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be considered as an antitumor treatment, the actual challenge for PDT is to translate the advances in
understanding the effects in the cell-line-based and animal models studies into the clinical practice.

Clinical applications of PDT; Combination with other therapies; On-going trials
Despite the increasing number of studies with a growing number of chemical compounds and their generally
increased number of favorable aspects as compared to more standard treatments, only a few PS have already
been approved for clinical use and only for the treatment of a few diseases.

While the majority of PDT uses involve different types of cancer, ALA use with distinct formulations is
already approved for several clinical applications, ranging from mild and moderate actinic keratosis to non-
[40]
hyperkeratotic actinic keratosis. Some are also used to treat the Bowen’s disease and basal cell carcinoma .
Moreover, for serious ocular diseases such as age-related macular degeneration and myopic choroidal
neovascularization there is a clinically approved PS called Verteporfin in current use [108,109] . In 1993, Porfimer
sodium (Photofrin) was the first PS approved for clinical used of PDT by the Canadian Health Agency for
bladder cancer treatment. Later on, it was approved by the Food and Drug Administration (FDA) and also
in several other countries for the treatment of various types of cancer, such as lung, esophageal, gastric,
and cervical cancers as well as for cervical dysplasia [110] . This photosensitizer is still widely used in PDT
for treatment of various conditions [111,112] . However, being a complex mixture of molecules with poor tissue
selectivity and low light absorption, high concentrations of porfimer sodium are needed, which make
it to persist over 2 months after the administration [113] , rendering patients photosensitive [114] . A second-
generation of PS has been then developed, with improved purity, longer wavelength absorptions and higher
photosensitivity and tissue selectivity. Temoporfin was the second PS to receive approval and extensively
used for treatment of advanced head and neck squamous cell carcinomas [115,116] . Temoporfin was also tried
for the treatment of breast, pancreatic and prostatic cancer [117-121] , with mixed results. For breast cancer there
was response in all patients with minimal-invasive and few side effects [119] . Similarly, for prostate cancer
it appeared a safe procedure and after 8 of 10 PDT sessions, the prostate specific antigen fell by up to 67%
and biopsies of treated areas revealed necrosis and fibrosis at 1-2 months [120] . However, in patients with
malignant biliary obstruction, endoscopically delivered Temoporfin-PDT caused efficient tumor necrosis
and recanalization of blocked metal stents, but it showed a significant risk of complication with one leading
to a fatal liver abscess and two patients developing haemobilia within 4 weeks of treatment, one of whom
died with a gall bladder empyema [118] . A mono-L-aspartyl chlorin, Talaporfin, was approved in Japan as a
PDT for lung cancer but was also employed for early head and neck cancer patients and is going through the
phase II trial for the treatment of colorectal neoplasms and liver metastasis [122] . There are also other drugs
approved as orphan drugs by the FDA for PDT treatment for Cutaneous T-cell lymphoma (SGX301) and for
[40]
biliary tract cancer (LUZ11) .
Since PDT has the potential to present a local effect, it lacks systemic adverse effects seen in other
therapies. Additionally, because of its mechanism, PDT can be used in the clinic in combination with
other procedures, such as radiotherapy, chemotherapy or surgery. At the present time there are a number
of on-going trials using PDT with distinct PS for different types of cancer. Among all the on-going trials
registered at clinicaltrials.gov (not concluded), about 50% of them use PDT alone or in combination with
other therapies for at least one condition [Table 2]. So far PDT using distinct photosensitizers appears to
be effective in decreasing tumor size and increasing patient survival in several of the trials, which target
different kinds of tumors [Table 3]. Interestingly, the clear majority of current on-going trials for cancer are
using photosensitizers that have already been approved for clinical use, mainly with Photofrin and ALA but
also with Verteporfin and other still unapproved compounds.

The majority of approved PDT protocols are related to the treatment of superficial lesions of skin and
luminal organs. However, due the enhancement of PS efficiency and light delivery, interstitial and intra-