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therapeutic outcome [64,95,97] . Another strategy could be to associate PDT with other existing compounds used
for chemotherapy. In a recent study the combined use of ferroptosis inductors and Gencitabine has shown to
be able to significantly overcome the resistance to the chemotherapeutic agent displayed quiet frequently in
[98]
pancreatic adenocarcinomas .
PDT in preclinical models of invasive cancer: an up-dated report
Most people diagnosed with cancer will require surgery as the main strategy for tumor removal with or
without radiotherapy and systemic therapy. Tumor cells generally migrate from a primary tumor through
the blood stream and lymphatic system and may be detected in one or more sentinel lymph nodes before
spreading further to a secondary site. In the case of non-metastatic cancer, identifying cancer cells in the
lymph nodes is one of the most important prognostic factors for determining the need for adjuvant radiation
therapy and/or chemotherapy. Once cancer has spread to distant sites, the removal of tumor has not
consistently shown a survival benefit. In these cases, surgery may help with palliative control of an ulcerated
tumor on the chest wall and only unspecific broad-spectrum therapies are the currently treatment option
[99]
available . Thus, effective and safe therapies for this stage of the disease are still needed.

Several in vitro studies have shown a synergism between PDT and ionizing radiation in killing cells [100,101] .
The combined application of low dose of radiotherapy (4Gy) and indocyanine green, with light proved to
be very effective and resulted in a nearly complete reduction of survival [101] . In a preclinical animal model,
PDT following radiotherapy showed evidences of improved trabecular structure. Quantitative histological
examination suggested that PDT induced increases in the bone-to-marrow ratio, due mainly to the increased
formation of newly formed woven bone and an increase in osteoid formation in comparison with the
situation in rats treated with radiotherapy alone [102] . A subsequent study demonstrated that PDT appeared
to improve vertebral integrity in combination with bisphosphonates or radiotherapy [103] , suggesting its
potential use in adjuvant treatment of spinal metastases. These reports suggest that treatment of tumors with
a combination of PS-mediated PDT and ionizing radiation could be superior to their individual use. The
interaction of PDT and ionizing radiation could enhance the systemic therapeutic effect, thus reducing the
radiation dose and potential side effects.

The effect of PDT combined with traditional chemotherapy for the treatment of breast cancer has also
been studied and there are many examples. The treatment with appropriately combined low doses of
cisplatin and indocyanine green- based PDT in vitro was proven to be more effective than each therapy
alone [104] . This synergistic effect is of extreme importance to be considered since cisplatin is one of the
chemotherapeutics which is likely to cause severe side effects. Also the combination of mTHPC mediated
PDT and 5-fluoro-2-deoxyuridine resulted in lower cell survival than the corresponding single mode
treatment [105] . Additionally, the enhanced antitumor effects between PDT and doxorubicin has already
been demonstrated both in vitro [106] and in vivo [107] in a preclinical study on breast cancer. Although little
is known about the mechanisms involving the interactions between chemotherapeutic drugs and PSs,
or how they can be combined to increase cell killing and reducing side effects, all the cooperative effects
between PDT and traditional chemotherapeutics cannot be neglected. Hence, PDT in combination with
chemotherapy is among many strategies which have been proposed to potentiate the therapeutic outcome
[35]
of low-dose chemotherapy and thus minimize side effects and acquisition of drug resistance . A great
advantage of PDT is that it can be used either before or after chemotherapy, radiotherapy or surgery, without
compromising these therapeutic modalities. Moreover, the adverse effects of chemotherapy or radiation do
[35]
not affect sensitivity to PDT . These findings support the use of PDT, at least as an adjuvant therapy, for
enhancement of anti-tumor immunity which may be capable of controlling cancer secondary disease.

Further research and more effort are required in order to allow PDT to be accepted as a suitable treatment
for breast cancer. Even though, there is lot of evidence pointing that this therapeutic approach should