Systems, devices, and methods are described for providing, among other things, improvement in treatment of abnormal tissues including cancer, utilizing light activated drug therapy. Improvements include the use of optical penetration and drug penetration enhancers, in combination with photosensitizing drugs, and the use of localization aids and implements, which enable treatment of larger tissue volumes using minimal tissue access. The cytotoxic photoactivation process is also improved by using internal guidance to direct the light source to and at the lesion site using a naturally occurring orifice or intravascular access route.