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Objectives/hypothesis: Interstitial laser therapy (ILT) has become useful for tumor palliation in patients with advanced head and neck cancer. Cisplatinum chemotherapy also is a frequent adjuvant treatment for recurrent tumors, but systemic toxicity limits application. Intratumor cisplatinum injection combined with ILT may improve therapy of these recurrent tumors with reduced toxicity., Study Design: Prospective. Tumor transplants were injected with cisplatinum in a gel implant before ILT to evaluate treatment response and toxicity in a preclinical study., Methods: UCLA-P3 human squamous cell carcinoma tumors were grown as subcutaneous transplants in nude mice and treated by intratumor injection of 2 mg/mL cisplatinum in a slow-release, collagen-based gel carrier 4 hours before interstitial implantation of Nd:YAG laser fiberoptics to induce local tumor hyperthermia. Treatment efficacy and toxicity were followed for 12 weeks after combined drug and laser therapy compared with ILT alone., Results: Combined cisplatinum gel and ILT was a significant improvement (P < .01 by chi-square test) and induced 57% complete responses without regrowth in 21 transplanted tumors compared with only 24% in 21 tumors after ILT alone during 12-week follow-up. Recurrences in both cases appeared to result from nonuniform laser energy delivery within tumors via the implanted fiberoptic tip., Conclusions: The results of this experimental combined cisplatinum and ILT study suggest it may be possible to improve treatment of advanced head and neck cancer by intratumor injection of gel implants containing the drug followed by interstitial Nd:YAG laser hyperthermia.

Objectives: Laser therapy is becoming a more precise, minimally invasive alternative for tumor ablation. Recent reports confirm successful palliation of pain and functional disabilities in patients with advanced deep carcinoma of the head and neck using interstitial laser phototherapy (ILT)., Study Design, Patients, and Methods: The current study describes an ongoing Phase II trial of neodymium/yttrium-aluminum-garnet (Nd:YAG) laser therapy for palliation of advanced head and neck cancer. A total of 40 advanced cancer patients have been entered into this protocol (25 men and 15 women)., Results: Nineteen of these patients had no evidence of recurrence after ILT with an average follow-up of 11 months (range, 2 to 24 mo). Currently, 19 of these patients are alive, 14 with tumor remission and six with persistent disease. A total of 79 tumor sites received ILT with 43 (54.5%) completely ablated. Stratified by tumor site, ILT led to a complete response in 21 of 24 in the oral cavity, eight of 28 neck tumors, four of 10 in skin, and 10 of 17 in other sites. The procedure was well tolerated in most cases and was repeated at intervals in patients with residual disease or recurrences for a total of 118 laser treatments (average, 2.95 treatments per patient)., Conclusions: The results suggest that ILT can be performed safely and repeated as needed, and may be less costly than conventional surgery for head and neck cancer. However, additional follow-up is needed to obtain convincing evidence of long-term therapeutic benefits.

Laser activation of anthracycline-related drugs combines chemotherapy with photoablation for improved treatment. Hypericin, a structurally related anthraquinone, was tested for laser activation and cytotoxicity in human cancer cells. Viability of P3 squamous cell carcinoma cells incubated with 1 to 20 microgram/mL hypericin was reduced by more than 95% after 1 minute exposure at 4 degrees C to an argon laser (514 nm, 5 W), a KTP-532 laser (532 nm, 5 W), or a 20-A xenon lamp. Viability was reduced over 90% in six human carcinoma, sarcoma, and melanoma cell lines by this combined treatment, but only trace toxicity was seen after separate exposure to hypericin or light alone. These results show that hypericin is a sensitive agent for phototherapy of human cancer cells in vitro and indicate that this drug may be useful for tumor targeting via minimally invasive imaging-guided laser fiber optics.

A new treatment for cancer has been tested in vitro using light-sensitive anthracyclines followed by laser photoactivation, as described by several investigators. We previously reported 10-fold enhanced laser killing after 2 hours of incubation with daunomycin by cultured human carcinoma cells. This short-term uptake leads to drug localization in cytoplasmic and membrane sites prior to nuclear accumulation and topoisomerase inhibition. In the present study, daunomycin was incubated for 2 or 24 hours with P3 squamous carcinoma cells to directly compare cytoplasmic vs. nuclear drug targeting before and after KTP-532 laser activation. Monolayer cultures of the P3 cells sensitized with daunomycin for 2 hours, then chilled (4 degree C), and exposed to the KTP laser (532 nm, 94.2 J/cm2) had a 2- to 10-fold increased therapeutic response compared with drug or laser alone when measured by MTT tetrazolium assays. After 24 hours of incubation with daunomycin, the chemotherapeutic response of P3 tumor cells was amplified 2-fold by laser exposure. The results suggest that daunomycin and laser treatment can be combined for improved therapy of human cancer.

Interstitial laser therapy (ILT) is a promising therapeutic technique in which laser energy is delivered percutaneously to various depths in tissue. In this study, the authors compared high-speed magnetic resonance imaging (MRI) of ILT in tissues during treatment with post-treatment histopathologic specimens. The use of 5-second MRI scans allowed detection of thermal damage by the 1064-nm neodymium:yttrium-aluminum-garnet laser in ex vivo liver and brain tissues. These tissues were treated by ILT with 20 W of laser output for 5 to 30 seconds via a 600-microns fiberoptic inserted 1 cm into the specimens at a power density of 7 kW/cm2 at the tip of the bare fiber. Sequential MRI measurements of lesion areas made during and after treatment were compared to measurements of laser-induced tissue damage in histopathologic sections. Fast MRI scans and tissue histology both demonstrated increased lesion size with time of ILT. Serial images obtained during ILT detected thermal changes as areas of low signal intensity that exceeded the size of the post-treatment lesions as measured on either final MRI or histology. The thermal effects detectable by these high-speed MRI sequences can be used to monitor laser-induced tissue changes during therapy, thereby providing a valuable noninvasive method for the intraoperative assessment of heat distribution during ILT.

Tissue uptake and biodistribution of hypericin was measured in rabbits and in nu/nu mice xenografted with P3 human squamous cell carcinoma to assess the value of this dye as an in vivo sensitizer for laser photoinactivation of solid tumors. Hypericin has absorption maxima at 545 and 590 nm with a fluorescence emission peak at 640 nm in ethanol. Dye uptake after intravenous injection was tested at 4 and 24 hours in rabbit tissues by ethanol extraction and quantitative fluorescence spectrophotometry. Maximum dye levels were seen at 4 hours in most vascular organs with lung having fivefold higher uptake than spleen followed by liver, blood, and kidney. Mice were examined after 2, 4, 6, 8, and 24 hours and after 3 and 7 days for dye uptake. The peak concentration of hypericin in murine organs was reached at 4 hours with uptake per gram of tissue as follows: lung > spleen > liver > blood > kidney > heart > gut > tumor > stomach > skin > muscle > brain. Elimination of hypericin was rapid in most murine organs with residual dye under 10% of maximum by 7 days compared to 25% to 30% retention for the squamous cell tumors and several normal tissues. These results suggest that hypericin may be a useful photosensitizer for KTP/532 laser interstitial therapy of human cancer.

Previous studies have shown that Rhodamine 123 (Rh123) is an efficient tumor targeting agent for argon laser photodynamic therapy in vitro. Effectiveness of this approach for cancer treatment in vivo will depend on Rh123 tumor uptake kinetics and laser energy delivery via fiberoptics to the tumor site. In the present study, tumor and normal cells were exposed in vitro to 1 micrograms/mL Rh123 until 10%, 50%, and 100% of maximum uptake was achieved. Laser treatment response was monitored by trypan blue exclusion for tumor cell viability and by MTT tetrazolium assays to measure mitochondrial dehydrogenase activity. TE671 fibrosarcoma cells were highly sensitive to argon laser phototherapy (514 nm, 5 W, 1 minute, Tmax = 8 degrees C), with mitochondrial inhibition seen after Rh123 uptake of 12, 50, and 100 ng/million cells. P3 squamous cell carcinoma cells were inhibited 20% and 75% by the laser after Rh123 uptake of 13 or 30 ng/million cells, respectively. M26 melanoma cells were not sensitive to the laser after 15 ng/million cells Rh123 uptake but were inhibited 45% and 75% after Rh123 uptake of 80 and 160 ng/million cells. Micro2 fibroblast mitochondrial activity was reduced less than 25% by the laser after Rh123 uptake of 50 ng/million cells. Cell viability after maximum Rh123 uptake and laser treatment was decreased to 30%, 15%, and 2% for M26 melanoma, P3 squamous cell carcinoma, and TE671 fibrosarcoma cells, but remained over 80% for Micro2 fibroblasts. The results suggest that Rh123 laser treatment response depends on tumor type and drug uptake level, with normal cells being much less sensitive to phototherapy.

The search for improved photosensitizers for laser phototherapy of malignancies has led to the examination of a new group of carbocyanine dyes as effective fluorochromes. In this study, four carbocyanine dyes with different absorption maxima of 483 nm [DiOC6(3)], 545.5 nm (DiIC5(3)], 556.6 nm [DiSC5(3)], and 651.0 nm [DiSC3(5)] were tested in vitro. The kinetics of uptake and toxicity of these four dyes were assessed for P3 human squamous cell carcinoma, HT29 colon carcinoma, M26 melanoma, and TE671 fibrosarcoma cell lines at 15, 30, 45, 60, and 180 minutes after exposure with each dye. After sensitization with DiOC6(3), the P3 and M26 cell lines were also tested for phototherapy by treatment with 488-nm light from an argon laser. The results showed that these four carbocyanine dyes had rapid and significant uptake by the carcinoma cell lines with no toxicity at concentrations < 0.1 micrograms/mL. Nontoxic DiOC6(3) levels in sensitized tumor cells after laser phototherapy resulted in approximately 85% inhibition of P3 and approximately 95% inhibition of M26 cell lines by MTT assays. The results suggest that these carbocyanine dyes can be used for tumor photosensitization and wavelength-matched laser photodynamic therapy. Further in vivo studies will be necessary to define the clinical potential of carbocyanine dyes as tumor-targeting agents for phototherapy of cancer.

Interstitial laser phototherapy (ILP) guided by magnetic resonance imaging (MRI) may become an attractive adjunctive modality for the treatment of deep and surgically inaccessible tumors of the head and neck when accurate methods of laser dosimetry and "real-time" monitoring techniques with the MRI are introduced. We recently demonstrated in ex vivo and in vivo models, a linear relationship between levels of laser energies, thermal profiles, MR signal intensity changes, and histopathological tissue damage. Results of treatment in a patient with an unresectable large right jugulodigastric metastatic squamous carcinoma using new approach of MRI guided ILP are now reported. The patient complained of significant right-sided neck pain and headaches secondary to a rapidly growing metastatic lymphadenopathy which recurred after previous surgery, radiation, and chemotherapy. Two treatment sessions were used at an interval of 2 weeks. Each treatment was performed in the MRI suite under heavy sedation. Using a 600-microns bare fiber of the Nd:YAG laser implanted interstitially under MR guidance, the metastatic node was treated at three sites. T1- and T2-weighted images were performed prior to, immediately after, 24 and 48 hours, and 4, 5, 7, 9, 16, and 25 days post-treatment. Successful relief of pain and growth arrest of this node was observed after the second treatment and at the 3-month follow-up. These results demonstrate that this technique of ILP guided by MRI may be feasible in humans, and will become clinically practical when appropriate methods of dosimetry and instrumentation are developed.

The mitochondrial dye Rhodamine 123 (Rh-123) has been shown to be an effective photosensitizer for argon-laser irradiation of some types of human cancer cells in vitro. We reported that 514.5-nm laser illumination of Rh-123 sensitized human melanoma, and squamous carcinoma cells strongly inhibited tumor-cell proliferation as measured by decreased 3H-thymidine (3H-T) uptake in vitro and may eradicate some tumors when grown as transplants in nude mice. However, several other human tumors were resistant to Rh-123 laser therapy in vitro and in vivo. In the current study, it was possible to obtain 100- to 1000-fold increased sensitivity to 514.5-nm laser illumination by replacement of Rh-123 with the cationic rhodamine dyes Rh-3G and Rh-6G. Cell viability was decreased over 95% and 3H-T incorporation reduced at least 80% by laser phototherapy after sensitizing tumor cells with 1 micrograms/mL Rh-123, 0.01 microgram/mL Rh-3G, or 0.001 microgram/mL Rh-6G. However, Rh-123 alone did not decrease 3H-T uptake significantly unless present at over 10- to 100-fold higher levels than Rh-3G, respectively. The tumor cell dye uptake level was measured by N-butanol extraction and absorption scans at 400 to 600 nm. The results revealed that dye uptake was more rapid, and retention of Rh-3G and Rh-6G was 5- to 10-fold higher than for Rh-123 in the human tumor cells. The data suggest that Rh-3G and Rh-6G may be highly sensitive chromophores for laser phototherapy of human cancer cells.

A new and highly promising adjunctive modality for the diagnosis and therapy of malignancies is under development using lasers and tumor targeting dyes. To reach the eventual goal of clinical treatment, several current "fantasies and fallacies" regarding laser applications in medicine must be identified and their problems clearly outlined. A multidisciplinary scientific approach is also required to enable the clinical practicality of this laser targeting approach. Many new dyes and laser wavelengths are being tested to improve specific tumor uptake and/or retention, lower systemic toxicity, increase tissue penetration, and identify fluorochromes with synergistic properties to further enhance laser tumoricidal effects. Rapid technological advancements in magnetic resonance imaging may now provide an extremely sensitive way to detect and monitor laser-tissue effects, and allow efficient interstitial laser phototherapy of deep and sometimes inaccessible tumors. The current and future prospectives of the emerging field of laser phototherapy are described.