Chrono Modulation and Metronomic Dosing

INTRODUCTION
Chrono modulation and Metronomic dosing is a new concept of cancer chemotherapy
in which anticancer lower dose drugs is administered than the maximum tolerated dose
over a long period of time to treat cancers with fewer side effects. The idea of
metronomic chemotherapy, the term first used by Hanahan, was first revealed with this
standpoint. The mechanisms of action include, disrupt tumoral angiogenesis and
modulation of hosts’ immune system, affecting directly tumour cells and neighbouring
stromal cells. There researches still ongoing about the current role of metronomic
regimens in the treatment of cancer. Metronomic chemotherapy is a productive model
for this intellect, integrating the concepts of angiogenesis, tumoral microenvironment,
stem cells, angiogenic cancer machinery, and tumoral immunology. The collaboration of
molecular biological studies for preclinical and clinical investigations together, an
appreciable prospect for metronomic chemotherapy.

Mechanism
The tumour transforms its surroundings to create a viable microenvironment and
modifies the hosts’ immune system, and establishes an appealing climate. Enhancing
and Restoring the antitumor immune response is another aspect of metronomic
regimens.MTC (metronomic chemotherapy) enhances the cytotoxic response by
inducing the antigen-presenting dendritic cell maturation, augmenting the function and
increasing tumorigenic antigen presentation that foregathers the immunogenic cancer
death. it is the process in which the dendritic cell recognizes the immune damage-
associated molecular patterns (DAMPs) and complements the cytotoxic cell death.
The other action mechanism is selective modulation of certain protein and gene
functions in tumour cells, which can be used as an antiproliferative effect on tumour
cells or to sensitize the tumour to certain chemotherapy actions.
The drawback of metronomic therapy as the therapeutic activities of therapy are not
supervised appropriately. The cost of cancer treatment is another matter of concern.
The expense of cancer treatment is increasing with more expensive drugs and
increasing incidence.

Clinical practice in Breast cancer
Cyclophosphamide (CP) and methotrexate (MTX) was on the top of the list to be
tested in a metronomic scheme in breast cancer. Several studies investigate that the
oral metronomic use of CP and MTX together (CM) in pretreated metastatic breast
cancer patients. MTX and CP have diverse combination schedules with targeted
agents.

Triple-negative breast cancer (TNBC) is the area where we have a significant
number of viable treatment strategies. In metronomic chemotherapy, we can employ
multiple settings—a study illustrates the action of metronomic chemotherapy in TNBC.
In the study, pazopanib and metronomic topotecan were combined in an orthotopic
metastatic breast cancer model to judge its potential action mechanism and the
therapeutic effects. The combination was to modulate angiogenesis, drug resistance,
apoptosis, and proliferation and subsequently prolonged the survival.

Clinical practice in ovarian cancer
High recurrence rates after achieving complete standard surgical debulking and
platinum-based combination therapy make ovarian cancer a challenging entity for
clinicians. As angiogenesis plays a prominent role in the pathogenesis of ovarian
cancer, metronomic chemotherapy with other antiangiogenic agents has been a
distinguished area for research. Bevacizumab as an antiangiogenic molecule and its
synergism with metronomic chemotherapy were tested for ovarian cancer.
Bevacizumab and CP were also tested for pretreated platinum-resistant ovarian cancer.
Metastatic ovarian cancer is a long-standing malignancy with a need for further
treatment options.

Clinical practice Gastrointestinal Cancer
Antiangiogenesis had been the area of research in gastrointestinal malignancies.
Bevacizumab is an antiangiogenic agent that is approved for metastatic colorectal
cancer patients. Pharmacokinetic and Pharmacodynamic profiles of metronomic
regimens in gastrointestinal cancer were evaluated using a combination metronomic. In
the metronomic treatment of gastrointestinal malignancies, the role of capecitabine with
or without bevacizumab has an important role in the palliative setting and in
maintenance therapy for patients who have a response on first-line treatment.

Clinical practice Neck and Head Cancers
Neck and head cancers are another group of cancer with limited surgical options and
insufficient efficacy of cytotoxic chemotherapy. In oral cancer, the success of a
metronomic regimen of oral methotrexate and celecoxib starting preoperatively and
continuing as maintenance after the standard treatment protocol.