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Page 10 of 20 dos Santos et al. J Cancer Metastasis Treat 2019;5:25 I http://dx.doi.org/10.20517/2394-4722.2018.83

can prevent oxygen depletion and allow sufficient time for the replenishment of oxygen in the target tissue.
[90]
However, it has already been reported that different PS affect the oxygen consumption rates differently and
thus PDT outcome may vary. Altogether, these results point to the need of more studies addressing how to
maintain PDT performance. An interesting study employing a combination of the fractionated PDT with a
[91]
PS that could produce singlet oxygen during the dark periods has recently addressed this issue. Moreover,
the presence of pre-existing hypoxic areas in tumors can be circumvented by a variety of strategies such
as improving tissue oxygenation prior to PDT as well as by efficiently producing radical species via type I
[88]
photochemical reactions .

Regarding light source technology, researchers have been developing light delivery systems with uniform
illumination, which is essential to improving light penetration and reproducibility. An example of this is
the use of bulb-shaped isotropic emitters along with light detectors which have been used in hollow organs.
Light dosimetry can also help to optimize the positioning of light diffusers. Furthermore, increasing
the selectivity of PDT could be achieved by customizing the diffusers such as balloons and cylindrical
applicators according to the form and dimensions of the target tissue [92,93] .

Additionally, recent advances in LED and diode lasers have allowed to merge their ability of output potency,
enhanced portability and precision optical fiber coupling. These, non-collimated and less expensive light
sources will certainly ease the translation of PDT to clinical procedures. They are usually employed due
to their robustness, short bandwidth, relatively low maintenance cost and ability to be configured to the
wavelength required by the PS. Lamps such as Tungsten filament lamps, metal halide lamps, powerful
[92]
Xenon arc lamps and pulsed lasers are also commonly used in the PDT field .
Besides the light source itself, defining the strategy of light application is of fundamental importance since
different irradiation protocols using the same source can lead to different outcomes in PDT. Another
drawback to be dealt with in PDT prescriptions is light dose regimens because they might also influence
the host anti-tumor reactions and optimal strategies are likely case dependent [35,85] . Therefore, a full
understanding of light dosimetry is an important part of PDT. The issue of light in PDT is under careful
investigation and improvements and new technologies in this field will certainly lead to optimized overall
[94]
PDT efficacy and protocols . For example, one strategy to induce deep tissue phototoxicity is to perform
[95]
repeated PDT or metronomic PDT (slow infusion of PS and low dose light) . Recent studies have shown
that fractionated PDT might induce a high degree of necrosis deeper than PDT alone [35,84,94] . The fact that
this strategy may allow for continuous accumulation of PSs at the treatment site contributed to providing a
better treatment response profile and increased the feasibility of reaching deeper tissues .
[84]

In terms of adverse events associated with PDT, the most common is skin photosensitivity, especially when
PSs of the first generation were systemically administered. In these cases, patients have to avoid sunlight
[21]
and strong artificial light for weeks . Another side effect often reported is pain . The main mechanism
[35]
behind PDT-induced pain has not yet been elucidated, but several studies have found it to be associated
with the size of the treated area, PS type, lesion type, gender, age and light protocol. There are evidences
suggesting that continuous activation of low levels of PS with methods using lower irradiance and possibly
[96]
shorter incubation times are associated with decreased pain without loss of PDT efficacy . Additionally, the
occurrence of inflammation, fever and nausea are typical but often successfully managed with medication.
Tumor recurrence is often reported in clinical trials, probably due to inadequate tumor eradication. It
can be a result not only to insufficient light or PS penetration, but also the presence of PDT resistant
tumors. Although the causes for recurrence often lie beyond the scope of clinical trials, there is a strategy
to overcome incomplete tumor elimination by PDT that is to combine two or more PSs. The idea behind
this is to choose PSs that target different cellular compartments of the tumors allowing for a better overall