fractal and fractional

Review
An Overview of Mathematical Modelling in Cancer Research:
Fractional Calculus as Modelling Tool
Lourenço Côrte Vieira 1 , Rafael S. Costa 1,2, * and Duarte Valério 1, *

1 IDMEC, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal;

[email protected]
2 LAQV-REQUIMTE, DQ, NOVA School of Science and Technology, NOVA University Lisbon,
Campus da Caparica, 2829-516 Caparica, Portugal
* Correspondence: [email protected] (R.S.C.); [email protected] (D.V.)

Abstract: Cancer is a complex disease, responsible for a significant portion of global deaths. The
increasing prioritisation of know-why over know-how approaches in biological research has favoured
the rising use of both white- and black-box mathematical techniques for cancer modelling, seeking to
better grasp the multi-scale mechanistic workings of its complex phenomena (such as tumour-immune
interactions, drug resistance, tumour growth and diffusion, etc.). In light of this wide-ranging use of
mathematics in cancer modelling, the unique memory and non-local properties of Fractional Calculus
(FC) have been sought after in the last decade to replace ordinary differentiation in the hypothesising
of FC’s superior modelling of complex oncological phenomena, which has been shown to possess
an accumulated knowledge of its past states. As such, this review aims to present a thorough
and structured survey about the main guiding trends and modelling categories in cancer research,
emphasising in the field of oncology FC’s increasing employment in mathematical modelling as a
whole. The most pivotal research questions, challenges and future perspectives are also outlined.

Keywords: Mathematical Oncology; computational modelling; Fractional Calculus; cancer; systems

biology

Citation: Vieira, L.C.; Costa, R.S.;

Valério, D. An Overview of
1. Introduction
Mathematical Modelling in Cancer Cancer is the quintessential complex disease, posing a major public health problem
Research: Fractional Calculus as and being one of the leading worldwide causes of death [1]. The term itself is often used to
Modelling Tool. Fractal Fract. 2023, 7, designate more than 100 distinct diseases. Nonetheless, all relate to the unregulated growth
595. https://doi.org/10.3390/ and spread of abnormal cells in the body, resulting from a malfunction of the natural
fractalfract7080595 biological control mechanisms of cell division [2], in which the cells grow and multiply
Academic Editor: Corina S Drapaca uncontrollably [3], despite restrictions of space or nutrients shared by other cells [4]. This
phenomenon produces what is known as malignant/cancerous tumours, distinguished
Received: 27 June 2023 from benign tumours in that, unlike the latter, the former can propagate its malfunction
Revised: 27 July 2023
from a primary tumour, leading it to invade and destroy nearby normal tissues (locally
Accepted: 28 July 2023
invasive cancer), or spread its cells to other tissues in the body, distant from the primary
Published: 1 August 2023
tumour (metastatic cancer) [4]. Some benign tumours may also develop to the state of
cancer, as with some instances of adenoma and leiomyoma [5]. In any case, tumours are not
to be viewed merely as a collection of mutated cells growing in isolation, since they interact
Copyright: © 2023 by the authors.
with and modify their physical micro-environment [6], being better regarded instead as a
Licensee MDPI, Basel, Switzerland. part of a larger ecosystem in which they actively compete with and disrupt the attempts of
This article is an open access article a complex interacting cellular community to maintain homeostasis [7]. If untreated, cancer
distributed under the terms and may inevitably lead to the patient’s death, thus requiring cautionary clinical response
conditions of the Creative Commons through surgery, chemotherapy, radiotherapy, immunotherapy or other [8].
Attribution (CC BY) license (https:// According to the World Health Organisation (WHO), statistics reveal an estimate of
creativecommons.org/licenses/by/ 10 million cancer deaths in 2020 alone [9]. In the United States, it affects approximately 1 in
4.0/). 3 people, with around 442.4 new cases per 100,000 men and women every year [10], and a

Fractal Fract. 2023, 7, 595. https://doi.org/10.3390/fractalfract7080595 https://www.mdpi.com/journal/fractalfract

Fractal Fract. 2023, 7, 595 2 of 22

predicted 609,360 total deaths in 2022—corresponding to almost 1700 deaths per day—with
the greatest predicted deaths being due to lung, prostate and colorectum cancer in men
and lung, breast and colorectum cancer in women [11] (Table 1).

Table 1. Ranking of the ten leading types of cancer for both men and women, pertaining to estimated
new cases and deaths, as projected for 2022 in the United States (adapted from [11]).

Estimated New Cases

Males Females
Prostate 268,490 27% Breast 287,850 31%
Lung and bronchus 117,910 12% Lung and bronchus 118,830 13%
Colon and rectum 80,690 8% Colon and rectum 70,340 8%
Urinary bladder 61,700 6% Uterine corpus 65,950 7%
Melanoma of the skin 57,180 6% Melanoma of the skin 42,600 5%
Kidney and renal pelvis 50,290 5% Non-Hodgkin lymphoma 36,350 4%
Non-Hodgkin lymphoma 44,120 4% Thyroid 31,940 3%
Oral cavity and pharynx 38,700 4% Pancreas 29,240 3%
Leukaemia 35,810 4% Kidney and renal pelvis 28,710 3%
Pancreas 32,970 3% Leukaemia 24,840 3%
All Sites 983,160 100% All Sites 934,870 100%
Estimated Deaths
Males Females
Lung and bronchus 68,820 21% Lung and bronchus 61,360 21%
Prostate 34,500 11% Breast 43,250 15%
Colon and rectum 28,400 9% Colon and rectum 24,180 8%
Pancreas 25,970 8% Pancreas 23,860 8%
Liver and intrahepatic bile duct 20,420 6% Ovary 12,810 4%
Leukaemia 14,020 4% Uterine corpus 12,550 4%
Esophagus 13,250 4% Liver and intrahepatic bile duct 10,100 4%
Urinary bladder 12,120 4% Leukaemia 9980 3%
Non-Hodgkin lymphoma 11,700 4% Non-Hodgkin lymphoma 8550 3%
Brain and other nervous system 10,710 3% Brain and other nervous system 7570 3%
All Sites 322,090 100% All Sites 287,270 100%

Despite there still being no definite cause for cancer [4], there have been positive
prospects of oncological understanding in light of the wide-ranging use of mathematics in
cancer research, since it has become clear that many biological problems demand meth-
ods and techniques requiring not only traditionally applied mathematics, but also pure
mathematics, statistics and computation [7]. Thus, with the rapid evolution of biological
modelling, control and optimisation theory and its potential of application in the cutting
edge of the medicinal field (e.g., in nanomedicine [12]), the role of mathematics in can-
cer research has continued to be increasingly prominent in whatever theoretical forms it
manifests its importance [13], as presented through the field of Mathematical Oncology.
One sub-area of exponential incidence of mathematics in Mathematical Oncology has
been in the modelling of tumour responses [14], since it poses a valuable and inexpensive
tool for prediction of treatment outcomes and identification of potential therapeutic combi-
nations with minimal adverse effects [15]. A large part of this modelling research has been
obtained through the development of models comprising Ordinary Differential Equations
(ODEs) [16], though the existent and severely studied ones for cancerous tumour growth
lack in non-locality effect, affecting the system’s overall robustness [17]. In response to this
major shortcoming, Fractional Calculus (FC) has come into the oncological fold through
fractional order modelling (also referred to as non-integer or arbitrary order), i.e., through
models employing Fractional Differential Equations (FDEs), since its mathematical nature
may allow for a better description and understanding of oncological particularities [18].
Yet, in spite (or even because) of the rise of Mathematical Oncology’s relevance in can-
cer research, criticism has surged as to the responsibility of the scientific community to
Fractal Fract. 2023, 7, 595 3 of 22

“critically evaluate and discuss if model predictions are an academic exercise or have true
translational merit” [14].
In light of all this, and with the relatively recent implementation of FC in oncology,
attempts have risen in prospects of conceiving mathematical models that may describe the
real cancerous phenomena with greater fidelity in its utmost complexity, thus aiming for a
better understanding of the system’s interactions and potentially the apt prediction of its
future states.
Here, we present a comprehensive review on both the trends of mathematical mod-
elling in oncology research and FC’s own increasing usage in mathematical modelling,
with special emphasis in oncology. It is organised in two main sections, as follows: Section 2
provides a thorough contextualisation of mathematical modelling in oncology as a re-
search procedure, exposing different modelling categories, techniques, considerations and
methodological frameworks; Section 3 presents a brief history of FC as a theoretical field,
emphasising its advantageous features as a modelling tool through general applications
and, most crucially, through the study of its use in Mathematical Oncology, highlighting
the ways in which Fractional Calculus has been shown to be a welcome fit for this still
novel research branch. Section 4 closes the paper with concluding remarks.

2. Mathematical Modelling in Oncology

Mathematical models may describe a system through abstraction and mathematical
formalism, possibly enabling extrapolation beyond cases originally analysed, quantitative
predictions and/or inference of mechanisms, among other purposes [19]. In fields such as
chemical, electrical and biotechnological engineering, mathematical modelling has already
cemented its wide-ranging value in representing an essential step for problem solving
and product development, by using the available information of a given system to obtain
an integrated picture that permits its analysis and prospects of optimization [20]. When
applied to biology, a general mathematical modelling approach may be defined as “the
art of using mathematical tools and concepts, usually supported by computing power,
to represent natural systems, properties and phenomena” [18], thus providing a rigorous
framework enabling the comprehension of disease evolution and testing of biological
hypotheses [21].
In this line of thought, for more than 15 years now mathematical models of cancer
have significantly increased their impact and number in the research field [14]. In fact,
its history goes back more than half a century, yet it had been largely ignored by most
experimental biologists [22]—though many of its initial conceptions dating back as far
as 1928 can be consulted in [23]. Nonetheless, as expressed, renewed interest has been
shown for the last few years, which may be partly explained by the research community’s
realization of their potential for a more mechanistic understanding of such complex sys-
tems [7]. Its driving principle in oncology is the use of mathematical approaches able to
maintain deductive–reductionist model features without the mischaracterisation of even-
tual complexities of the biological system [18]. The mechanistic paradigm in the modelling
world is easily understood as a welcome fit in an oncological context, given the accepted
notion that cancer is a fundamentally physical process subject to laws of nature studied
in chemistry and physics [13]. Thus, enabling the value of mathematical modelling in the
extraction of fundamental behaviour from such multiple and complex components and
their relations [22]. As put forward in [19], “the power of mathematical modelling lies in
its ability to reveal previously unknown or counter-intuitive physical principles that might
have been overlooked or missed by a qualitative approach to biology”. This is moreover
prompted by the shortcomings of strictly molecular reductionist approaches—the dominant
mode of current biology [22]—in their inability to model the pivotal interactions between
individual components, which has had experimental biologists recently embrace a more
systemic view of cancer that mathematical models can indeed cover [7].
The focus on separate cancerous molecular species through traditional in vitro and
in vivo approaches has been partially unable to grant significant insights, by failing to
Fractal Fract. 2023, 7, 595 4 of 22

provide a global view on the pathogenesis of this disease, for which in silico techniques—
understood as studies performed and/or relying on computer simulations—have then
been gradually sought after in oncology [20]. These in silico approaches—of which mathe-
matical modelling is part of—are also crucial in the realization of the 3R’s (replacement,
reduction and refinement) that will lead cancer research toward efficient and effective pre-
cision medicine [24], while also allowing for the reduction in animal experiments in clinical
studies [25]—and even though validation of computational models still requires results
stemming from in vitro and in vivo experiments, the shift still does reduce laboratory
work [24]. This transition may also be given to research activities progressively prioritising
know-why over know-how, thus contributing to the further conception of models suitably
combining both data-oriented and phenomenological approaches [18], though the latter
still remains an underexplored niche to a large extent [22]. Additionally, the financial angle
also presents a major upshot when adhering to mathematical modelling methods, consid-
ering that it may help researchers answer questions of oncological nature by modelling
therapeutic options and thus predicting treatment and toxicity outcomes prior to the onset
of lengthy and expensive trials [15], since studies have shown the costly reality of drug
developments [26].
In this context, Mathematical Oncology has gradually developed as an accepted area
of cancer research [22] that broadens the development and potential application of models
in comprehending manifold phenomena, of which tumour growth dynamics, personalized
treatment and anti-cancer therapies are part of [18]. It is mostly characterized by two
main ideas [21]: (1) that mathematics can be applied to improve biomedical knowledge
of cancer; (2) that biology itself produces new mathematical challenges which compel the
development and enhancement of mathematical tools. As of the last years, the authors
of [7] specifically list some of mathematical oncology’s main research goals which it aims
to achieve in the future (here adapted, with recent cases of positive progression), as its
role becomes more and more prominent in oncology: (i) prediction and optimization
of patient-specific treatment strategies (e.g., [27]); (ii) definition and facilitation of the
immune system’s role in cancer (e.g., [28]); (iii) integration of molecular scale data into
multi-scale models (e.g., [29]); (iv) understanding and minimisation of the emergence of
drug/treatment resistance (e.g., [30]); and (v) and greater integration with systems biology
(e.g., [15]). Naturally, this implies the pivotal demand of an inter- and multidisciplinary
approach in the research field [22] (Figure 1), further evidenced by the many distinctions to
be made of mathematical models according to their assumptions and purpose, as well as
their invoking of concepts from different areas [18]. It has also been supported and further
shown how cross-disciplinary collaboration can accelerate positive results in the further
understanding and treatment of cancer [31].

Figure 1. Mapping of possible interdisciplinary approaches to Mathematical Oncology, with respec-

tive keywords for each convergence (adapted from [18]).
Fractal Fract. 2023, 7, 595 5 of 22

Given the plethora of methods pertaining to the mathematical modelling approach

of cancer, it can be difficult to decide which type of model best suits a particular problem,
as well as to what level of detail [31]. In response to this, many categories have been
traced over the years in order to characterise each model and set their purposes apart,
usually falling in each of the following distinctions: (1) white-, grey- or black-box [20];
(2) continuous, discrete or hybrid [20]; (3) deterministic or stochastic [1]; (4) its placement in
the spatio-temporal length scale, from the gene level to a population level [20]; (5) the type
of cancer, (6) its features [20]; (7) treatments in question, if any, combined or not [15]; (8) the
modelling techniques themselves [32], along with their assumptions [33], approach [30];
and even (9) their underlying philosophy [34]. As noted, most of these distinctions are perti-
nently reviewed in [20], which shall be referred to extensively in the following explanations
of each modelling category.

2.1. White-, Grey- and Black-Box Modelling

In order for a mathematical model to be constructed, information pertaining to the
system to be modelled is key. However, this same information may be available through
qualitative knowledge or quantitative data. The nature of the information used thus
gives rise to the labelling of mathematical models as either white-, grey- or black-box.
As concisely expounded in [20] and hereinafter summarised, white-box models (also
known as mechanistic, hypothesis-driven or physics-based models) base their conception
on first principles of physics. The term directly refers to the “transparent walls” the
concept assumes in the system’s presenting of its events and all dynamic stages as directly
visible [35]. Given this, by evidently showing the mechanisms of the studied phenomena,
most of their parameters usually have a direct significance physically or physiologically,
as is the case for plenty of models of cancer using differential equations (e.g., [36]).
This approach stands in stark contrast to black-box modelling (resulting in models
known as data-driven empirical), which is purely established on experimental data and
hence does not usually seek the attribution of any clear biological significance to its param-
eters. Instead, black-box models—of which deep learning and neural networks are part
of—merely determine abstract operational connections between the system’s defined in-
puts and outputs, “hiding” their internal logic [37] and tracing predictions without evident
explanation, which has been increasingly demanded in the medical field, though there have
been some positive prospects [38]. Reacting to these black-box tensions and, on the other
extreme, criticism sprouting from white-box models relying on some form of experimental
data for their theoretical constructions [20], grey-box modelling has appeared in attempts
to merge both notions, thus marrying experimental, clinical data with theoretical structures
of a hypothesis-driven nature through data fitting strategies.

2.2. The Spatial Scale

As has been noted before, cancer is in its biological nature a multi-scale process.
However, decades of dedicated efforts have made possible advanced scale-specific models
which are significant in their own right [39]. In this respect, a classification to be made
to a potential mathematical model of cancer resides in the biological level it assumes
and operates in, thus prioritising a position in a spatio-temporal length scale (Figure 2)
ranging from the gene to the protein, cell, tissue, organ, patient and population levels [16].
Defining the spatio-temporal realm is pivotal for what is merely one of several modelling
decisions, and noteworthy advancements have been registered on the basis of a tissue
level [16], since it groups many different cells and their integral interactions based on sets
of rules [20], being frequently linked with white- or grey-box approaches. Nevertheless,
resources stemming from these various scales have inspired attempts at conceiving multi-
scale models combining the different levels, though defining the links between them still
poses a great barrier [39].
Fractal Fract. 2023, 7, 595 6 of 22

Figure 2. Classification of in silico models based on the spatial length scale, from the gene to
population levels (adapted from [20], with figures from [40–45]).

As a consequence of the modelling scale decision, another modelling differentiation

can be traced, being the numerical type of the variables involved: continuous, discrete or
hybrid. Continuous models, usually used in the tissue level [20], describe the tumour as a
continuous medium by considering concentrations of cells (i.e., a population) being a choice
apt for modelling larger-scale volumetric dynamics [39] and one supported to some degree
by fundamental physical principles [46]. Models of this type usually make use of partial or
integro-differential equations, with common variables such as nutrient, oxygen and growth
factors being relatively simple to obtain when compared to the discrete case [39]. Despite
their advantages in characterising global properties of tumour growth, this numerical type
cannot be used to examine individual cell dynamics, for which discrete modelling is often
used, being a particularly useful approach in the study of carcinogenesis [47], natural
selection and cell–cell interaction mechanisms [39]. Its primary upshot—as implemented,
e.g., through cellular automaton models [48]—resides in the possibility of translating
detailed biological findings on a cell level into rules for the model, though the computational
cost is heavily increased by the number of cells considered [39].
The limitations on both ends are alleviated with the use of hybrid modelling ap-
proaches, which conjugate both continuous and discrete notions into having specific cells
of interest be discretely modelled and continuous methods for environmental variables [20]
(e.g., [36]). However, on this final type, a distinction must be traced between the term
“hybrid” (numerical type), when used to denote the presence of both numerical types in a
model, and “hybrid” (method), when descriptive of a methodological conjugation of both
continuous (e.g., ordinary or partial differential equations) and discrete approaches (e.g.,
agent-based modelling) in a single model [49].

2.3. Models of Ordinary and Partial Differential Equations

Population, ecological and kinetic models are common approaches when aiming to
grasp phenomenological foundations of general avascular tumour growth, for which ODEs
are often used [50]. Though elementary in nature when compared to Partial Differential
Equations (PDEs), ODE-based models employ deterministic, time-dependent equations
that enable analytical solutions and mathematical description of phenomena evolution [18],
while allowing for the fine-tuning of its parameters when faced against clinical data in a
grey-box procedure [51], favouring their flexibility [18]. Relevant hallmarks have been the
earlier models thoroughly mentioned in [52] and some in [53], while recent developments
on this end can be seen in [33,54], with there being a wide array of assumed tumour growth
laws [51]. The different considerations in constructing an ODE-based model are well
documented in [55]. On this latter note, this mathematical technique also has the primary
modelling assumption of the tumour being viewed as a spatially uniform homogeneous cell
population, thus neglecting its spatial effects [32] and posing a weakness in the capturing
Fractal Fract. 2023, 7, 595 7 of 22

of the complexities of real-life carcinogenesis. Moreover, there still is no consensus as to

choosing the most appropriate ODE-based model for a particular type of cancer [56]. In light
of this, criticism such as in [57] has claimed that ODE models should be carefully employed
and only used to describe general trends in tumour behaviour, instead of characterizing
specific clinical cases. Additionally, other downsides as put forward in [32] are the inability
to relate its system’s parameters to behaviour of individual cells as well as the focus on a
limited number of species at a time. Other general limitations relate to the phenomenon of
tumour shrinkage, in which deterministic differential equations fail to accurately describe
the system’s dynamics when predicting response to treatment [32], though this may be
mitigated by the switching of these models to their stochastic counterparts [20] (e.g., [58]).
It has been largely noted that a lot of cell functions depend on their microenviro-
ment, as with cases of tumour cells proliferating in well-oxygenated regions [32], thus
requiring a modelling approach that matches its natural heterogeneity. In this context,
many of the downsides of ODE-based models pertaining to their oversimplistic spatial
assumptions have been accounted for and assuaged with the employment of Partial Differ-
ential Equations (PDEs) instead [18]. As such, these PDE models take into consideration
the effects of spatial gradients in the local microenvironment of the tumour as well as
those provoked by tumour cell density [32], by not only having their equations be time
dependent as also spatial dependent [18]. Moreover, these models have a propensity to
integrate well-established conservation laws into their modelling assumptions. This has
thus enabled the modelling of phenomena such as vascular growth processes through
the transport equation [59], the tumour’s metastatic spreading adjoined to the possibility
of drug resistance from treatment [60] or the evolution of cell population density across
tissues by means of diffusion equations [61]. Noteworthy initial contributions on this end
have been the Greenspan and proliferation-invasion models (both approached in [32]) with
other relevant developments seen in [18,62]. For these reasons, PDE-based models have
been considered to be a more comprehensive choice when studying tumour growth into
surrounding tissue [18].

2.4. Other Modelling Techniques

Despite the listed advantages of differential equation-based models, certain impor-
tant features of tumour biology still cannot be accounted for through their mathematical
techniques, particularly given cancer’s aforementioned multi-scale nature [39]. As referred
to, other modelling techniques relying on computational simulations such as Agent-based
Models (ABM) may be of preference here, which admit discrete cell-scale spatial resolution
and may even present a methodologically hybrid approach so as to consider the various
biological scales and their interactions [32] (e.g., [22], for the modelling of brain cancer).
In this sense, by being modelled on an individual-cell level, ABMs are able to represent
the behaviour of discerning autonomous agents—encoded with a set of pre-specified
rules [47]—while highlighting the whole system as the integration of the different actors
involved [20]. Through their adaptability to a hybrid approach when bridging the different
scales, these models reveal a pertinent and accessible cancer modelling tool to a biologist
in terms of understanding and experimental validation [22]. The different scales to be
considered and their overarching modelling implications have been well documented
in [39] while several contributions can be consulted also in [47]. When modelling under an
ABM approach, the behaviour of the agents varies according to the assumed framework,
which can be: lattice-based, in which agents are confined to specific locations on a rigid
grid (e.g., cellular automata [48] or Potts models); or off-latice, with agents moving freely
in space (e.g., vertex-based models). Thorough details for both frameworks and given
examples are well documented in [63].
Lastly, other significant modelling techniques of black-box nature used over the last
years have been neural networks [38], neuro-fuzzy systems [64] and Petri net models [65].
Several of all the aforementioned modelling techniques—from ODE-based to Petri nets—
are often too complex and thus unlikely to be amenable to standard mathematical analysis,
Fractal Fract. 2023, 7, 595 8 of 22

hence relying on computational solutions, whether it be numerical or simulation based [22]—

though limitations stemming from computing power have been well documented [39].
Given this, the authors of [15] provides a thorough list of existing software for implement-
ing many of the mentioned mathematical models, detailing their relevant packages and
designed purposes.

2.5. General Modelling Assumptions

Past the modelling techniques themselves, another referred distinction regarding
the model employed pertains to the cancer features it tackles in their agents’ individual
study and overarching interactions [20]. For this purpose, many hallmarks of cancer
cells have been collected in sources such as [66], detailing characteristics of normal cells
that enable them to become malignant during the multi-step development of tumours,
whatever their origin and phenotype [20], as well as other processes/phenomena, such as
the activation of invasion and metastasis or resistance of cell death. Thus, mathematical
models in oncology may also be described by the cancer trait they aim to question and
analyse, with relevant curated examples being the cases of tumour growth [51], cancer
metabolism [67], blood and lymphatic vasculature [59] and tumour immunity [16], as well
as its microenvironment/heterogeneous nature [68] or its referred invasion and metasta-
sizing [69]—most features already best associated to each previously described modelling
techniques. Accordingly, to approach such cancer features also implies the commitment
to certain biological assumptions (e.g., tumour growth laws or the involvement and inter-
action of certain species in the system [70]) yet given that this trait is common across all
models and widely varied [33], it is not here considered as a category in itself.

2.6. Modelling Treatment Intervention

A great part of Mathematical Oncology also has its focus on modelling phenomena
stemming from treatment-related effects, such as optimal regimens [71] and dosages in drug
delivery [72] and their impacts on tumour and healthy cells in general [18]. Reasonably then,
the treatment in question also plays a crucial role in choosing which mathematical model to
conceive, of which there is an existing large variety [8]. In fact, it is through the knowledge
of the treatment in question that mathematical models may be developed to support drug
decision making, dosages and regimens, e.g., by characterising and predicting the rela-
tionships between drug exposure/pharmokinetics (PK), drug effects/pharmacodynamics
(PD) and disease progression [33], as enabled by some PK/PD models [73]. In light of the
treatment under consideration, the authors of [21] select many noteworthy publications
pertaining to the modelling of certain breast cancer features that advances interventions
in treatments such as chemotherapy, immunotherapy, radiotherapy or surgery. Other
treatments have also been of interest for many mathematical modelling contributions, as is
the case for virotherapy, hormone therapy and hyperthermia (some examples in [74]), all
requiring the consideration of specific features of the cancer type in question, as well as
biological assumptions [75].
Moreover, the adherence to novel therapies stemming from the combination of more
than one treatment and the rise of personalised patient-specific strategies [76] has further
required the advancement of modelling approaches, as thoroughly documented in [15],
with instances of mathematical models of cancer to be treated with chemoimmunotherapy,
chemovirotherapy, chemoradiotherapy, radioimmunotherapy, etc. For most of the treat-
ments mentioned, whether mono-therapeutic or combined, one of the biggest challenges
facing cancer research today is to account for and understand the causes underlying drug
resistance [77], it being one of the major reasons for oncology patients experiencing treat-
ment failure [33]. To advance research in the understanding of this, the authors of [33] have
exhaustively covered the prospects of various assumptions and techniques when tackling
clinical data and considering the possibility of drug resistance in mathematical modelling
of cancer.
Fractal Fract. 2023, 7, 595 9 of 22

2.7. General Modelling Limitations

Besides the referred specific limitations residing in most categories for mathematical
models of cancer, there are also general shortcomings when working with these in silico
approaches. As thoroughly listed in [20] and here summarized, most challenges Math-
ematical Oncology still faces are, namely: (1) the necessity of simplifying assumptions,
thus unable to grasp all the necessary intricacies of the real biological system, with the
counter-risk of overparameterization in large, complex models; (2) the critical importance
of parameter estimation, usually proceeded through data fitting techniques—since it is
sometimes impossible to measure such values in subsequent in vitro or in vivo experiments;
(3) the severe computational limitations that forces a trade-off between accuracy and time
efficiency, only leading to the (at best) mean behaviour of the species modelled; (4) the
dire need for the aforementioned multidisciplinary effort to develop pipelines for data
sharing between research communities, given that experimental inaccuracies are directly
transmitted in model outcomes; (5) the incorporation of the development of biomarkers
capable of predicting degrees of response in various cancer patients [30]; and (6) the ethical
and philosophical implications when recurring to simulation-based predictions for decision
making [78].
Noticeably, limitations such as these have posed great barriers in enabling the use of
most models in a clinical context [20], though contributions have surged in efforts to miti-
gate these shortcomings. Guidelines and best practices for development of mathematical
models have been approached in [55] while a code of professional ethics for simulationists
has been proposed in [78], as well as steps toward a verification procedure in this context,
for a correct potential implementation of in silico techniques in clinical trials—similarly
approached in the concept of virtual clinical trials in [76]. However, the most affecting
drawback preventing most mathematical models’ application has pertained to the scarcity
of the data itself [7], with cases of models recurring to parameterisation from multiple
sources mixing cancer types, experimental conditions or spatio-temporal scales, sometimes
leading to interesting yet biologically and clinically unrealistic dynamics [14]. Therefore,
despite the rapid evolution of this field prompted by the increasing data availability of
bio-informatics [18], there still has been a lack of proper theoretical models that manage
to understand, organise and apply real clinical data effectively, though the principles of
Mathematical Oncology do recognisably represent a necessary next step beyond verbal
reasoning and linear intuition in research [79]. Sources such as [7] centre the problem on
there still not being the “right” data that allows for a better definition of the cancer system
in connecting its multi-scale processes, since most of the available data is often scale-specific
and scarce in spatial information, being averaged and homogeneous. This has prompted
the development of specific databases such as for the employment of combined treatment,
gathered in [15].

2.8. Mathematical Oncology or Oncological Mathematics?

Unresolved tensions stemming from the aforementioned inabilities of mathemati-
cal modelling of cancer have prompted what is known as the Oncological Mathematics/
Mathematical Oncology split, as put forward by [14]. It evokes the necessity for the mathe-
matical oncology profession to deploy a standard to only predict novel treatments if the
model in question has been properly trained and validated for such—echoing the criticisms
posed in [78]—thus clearly identifying a model’s purpose and its predictions as either
“academic” (Oncological Mathematics) or “translational” (Mathematical Oncology), i.e., apt for
potential medical use and providing pertinent clinical insight [14]. Naturally, this results in
a new category with which to distinguish models.
The characteristics pertaining to the former category of academic models—as op-
posed to the already extensively mentioned nature of the translational ones—are then
noted by their employment of cancer biology to motivate the development of “interesting”
mathematics [14], thus not positioned to engage in the answering of certain oncological
questions, namely the speculation of optimal therapy, as such misapplication could ulti-
Fractal Fract. 2023, 7, 595 10 of 22

mately hurt patients if treated with ill-informed protocols [78]. Clear suggestions towards
the creation of a biologically sound academic model can be found in [31], listing the fol-
lowing stages of development: (1) formulation of a biological hypothesis; (2) stating of
modelling assumptions, as well as identification of key physical variables; (3) conception of
“word” equations for all involved variables and identification of of the physical processes
regulating their dynamics, followed by (4) conversion of said equations into mathematical
language, specifying all functional forms; (5) solving the resultant mathematical model
through appropriate numerical and analytical techniques; and (6) checking the consistency
of the results with the originally formulated biological hypothesis.
Lastly, regarding the conception of translational models, three distinct modelling ap-
proaches when dealing with data are depicted in [30]: (1) top-down data-driven modelling,
built predominantly upon observed clinical data and leaning towards a more empirical
description of the system (e.g., PK/PD models [73]), though they may neglect important
tumour-immune interactions; (2) bottom-up modelling, being of a more white-box na-
ture by invoking clinical information as input data, fitting a mechanistic structure; and
(3) middle-out modelling, which combines both previous approaches into one that pro-
vides a quantitative platform for model development in clinical scenarios [30]. Noticeably,
the mentioned approaches parallel the black-, white- and grey-box natures, respectively.
Furthermore, the authors of [14] extensively list the crucial stages that have to be
followed and verified for a mathematical model to make reliable and testable predictions of
novel treatment strategies (here adapted): (1) identification of a putative biomarker, which
may range from the number of cancer cells in a petri dish to tumour volume derived from
medical imaging; (2) development of a mechanistic model by means of one of the modelling
techniques already referred, taking into consideration the spatio-temporal nature of the
available data, as well as balancing the model’s complexity with the degrees of freedom—
also employing Occam’s razor concept if possible [55]; (3) calibration of the model through
existing data, derived as less as possible from empirical wisdom or the literature but
from realistic conditions, using machine learning and statistical tools to derive values if
need be; (4) validation of the model with untrained data, evaluated via methods such
as R2 analyses, for instance; (5) evaluation of the predictive performance for a known
treatment, since a model’s ability to fit data does not imply its predictive power [57],
being the calculation of Positive Predictive Value (PPV) and Negative Predictive Value
(NPV) strongly advised—while yet there being no conventional notion of acceptable cut-
offs for predictive performance; and (6) simulation and prediction of untested treatment
alternatives, i.e., therapy dosages and schedules that can be derived from the model,
posterior to calibration and validation, for which it was trained to predict—and being
carefully considerate of determinants such as clinical feasibility, drug half-life or toxicity
when evaluating optimal regimes and dosages, requiring a rigorous control approach.

3. Fractional Calculus in Mathematical Modelling

Fractional Calculus may be considered both an old and yet essentially novel topic [80].
Its early conception can be said to derive from a question of extension of meaning [81] and
dates back more than 300 years now, first registered in a 1695 letter directed to Gottfried
Wilhelm Leibniz by Guillaume de l’Hôpital [81]. Up until then, Calculus had made clear
the iterative process of both differentiation and anti-differentiation (i.e., integration) of a
given real-valued function y of a real variable t [82], being informed by n, the order of
such process, but was that all there could be of it? Could the order only be understood
as an integer? With this in mind, in the letter l’Hôpital questions the possibility and
consequent interpretation of a fractional order derivative [81], i.e., having n be a fraction in
dn
the computation of dt n y ( t )—this latter notation for the derivative operator D having been
invented by Leibniz himself. At the time, the question was promptly and prophetically
answered by the philosopher as being “an apparent paradox from which, one day, useful
consequences will be drawn” [81].
Fractal Fract. 2023, 7, 595 11 of 22

Later on, this mathematical conundrum did not escape Euler’s attention, who also
questioned the subject’s nature, as well as that of other mathematicians, such as Lagrange
and Laplace [81]. Years of speculations also prompted the reformulation of the initial
question to one in which the derivative’s order n (now taken as α) could generally be taken
as any value, thus embracing the possibilities of it being irrational or even complex [82].
Despite a history of subsequent hypothesising, fractional derivatives remained for the
longest time an abstract albeit interesting mathematical concept [83].

3.1. Early Development

The true beginning of FC as a mathematical field in itself could be said to have only
begun in 1832 with Liouville’s contributions, as well as posterior 19th and 20th century
developments [84], having its foundations built through several contributions from other
mathematicians such as Abel, Riemann, Grünwald and Letnikov [85], some of which are
thoroughly documented in [81]. However, given that the new formulations of the notion
allowed the order to go beyond mere fractional values, the term “fractional calculus” really
is a misnomer, being “differentiation of arbitrary order” a more apt designation of its
mathematical theoretical nature [81], while other terms like “Non-Integer Calculus”—liable
to criticism, since it implies the ruling out of integer orders—and “Generalized Calculus”
never got any real hold [82]. In this sense, fractional integrals are understood to be a
particular case, one of differentiation of negative order (α < 0), which is sensible due to the
blurry distinction of both cases in such field [82]. For this reason, FC is strictly related to
the theory of pseudo-differential operators [80].
Under these considerations though, agreement over the true qualifications of a frac-
tional derivative has been hard to meet [86], while a number of competing definitions
have been postulated, noticeably the Riemann–Liouville (late 1840s) and Caputo (1967),
widely adopted in many fields [87], followed since by a plethora of adaptations and original
contributions—though the Grünwald–Letnikov definition (late 1860s) has been shown to
possess great mathematical coherence in its generalisation of integer order derivatives [87].
Indeed, there exists a desire to explore and create new definitions and models, possibly
motivated by the pure mathematician’s desire to generalise [88]. Given that each possess
its own particularities and presuppositions, debates have questioned the criteria that may
secure a strict notion of the fractional derivative concept, which established definitions
do comply to it [86] and what classifications may be drawn to distinguish the various
approaches [88]. Analysis of these considerations are well put forward in [89], while also
presenting the many definitions.
Moreover, definitions and their implications expanded again once the possibility of a
variable arbitrary order came into the fold, leading to Variable Order Differential Equations
(VODEs) and the systems they may constitute, well documented in [90]. Additionally,
the progress of FC as a whole up until 2017 may be consulted in the survey [91]. Naturally,
all these kaleidoscopic offerings have enabled many differing approaches to and from
FC as a field, and since the early 1990s more practically oriented scientists and engineers
have been working with such various forms in hopes of converging them with physically
meaningful formalisms and applications [83].

3.2. The Memory Effect

While entirely comprehensible in its extension of mathematical meaning, the theory
underlying FC could be said to evidence a logical formalism of sorts, i.e., a formal language
of pure syntax and no semantics. This is since that, contrary to integer order derivatives and
integrals, FC does not carry in itself a clear physical and/or geometrical interpretation [92].
As put forward in [93], a possible reading of fractional derivatives both geometrically and
physically could be that of “shadows on the walls” and “shadows of the past,’, respectively—
an interpretation directly related to fractional derivatives’ main property: its memory
effect [74]. This feature, also commonly referred to as non-locality, derives from a given
fractional derivative operator’s D α ability to take into consideration a given function’s past
Fractal Fract. 2023, 7, 595 12 of 22

values (if the independent variable is temporal, thus y(t)) or long-range interactions (if the
independent variable(s) is/are spatial), since the fractional derivative computation of a
specific point depends on an average over an interval containing such value [94], granting
thus a history or accumulation of information which integer order differentiation, using a
local operator, does not supply. This same property could then be exploited into the forms
of short- and long-term memories [83].
Taking this property into account, a possible physical interpretation was provided
by [95], defining the fractional order α as the index of memory for the physical process,
for which then α = 0 means that nothing is memorized, while α = 1 that nothing is
forgotten. It is then supposed that many physical processes are best modelled by means
of a fractional order operating between these extremes [74]. As Westerlund boldly and
optimistically claimed in 1990, this reveals a powerful advantage when employing fractional
order differential equations (FDEs), when compared to their integer counterpart, i.e.,
ODE: “all systems need a fractional time derivative in the equations that describe them.
(. . . ) It is necessary to include this record of events in order to predict the future (. . . )
[as such behaviour is impossible to predict] with less than an infinite number of initial
conditions, which is the same as saying that the whole function describing the past must be
known” [96].
Nonetheless, as expressed in [94], this mathematical property mainly sets out three fun-
damental questions. (1) Are models composed of space and/or time fractional derivatives
consistent with the governing and fundamental laws and symmetries of nature? (2) Even if
so, how is the fractional order α to be experimentally observed? (3) How may a fractional
derivative emerge from models not containing them? Additionally, [97] identified yet
more open problems stemming from FC’s mathematical analysis, numerical processing,
and application in physics, specifically, mentioning issues such as the computational cost
related to the non-locality property and its numerical implications. On the theoretical end,
monograph [98] offers a selection of problems related to positive one- and two-dimensional
fractional linear systems, mapping out its fundamentals notions. These are some of the
questions Fractional Calculus’s theory and main property opened up, having prompted
researchers to further investigate its possible applications in real-life phenomena.

3.3. General Applications

Integer-valued operators, as noted, are local and isotropic in both space and time,
having dominated science and engineering for centuries [99]. However, with the increasing
need to model complex phenomena with underlying properties as spatial heterogeneity
or the effects of memory, new quantitative ways of thinking have steadily brought FC to
the front end of dynamics’ modelling research, as it enables a framework for such think-
ing [99]. Indeed, the interest for FC’s many possible applications has been such to have
prompted a number of cyclical conferences, adding to its already rich literature, with some
resulting materials among them present in [100–102]. Ever since the establishment of FC
as a respected branch of mathematics, its real-world applications have been plenty and
wide-ranging, being used as a powerful tool in several areas of science and engineering for
the last decades now [85], such as, e.g.: (1) signal and image processing, for instance in edge
detection [103]; (2) the assessment of cryptocurrencies’ price dynamics in economy [104];
(3) the understanding of the epidemic spread of diseases [105]; (4) the flow of highway
traffic and its control [106]; (5) determining the properties of viscoelasticity [92]; (6) the
modelling betterment of thermoacoustic engines [107]; (7) the understanding of long-term
memory and multi-scale phenomena in materials [108]; (8) the description of complex
shapes of microbial survival and growth curves in food science [92]; (9) the modelling
and analysis of industrial processes [109]; and (10) the study of pulse propagation in
electromagnetism [110]. Other examples may be consulted in [94]. In several of these
areas, it is the hereditary property of the fractional order models that has granted a sig-
nificant advantage in comparison to other integer order models, as stated years before
in [111]. Other noteworthy examples of applications across many fields are thoroughly
Fractal Fract. 2023, 7, 595 13 of 22

exposed in [112], also highlighting its increasing use as a control tool, for instance in the
improvement of a precision positioning stage, betterment of active damping controllers or
solution of problems pertaining to the asymptotic stability of inverted pendulum systems
(respective references in [112]).
On the realm of models making use of variable order fractional differential equa-
tions, their importance has been remarkably acknowledged as a precise and alternative
approach in the description of real-life phenomena [113], with some notable applications in
Duffing systems, time-dependent mechanical property evolution in materials with strain
softening behaviour, transient dispersion in heterogeneous media, digital cryptography,
with respective references in the survey [113] and other examples in [114].

3.4. Modelling Biological Phenomena

Nature has often revealed itself to follow simple rules that still lead to the emergence
of complex phenomena [115], and of the many different applications pertaining to FC,
the propensity to model biological phenomena has been one of the most notable. In this
respect, the authors of [115] compose a thorough review of FC’s many different applications
in biology, stating that evidence suggests that fractional order dynamic behaviour may
be possibly linked to self-similar/fractal structures or fractal kinetics, e.g., anomalous
diffusion, present in both physical and chemical cases [116].
Diffusion in general is of fundamental importance in several disciplines in the descrip-
tion of properties like growth phenomena [117]. In the anomalous case, these diffusive
processes are unlike normal ones, i.e., informed by Brownian motion of particles (for which
α = 1)—in the sense that they are instead governed by a probability density function (PDF)
in space that is not of the Gaussian type, hence its variance not being proportional to the
first power of time t [118]. Anomalous diffusion may be split in either sub-diffusion (α < 1)
or super-diffusion (α > 1). In light of this, the adoption of FC has been advantageous for
its straightforward way of including external force terms, calculating boundary value prob-
lems, having easy adaptability when incorporating standard techniques for solving PDEs
and showing a proximity to the analogous standard equations of diffusion processes [119].
As such, FC has been employed in the modelling of heat transfer, water transfer through
porous materials and gas exchange (see references in [115]), but one of its most pertinent
contributions has been in the description of anomalous diffusive processes occurring in
cancer-related phenomena [18], e.g., in characterising such behaviour in biological tis-
sue [115]. Moreover, cancer dynamics rarely meet ideal conditions such as symmetry or
isotropic or periodic paths of movement, for which then simple diffusion does not suffice
to approximate the modelling of its complexities [68], thus revealing one of the many ways
in which FC may be a powerful tool in mathematical oncology.

3.5. Toward a Fractional Mathematical Oncology

Indeed, FDE-based models have been under significant interest in Mathematical On-
cology for the past few years [18]. As such, “Fractional Mathematical Oncology” as a
branch is becoming more and more a possible reality [56], whether given the ability to
model said anomalous diffusive processes (e.g., in the tumour microenvironment or in
metastasis [68]) or other complex phenomena such as numerical solution and control of
invasion systems [120], description of multi-stage tumour characteristics [121], response
to treatments [74], exploration of ideal combined chemo- and immunotherapy through
optimal control [71], modelling of tumourous bone remodelling [122] and potential general
tumour growth [56]. Other noteworthy efforts in this domain are excellently reviewed
in [18,123], with the latter listing the fit FC grants in this modelling world by straight-
forwardly being able to deal with memory effects, heterogeneous scales and dormancy
periods related to the tumour’s onset and development, thus potentially contributing to
decision-making regarding tumour evolution, early diagnosis and personalized treatment
therapies (including that of combined treatment). Additionally, recent advances suggest
that ODE-based models for tumour growth may be improved by adopting FC’s tools,
Fractal Fract. 2023, 7, 595 14 of 22

and further prospects of modelling improvement have been shown with variable order
fractional equations-based models [121], identifying the arbitrary order α as an index of
tumour memory.
However, as noted, these are still early albeit promising prospects of application
of Fractional Calculus in oncology, and current literature is still somewhat scarce in the
systematisation and surveying of its many possible employments. In spite of this, Table 2
highlights and gathers 22 significant progresses registered in the last 9 years of literature
in cancer research, as modelled through FC. The selection criteria was proceeded so as
to provide a sufficiently wide-ranging representation of different fractional operators’
applications, across a variety of treatments and cancer types. Special emphasis is given to
the Caputo definition, since it is the one most often resorted to, notably due to its suitability
in dealing with initial-valued problems in natural phenomena modelling [18,121], and
with variants such as Caputo–Fabrizio revealing to be a revolutionary fractional operator,
given its nonsingular kernel, piquing the interest of scholars [124]. Examples of other lesser
used operators in oncological modelling such as Grünwald–Letnikov and Hadamard are
also present. While the following is not a systematic review, certain keywords resorted
to in the search were (“non-integer” OR “fractional” OR “variable order” OR “Caputo”
OR “Grünwald-Letnikov” OR “Riemann-Liouville” OR “Hadamard” OR “ABC”) AND
(“mathematical oncology” OR ((“cancer” OR “tumour”) AND (“mathematical modelling”
OR “differential equation(s)”))). Searches were furthermore complemented by citation
searching. Finally, some entries are adapted from the overview conducted in [74].

Table 2. Compilation of Fractional Calculus studies in cancer modelling.

Year Title Type of Cancer Treatment Fractional Operator Ref.

A fractional diffusion equation model for
2014 Not specified Not specified Caputo [125]
cancer tumour
Numerical simulation of fractional
2014 bioheat equation in Not specified Hyperthermia Caputo [126]
hyperthermia treatment
Dynamics of tumour-immune system
2016 Not specified Immunotherapy Caputo [127]
with fractional-order
Modelling doxorubicin effect in various
2016 cancer therapies by means of Not specified Chemotherapy Grünwald–Letnikov [128]
fractional calculus
Numerical simulation of time fractional
2017 dual-phase-lag model of heat transfer Not specified Hyperthermia Caputo [129]
within skin tissue during thermal therapy
New observations on optimal cancer Obesity- Chemotherapy,
2018 treatments for a fractional tumour growth associated Immunotherapy Caputo and Caputo–Fabrizio [71]
model with and without singular kernel cancer and Combined
Variable order fractional derivatives and
2018 bone remodelling in the presence Not specified Chemotherapy Grünwald–Letnikov [130]
of metastases
A new fractional model for the cancer
2019 treatment by radiotherapy using the Not specified Radiotherapy Hadamard [131]
Hadamard fractional derivative
Numerical solutions for time-fractional
2019 cancer invasion system with Not specified — Caputo [120]
nonlocal diffusion
Stability analysis and numerical
2019 simulations via fractional calculus for Not specified — Caputo [132]
tumour dormancy models
Fractal Fract. 2023, 7, 595 15 of 22

Table 2. Cont.

Year Title Type of Cancer Treatment Fractional Operator Ref.

A study on discrete and discrete
fractional pharmacokinetics
2019 Colon carcinoma Not specified Rieman–Liouville [133]
pharmacodynamics models of tumour
growth and anti-cancer effects
On multistep tumour growth models of
2020 Breast cancer — Caputo [121]
fractional variable-order
Can fractional calculus help improve
2020 Breast cancer — Caputo [56]
tumour growth models?
Mathematical modelling of cancer and
Co-infection of
2020 hepatitis co-dynamics with non-local and — ABC [134]
cancer & hepatitis
non-singular kernel
Mathematical modelling of radiotherapy
Uterine cervical
2020 cancer treatment using Caputo Radiotherapy Caputo [135]
cancer
fractional derivative
Memory effects on the proliferative
Breast & ovarian
2021 function in the cycle-specific Chemotherapy Caputo [136]
cancer
of chemotherapy
A mathematical model and numerical
Chemotherapy
2021 solution for brain tumour derived using Glioblastoma Caputo [137]
and Surgery
fractional operator
A fractional modelling of
2021 tumour-immune system interaction Lung cancer — Caputo [138]
related to lung cancer with real data
Comparison of fractional-order and
2021 integer-order cancer tumour growth Prostate cancer Chemotherapy Caputo [139]
models: an inverse approach
Modelling and analysis of breast cancer
2022 with adverse reactions of chemotherapy Breast cancer Chemotherapy Caputo–Fabrizio [124]
treatment through fractional derivative
The dynamics of a fractional-order
2022 mathematical model of cancer Not specified Chemotherapy Caputo [123]
tumour disease
Modelling the dynamics of
2022 tumour-immune cells interactions via Not specified Immunotherapy Caputo [140]
fractional calculus

From the wide array of contributions compiled in Table 2, common features, method-
ologies and conclusions may be traced. Regarding cancer dynamics, beyond the can-
cer types themselves, articles such as [127,132,138,140] rely on the modelling of tumour-
immune interactions through FDEs. They thus consider the mutual effect of a given
tumour’s cells with the immune system, represented by its effector cells (e.g., cytotoxic
T-cells, natural killer cells and possibly assuming interleukin-2 concentration [127,140]—or
macrophages and host cells [138]), and in cases adapt prey-predator dynamics [132]. How-
ever, most mathematical models of cancer in Table 2 either approach the tumour alone
through, e.g., modelling its volumetric growth [56,121], or consider merely tumour-immune
interactions with the possibility of treatment intervention, with few others considering
populations beyond (e.g., fat cells [71]). Moreover, the majority of the models presented
operate in the spatial scale of the tissue level. Other contributions concerning the modelling
of specific treatment drug effects feature PK/PD models instead [128,130,133].
As for the mathematical techniques employed, most selected contributions conceive
FDE-based models of cancer dynamics [56,127,128,132,134–136,139,140], with the fractional
Fractal Fract. 2023, 7, 595 16 of 22

operator most resorted to being Caputo’s, as noted in Table 2. On the other hand, the use
of Fractional Calculus when modelling anomalous diffusive processes occurring in on-
cological phenomena is conducted through PDE-based models [120,123,125,126,129,137].
Furthermore, the possibility of a shifting arbitrary order (whether time-variable or not) is
made possible with VODE-based cancer models, as expressed in contributions [121,130].
In spite of these differences, the majority of the aforementioned mathematical models
assume time-fractional differential equations [56,120,121,124–129], thus endowing the can-
cer dynamics with memory effects as granted by a positive, fractional α, and hence not
challenging the spatially isotropic nature of these models, when diffusion through PDEs
is concerned. Additionally, regarding parameterisation, seldom articles openly state data
fitting procedures (e.g., least squares curve fitting method (LSCFM) [138]) using exper-
imentally obtained clinical data [56,121,133,135,138], standing out as the ones with the
methodological prospects to be classified as translational, Mathematical Oncology-pertinent
models toward support in clinical decision making and prediction. At last, in spite of their
academic nature, certain mathematical models conduct an optimisation of either the frac-
tional order α that best renders treatment outcomes [126] or of the treatments themselves:
chemotherapy [136] or mixed chemotherapy and immunotherapy doses [71].
Despite all contributions from Table 2 depicting the application of Fractional Calculus
in the mathematical modelling of cancer, the studies on the obtained models vary widely,
ranging from theoretically-veered mathematical investigations to the aforementioned con-
ception of translational data-fitted models. On the former, the existence and unique-
ness (E&U) of solutions is established through fixed point theory [124,131,134,138,140],
with [120] adapting the Faedo-Galerkin approximation method for this effect. Equi-
libria and stability of the fractional differential cancer models is moreover proceeded
(e.g., [134]), with cases of stability of finite difference scheme [71,126], local stability through
Matignon’s theorem [127,132,138] (considering Routh-Hurwitz conditions) or Ulam-Hyers
stability [140]. Furthermore, numerical solutions are computed through approximations
enabled by methods such as: implicit finite difference method [126]; Euler approxima-
tion [127,128]; Legendre wavelet Galerkin method [129]; nonstandard finite difference
(NSFD) method [132]; Adams-Moulton rule [134,138]; Bernoulli polynomials [137]; Adams-
Bashforth [124] and Adams-Bashforth-Moulton predictor-corrector [138]; q-homotopy anal-
ysis method (q-HAM) [125]; Adomian decomposition method [139]; or reduced differential
transform method (RDTM) [123].
Lastly, ultimately hypothesising the role of Fractional Calculus as a modelling tool
in this research branch, several contributions in Table 2 claim that its usage provides in-
teresting and new dynamics’ description into the fold. Indeed, the employment of FDEs
has been shown to enrich the dynamics of tumour-immune interactions while increasing
complexity of observed behaviours [127], and also its order plays an essential role on the
stability of a system’s equilibria [132]. The order’s association with treatment procedures
such as fractioned dose of radiotherapy in [135] yielded a model that can simulate radio-
therapy process and predict results of other radiation protocols. In research resorting to
experimental data, the study of a VODE-based model in [121] pointed to the superiority
of the obtained model in describing such data, in this sense enabling new perspectives in
tumour growth modelling; moreover, the application of FC adjoined with real non-small
cell lung cancer data in [138] led to the stating that with the aid of this modelling tool,
cancer’s different mode of progression when it starts to appear in the body can be better
explained. In the context of PDEs, positive prospects have been registered in [123,129],
in which the time-fractional derivative has been recognised as pivotal in the former to
the success of modelling hyperthermia treatment for metastatic cancerous cells, making
its its prediction precise, while the latter highlights its importance in achieving a better
understanding of chemotherapeutic effects. Furthermore, contributions such as [128] claim
that fractional modelling of PK/PD models provides insight into certain drug dynamics
which would not be captured by classical techniques of ordinary differentiation.
Fractal Fract. 2023, 7, 595 17 of 22

As for the memory effect/anisotropic potential natural to fractional differentiation, the

authors of [127] theorised that the fractional order could play the role of the cancer system’s
memory. Indeed, as concluded in [56], the knowledge that tumours are constituted by cells
which accumulate an array of mutations along their evolution, it is sound that fractional
models’ account of non-local/past events is oncologically pertinent. FC’s application
through FDEs to model the time-evolution of proliferating and quiescent cell masses
in breast and ovarian cancer in [136] emphasises this advantage of the memory effect,
in which it is claimed that FDE models are appropriate to the real-life problems since it
gives important information on the proliferative function, with the model granting some
qualitative insight on how to better the implementation of cycle-specific chemotherapy.
Still along this notion, the VODE cancer study of [121] posited that a time dependent α(t)
could be interpreted as a variable memory index of cancer, a key translational reading of its
data-based results. Despite the novelty of these findings, they are still early albeit promising
prospects of application of Fractional Calculus in oncology, and the current literature is still
somewhat scarce in the systematisation and surveying of its many possible employments.
Moreover, given the insufficient existent data, most attempts at cancer modelling thus still
merely enable an academic, theoretical outlook on the matter.

4. Concluding Remarks
With the rise of mathematical modelling techniques into the fold of cancer research, it
becomes ever more urgent to grasp the multiplicity of the models employed by discern-
ing thorough categories pinpointing their modelling assumptions and approach, cancer
features tackled, data availability, spatial scale and involvement of treatments. In a field
initially prompted by the two main goals of applying mathematics in improving oncological
knowledge and simultaneously advance the very mathematical tools it employs, it has
become evident that the past years of mathematical oncology research have engendered
at times confusing purposes for the cancer models developed, with some contributions
adhering to literature parameters, conflicting experimental data and theoretical assump-
tions that disable their mathematical models as sound predictive treatment tools for clinical
decision support and optimisation. In this context, the necessity to devise pertinent frame-
works and distinctions between “academic” (Oncological Mathematics) and “translational”
(Mathematical Oncology) models is revised and highlighted in this article.
In spite (or even because) of this general gap between the academically and the trans-
lationally relevant in the modelling sphere, new mathematical techniques have been sought
after with the hopes to enhance pre-existing mathematical models and modelling frame-
works, with one of the most novel tools being those offered by Fractional Calculus. Indeed,
FC’s main purpose—to generalise integer order differentiation and integration to a frac-
tional, irrational or even complex arbitrary order α—has already shown positive modelling
results in areas like signal and image processing, cryptocurrencies, epidemic spread of
diseases, highway traffic flow and viscoelasticity. However, it is in the modelling of bio-
logical phenomena in which FC has made a bigger impact, since its non-locality/memory
effect considers the weight of a function’s past values in the computation of its fractional
derivative, thus aligned with real-life biological events. Given this, the employment of
FC in the modelling of cancer (e.g., replacing ordinary differential equations or refining
partial differential equations) has been a reasonable endeavour. To illustrate this current
research landscape of a prospective Fractional Mathematical Oncology, several contributions
were selected and reviewed, in which it was concluded that while there is a lack of models
conceived with/from clinical data, the qualitative modelling of phenomena such as tumour
growth and diffusion has revealed valuable insights in understanding the complexities of
this disease.

Author Contributions: Initial survey conducted by L.C.V.; L.C.V., R.S.C. and D.V. conceptualised
the survey; L.C.V., R.S.C. and D.V. wrote the manuscript. All authors have read and agreed to the
published version of the manuscript.
Fractal Fract. 2023, 7, 595 18 of 22

Funding: This work was supported by Fundação para a Ciência e a Tecnologia (FCT), through IDMEC,
under LAETA project (UIDB/50022/2020), and by the Associate Laboratory for Green Chemistry
(LAQV), financed by national funds from FCT/MCTES (UIDB/50006/2020 and UIDP/50006/2020).
R.S.C. acknowledges the contract CEECIND/01399/2017.
Data Availability Statement: Data sharing not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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