Abstract
Cancer is a major cause of morbidity and mortality worldwide, despite an increased understanding of factors influencing the development and proliferation of malignancies, and an expanding arsenal of effective treatments. Many more patients are capable of being cured of their disease entirely, or are living longer with the disease in remission or with better management of recurrences. These factors make it increasingly likely that cancer patients seek various forms of phototherapy for problems ranging from wound care to pain management, to manage or improve musculoskeletal disorders, to destroy tumors with photodynamic therapy, or for various other clinical applications. Providing treatment for these patients has always generated some degree of ambivalence in the clinical community, particularly as there is the nagging concern that inadvertent stimulation or proliferation of tumors might occur as a result of the photostimulatory effects of light therapy on tissues.
Photobiomodulatory effects of light on mammalian tissues, as are well known to this audience, have been demonstrated to influence a variety of biological processes, including the acceleration of wound healing, increased mitochondrial respiration and adenosine triphosphate (ATP) synthesis, cellular proliferation, enhancement and promotion of skeletal muscle regeneration following injury, enhanced collagen synthesis in the wound area, and increased wound tensile strength. 1,2 Stimulation of cell proliferation results from an increase in mitochondrial respiration and ATP synthesis, among other proposed mechanisms including nitric oxide (NO), and reactive oxygen species (ROS)-mediated pathways. The putative mechanisms for these observations remain unresolved.
It is known that photoradiation in the ultraviolet B (UVB) spectrum can produce temporary photodamage in the form of sunburn or chronic changes, including induction of carcinomas. Matichard, et al. studied the effect of neonatal phototherapy for hyperbilirubinemia on the melanocytic nevus count in children. 3 In their study, intensive neonatal phototherapy at irradiances of 3–4 W/cm2 at 450 nm, which have been considered the standard of care for hyperbilirubinemia since 1970, was a strong risk factor for nevus development in childhood. Exposed children demonstrated twice as many nevi as did unexposed controls. This is disconcerting, particularly as the incidence of melanoma is increasing, and as the risk of melanoma increases with increasing nevus counts. The authors were quick to point out that larger studies are warranted, that melanoma has not been associated with neonatal phototherapy, and that there may be a genetic phenotype that is most susceptible to this effect. 3,4
Liebow, et al. documented stimulation of wound healing and promotion of cancer growth after CO2 laser excision in 7,12-dimethylbenz(a)anthracene (DMBA)-transformed tissues in the hamster cheek pouch model, as a result of cytokine upregulation and reduction of the local inflammatory response. 5,6 Acute immune suppression secondary to overexposure sunlight and both ultraviolet A (UVA) and UVB have also been demonstrated, which may also contribute to the carcinogenic effects of these wavelengths 7 –10 Apoptosis has been shown to be induced or suppressed depending upon the degree of damage and exposure 7 –12 Growing lists of genes, oncogenes and cellular proteins, cytokines, NO, ROS, and other products associated with UVB injury and cellular and tissue responses have been shown to be upregulated or downregulated by light exposure. 7 –12
These studies demonstrate that relatively low doses of light can indeed induce long-term changes in humans, and support the empiric notion that phototherapy may promote neoplasia in some circumstances, while producing beneficial effects in others. It is not surprising therefore that cancer is generally considered to be a relative if not absolute contraindication to phototherapy. Caution is generally suggested even if one is treating areas remote to the neoplasm. 13
Despite these admonitions, there is also some support for the notion that low–level laser therapy (LLLT) may be useful in the treatment of cancer. 14 –18 It is proposed that anti-tumor effects can be achieved through the use of appropriate wavelengths and treatment parameters. Karu 14 proposed that the use of LLLT for tumor treatment should be reconsidered given the fact that ATP signaling can be modulated, which would induce “tumor cell suicide”. Others have suggested that these ATP signaling effects also induce release of NO from cytochromes oxidase, which in turn would modulate apoptosis in cancer. 17 Santana-Blank 13 –15 has described successful management of advanced malignancies using phototherapy.
Somer, et al. 18 have recently proposed the use of photobiomodulation as a means to promote the uptake of chemotherapeutic agents in cancer cells. These investigators demonstrate that exposure of cells to 670-nm laser light induces transmembrane convection, altering the density and viscosity of nanoscopic interfacial water layers in the cell, which forces cells to uptake high doses of these agents in a short period of time. They were able to demonstrate the potency of the method in HeLa cells, using doxorubicin, methotrexate and epigallocatechin gallate. They posit that method is applicable to virtually the entire chemotherapeutic arsenal and that it may be useful as a strategy to overcome multidrug resistance in tumors. 18
These developments are quite intriguing and underscore the complexity and diversity of biological processes and pathways. Perhaps we will one day see phototherapy used for cancer management based on this line of research. The future is bright. Stay tuned.