful
• Need for studies regarding pharmacokinetics and the
pharmacodynamic properties of metronomic chemotherapy
• Most promising applications of metronomic chemotherapy
may be in the maintenance treatment setting after induction
therapy
40
Future Directions
41. • Chronic administration of chemotherapy at low, minimally
toxic doses on a frequent schedule of administration, with
no prolonged drug-free breaks.
• Multi-directional mechanisms – Anti-angiogenesis,
Increased immune response
• Low incidence of treatment related side-effects
• Need to identify the right context and the right patient
group to benefit from metronomic chemotherapy
• Most promising applications of metronomic chemotherapy
may be in the maintenance treatment setting after
induction therapy
41
77.0% were due to disease progression while
Cancer Letters 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.
Conventional approach entails administering the drugs at doses close to the maximum tolerated dose (MTD). -> S/E
Also, it consists of time interval ranging between two and four weeks to allow for the recovery of the normal tissues, mainly the bone marrow progenitors. S/E on bone marrow progenitors, gut mucosal cells or hair follicle cells (DNA damage / microtubule inhibition)
Also, this strategy potentially allows regrowth of the tumor in the interval period and leads to the emergence of resistant populations of tumor cells. (IJC 2013)
Tumor thrives on vascular supply, hence why not target that?
The highest dose of a drug or treatment that does not cause unacceptable side effects. The maximum tolerated dose is determined in clinical trials by testing increasing doses on different groups of people until the highest dose with acceptable side effects is found. Also called MTD.
High CT doses required a treatment-free period to permit recovery of normal host cells, e.g., rapidly growing hematopoietic progenitors. Similar to hematopoietic progenitors, the vascular endothelial cells in the tumor bed might also resume growth during this treatment-free period. We hypothesized that endothelial cell recovery occurring during this treatment-free period could support regrowth of tumor cells. This could increase the risk of the emergence of drug-resistant tumor cells.
Metastasis plays a role in spread of tumors, conventional treatment is more effective in primary tumor rather than metastasis
cades, researchers have established that angiogenesis is the
key factor in the local and metastatic growth of cancer. The
discovery of the pivotal role of angiogenesis in tumor growth – MAITY
The scientific basis for metronomic chemotherapy
is that conventional anti‑neoplastic drugs target vascular
endothelial cell proliferation but the anti‑angiogenetic effect
cannot be sustained because endothelial cells get a chance to
recover during treatment breaks and this may be overcome by
frequent treatment at low doses.
A number of angiogenesis inhibitors or anti-angiogenesis drugs were developed and investigated in the 1990s and 2000s. – Approved for mets colorectal cancer, NSCC of lung, renal cancer – Bevacizumab , sunitinib, sorafenib (Tyr kinase inhi) (Bevacizumab given i.v. every 14 days in combination with 5-FU
S/E - High BP, Haemorrhage
Based on 2 expts – 1 – Browder and 2 – Klement et al
even when they displayed acquired drug resistance to the same agents given in a conventional way
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.
Douglas Hanahan
Repair process of?
Have been tested both as single agent and combination chemotherapy
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 of emergence of drug-resistant tumor cells. [Cancer Letters 2016]
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
The word Metronomic has been derived from
Metronomic chemotherapy induces important antiangiogenic effects (inhibition of endothelial cell proliferation, migration and morphogenesis, decrease in mobilization and viability of endothelial progenitor cells and increase in Thrombospondin-1 expression), resulting in a reduction of the
tumor vasculature. In addition, metronomic chemotherapy also decreases the number and activity of regulatory T cells
(TREG) and may promote dendritic cell maturation, leading to (re)activation of an anticancer immune response, in part
mediated by cytotoxic T cells and natural killer (NK) cells. (Nature)
This might be responsible when multiple drugs are used with differing periods of administration.
This theory might account for the success of regimens where multiple drugs are used with differing periods of administration.
Despitemore than a decade of clinical studies, very little work has been published on the PK data related to low-dose chemotherapy, primarily due
to an underestimation of the importance of plasma/tumour concentrations of drugs and their biological effects. This is particularly the case
when there are multiple mechanisms of action for MC, and that these may be operative at different drug concentrations.
Metronomic chemotherapy induces important antiangiogenic
effects (inhibition of endothelial cell proliferation, migration and morphogenesis, decrease in mobilization and
viability of endothelial progenitor cells and increase in Thrombospondin-1 expression), resulting in a reduction of the
tumor vasculature. In addition, metronomic chemotherapy also decreases the number and activity of regulatory T cells
(TREG) and may promote dendritic cell maturation, leading to (re)activation of an anticancer immune response, in part
mediated by cytotoxic T cells and natural killer (NK) cells. (Nature)
Ref- 6
An important distinction needs to be made between the anti-angiogenic effects of conventional anti-angiogenic drugs, which target individual molecules or signaling pathways, and the anti-angiogenic actions of metronomic chemotherapy, which inhibit the production of growth factors at the source. For instance, bevacizumab, an anti-angiogenic monoclonal antibody, binds to extracellular VEGF, rendering it incapable of activating cell surface VEGF receptors and thus incapable of initiating sprout formation [81]. In contrast, metronomic chemotherapy damages the source of these growth factors, namely, fibroblasts and TECs [28, 48, 79]. Therefore, while metronomic chemotherapy and anti-angiogenic drugs can both induce anti-angiogenesis, the underlying mechanisms are different, with metronomic therapy potentially having more lasting effects due to its targeting the source of vascular growth factors rather than the growth factors themselves.
OBD - Defined as that dose causing maximum reduction in the tumor volume with no or minimal toxicity.
There are some well‑defined criteria, which are necessary to be fulfilled for defining chemotherapy with anticancer agents as metronomic.
Anti-angiogenic dose of a drug that is higher than the dose required to kill malignant cells should not be considered anti‑angiogenic.
This pt removed from slide Dynamic contrast enhanced MRI or contrast enhanced ultrasonic examinations detecting changes in the permeability and blood‑flow in tumors suggesting altered function of endothelial cells
whether in mono- or combination therapy.
with good response rates and a favorable toxicity profile.
Maintenance treatments given over a long period after an induction therapy with MTD to control tumor growth
sometimes used in combination with target agents.
A comprehensive listing is available from the NCI at NCI CTCAE (common terminology criteria for adv events). Toxicity is graded as mild (Grade 1), moderate (Grade 2), severe (Grade 3), or life-threatening (Grade4), with specific parameters according to the organ system involved. Death (Grade5) is used for some of the criteria to denote a fatality.
Vinorelbine, cyclophosphamide, capecitabine,and methotrexate are the drugs mostly involved in thesetoxicities.
These adverse events are more frequent when acombination schedule is proposed. With this regard, it isimportant to note that metronomic chemotherapy can eas-ily become toxic through the addition of modern targeteddrugs, such as bevacizumab. In fact, hypertension, protein-uria and renal failure are described in some studies, even ifin a few cases. Moreover, fatigue and gastrointestinal symp-toms e.g. nausea, vomiting and diarrhea are more commonwhen targeted drugs are added to metronomic chemotherapy,and high accumulation over time of etoposide, temozolomideand cyclophosphamide can lead to secondary
Fatigue and gastrointestinal symptoms are more common when targeted drugs are added
High accumulation over time of etoposide, temozolomide and cyclophosphamide
Grades 1 nausea
And reduce the emprirism
Biomarkers to indicate achievement of pharmacodynamic effects are important to determine the optimal metronomic dose (OMD) of cytotoxics.
MTD determination is easily established with routine laboratory tests and clinical assessments, OMD determination faces significant
challenges.
CEP- On the other hand, the circulating endothelial progenitor cells (ceps) that are considered to be an alternative source for some of the endothelial cells of newly formed blood vessels represent a subset of immature vegfr2-positive cecs also found in peripheral blood
Functional imaging - DCE-MRI(dynamic contrast enhanced)) is an established technique for evaluation of tumor vasculature and has been utilized in early phase clinical trials of vascular targeting drugs
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 T1-
weighted 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.
The surrogate markers(SM) are the important factor for angiogenesis in cancer patients.In Metronomic Chemotherapy (MC) , physicians administer subtoxic doses of chemotherapy (without break) for long periods, to the target tumor angiogenesis. We propose a semiparametric approach, predictive risk modeling and time to control the level of surrogate marker to detect the perfect dose level of MC. It is based on the controlled level of surrogate marker, and the aim is to detect an Optimum Biological Dose (OBD) finding rather than a traditional Maximum Tolerated Dose (MTD) approach.
Removed from slideThe Continual Reassessment Method (CRM), is an another dose-response finding model and recently gained popularity. But both the models directly failed to detect the aim of any MC i.e. OBD. The OBD of MC is determined based on the performance of desired level of Surrogate Marker(SM).
READDDDDDD
Historical controls?
Response, in terms of tumour kill, may also be problematic in that metronomic therapy may improve OS or PFS without necessarily reducing tumour
volumes.
PFS has become a preferred endpoint for such phase II trials, particularly as it requires shorter follow-up and is not impacted by
salvage treatments.
However, when OS is generally short or salvage treatments not available, OS may be the preferred end-point.
Examples of trials - This is a phase II trial of the combination of Avastin(Bevacizumab) and metronomic temozolomide in recurrent WHO grade IV malignant glioma patients. Patients will receive up to 12 cycles of Avastin and temozolomide and cycles are continuous 28 days. Patients will receive daily temozolomide at a dose of 50mg/m2 and will receive Avastin every other week at a dose of 10mg/kg. Patients will be required to have a baseline MRI within 2 weeks of starting treatment and a repeat MRI every 8 weeks. [6 month PFS, RR/SE long term (Haemorrhage inta cranial etc)27 months ]
Colorectal cancer – 4 years [ double arm – a] CCT - Patients will be randomly assigned to receive induction chemotherapy with the G.O.N.O. FOLFOXIRI regimen plus bevacizumab:
BEVACIZUMAB 5 mg/kg over 30 minutes, day 1
IRINOTECAN 165 mg/sqm IV over 1-h, day 1
OXALIPLATIN 85 mg/sqm IV over 2-h, day 1
L-LEUCOVORIN 200 mg/sqm IV over 2-h, day 1
5-FLUOROURACIL 3200 mg/sqm IV 48-h continuous infusion, starting on day 1
with cycles repeated every 2 weeks for 4 months (8 cycles), followed after 2 weeks by (if no progression occurs):
BEVACIZUMAB 7.5 mg/kg over 30 minutes, day 1 (every three weeks)
B] Metronomic cyclophosphamide 50 mg/day
Capecitabine 500 mg tds
197 studies registered on fda.gov
13 studies on CTRI, 1st – 2013, 9/13 – TATA
Data from Indian studies (n = 30) include 1390 patients, with head and neck cancer patients (n = 544) and breast cancer(n = 260) being the most common.
The most common metronomic therapy combination used methotrexate and celecoxib, drugs that are easily available and inexpensive.
Colon cancer, prostate cancer and ovarian cancers using metronomic regimen showed favourable outcome in their endpoints.
3 trials of small cell cancer of lung, metronomic regimen did not produce any additional benefits.
Mtx – given at 40 mg/ m2 every 4 weeks – BrCa
Head and neck – given weekly
Cyclophosphamide – 600 mg/m2
A meta-analysis of studies of low-dose MC (n = 80), found that the most commonly used drugs were cyclophosphamide (43%), followed by capecitabine, etoposide and vinorelbine
dacarbazine – 1, docetaxel – 3, temozolamide – 3, cisplatin – 3, gemcitabine – 2, sirolimus – 2, doxorubicin – 1, paclitaxel – 1, irinotecan – 1, sorafenib, tegafur/uracil – 1.
Group 1 (Experimental group): Patients underwent adjuvant chemotherapy in the form of FEC-100 [FEC-100 was given in the form of 5-flurouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2 (day 1)] for 3 cycles then docetaxel 80 mg/m2, carboplatin AUC 5 for 3 cycles, followed by postoperative radiotherapy (PORT) (if indicated), followed by maintenance metronomic chemotherapy.
Group 2: Patients underwent adjuvant chemotherapy in the form of FEC-100 protocol for 3 cycles then docetaxel 100 mg/m2, for 3 cycles followed by PORT (if indicated), followed by no more treatment. Chemotherapy cycles were given on day 1 and repeated every 21 days
The 4-year DFS were 63% and 42%, while the
P values were 0.05 for DFS and 0.04 OS respectively.
Not all trials have shown favourable results.
Esp in head and neck cancers – effective in some cohorts [cetuximab and cisplatin more effective?]
Metronomic methotrexate and cyclophosphamide after carboplatin included adjuvant chemotherapy in triple negative breast cancer: a phase III study
Role of pharmacologist
Need for PK/PD studies - relevance of such knowledge in designing clinical trials to move away from empirical research
primarily due to an underestimation of the importance of plasma/tumour concentrations of drugs and their biological effects.
This is particularly the case
when there are multiple mechanisms of action for MC, and that these may be operative at different drug concentrations [2]. For example, in
mice the anti-angiogenic activity of daily oral cyclophosphamide is apparent at doses of 20 mg/kg [3], yet the activation of innate anti-tumour
immunity occurs on an intermittent six-day schedule and at a dose of 140 mg/kg [4]. There is some evidence that responses to low-dose daily
cyclophosphamide are primarily the result of anti-angiogenic action rather than induction of anti-tumour immunity. This begs the question as
to whether PK parameters can predict the outcomes of MC [5]. The key point is that low-dose drug is not a miniature version of high-dose -
PK may saturate at high doses and absorption, metabolism, clearance, distribution and free drug concentration could be different. Therefore,
where possible, PK sampling should be considered in clinical trials, particularly to look at correlations between plasma and intratumoral levels.
SAR, How to determine
Contrary to initial expectations, antivascular therapies are equally prone to inherent or acquired resistance as other cancer treatment modalities.
Typically acquired resistance ensues within months
performed a of metronomic cyclophosphamide–methotrexate and a number of other novel phase II regimens for the palliative treatment of metastatic breast cancer
Low cost – Use of generic old drugs
Oral administration, decreased hospitalization etc
Do not need to travel as can be taken at home
Low toxicity so no further added costs to manage toxicities such as infection, renal toxicities
Using old drugs for new indications
Phase 1 studies are therefore not mandatory and further clinical development can often start directly with phase 2 trials
Phase I trials may still be required to establish maximum tolerated doses of repurposed drugs if the dosing required to reach oncologically relevant levels is much higher than doses used in the initial indication of the drug, or if the repurposed drug must be used in untried combinations
It is true to say that drug repurposing is a short-circuit of the
extensive drug development process that must take place prior to any Phase I trial.
Called metronomic, given regularly
MC – Celecoxib – 400 mg in metronomic
OA/RA dose – 200 mg per day
Mebendazole – 2 phase 1 trials (paed glioma)
Propranolol – 2mg/kg/d (2 divided doses) – 120 mg (60 BD) [Avg dose 40-160 mg]
Repositioned drugs can exhibit new mechanisms of action that can otherwise be obtained only with expensive targeted anticancer drugs, therefore providing new opportunities to develop effective and affordable alternative treatment regimens for patients with cancer
IN VITRO ASSAY F BIOMARKERS
Short term – 36 hrs
Metronomic – 144 hrs
Plus pt 1. Ref 3 2009
Pt. 4 Ref 6 eg-
For example, in the care of brain stem glioma, even minimal progression can be lethal to the patient, calling for more drastic intervention with immediate tumor bulk reduction such as surgery or radiation. Similarly, treatment protocols for ALL include a period of high-intensity induction, followed by a milder dose consolidation, followed by 2–3 years of lower-dose, higher-frequency maintenance therapy [88]. This strategy gives 90–95% survival rates, and any attempts to omit the maintenance therapy yield inferior results
Need for PK/PD studies - relevance of such knowledge in designing clinical trials to move away from empirical research