Volume 46 | Issue 1 Article 1

1984 Photoradiation Therapy Sherri L. Ihle Iowa State University

Ronald L. Grier Iowa State University

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Recommended Citation Ihle, Sherri L. and Grier, Ronald L. (1984) "Photoradiation Therapy," Iowa State University Veterinarian: Vol. 46 : Iss. 1 , Article 1. Available at: https://lib.dr.iastate.edu/iowastate_veterinarian/vol46/iss1/1

This Article is brought to you for free and open access by the Journals at Iowa State University Digital Repository. It has been accepted for inclusion in Iowa State University Veterinarian by an authorized editor of Iowa State University Digital Repository. For more information, please contact [email protected]. Photoradiation Therapy

Sherri L. Ihle* Ronald L. Grier, DVM, PhD* *

EditorJs note: Currently, photoradiation (Hpd), was found to have. a superior tumor­ therapy is not performed in the Veterinary localizing ability.3 In 1973 the Mayo Clinic re­ Teaching Hospital at Iowa State University. ported the use of fluorescence bronchoscopy in early lung cancer. However, the fluorescence Introduction \vas faint and hard to document and so the One of the most difficult areas of both hu­ project was discontinued.2 The first reported man and veterinary medicine today is the case of complete tumor destruction of experi­ treatment of neoplastic disease. Numerous mental tumors was in 1975 when Hpd was techniques and agents have been used in this used with local application of red light the fol­ field but none are totally effective. The varia­ lowing day. In 1976 this treatment was used on bility of responses to treatment is as wide as the a human bladder carcinoma with light applica­ variety of cancerous conditions. For this rea­ tion via a transurethral quartz rod. '1 son, research continues to search for safer, more effective methods of cancer therapy. One Biochemistry development in this area is phototherapy, or While Hpd is selectively retained by malig­ more exactly, photoradiation therapy (PRT). nant tissue it is ~lso retained by liver, kidney, This technique was expanded to include its use spleen, and lymphS Studies indicate that the in pets. 21 relative hydrophobicity of a porphyrin is very Photoradiation therapy involves use of a important to both its localization and tissue photoactive drug which localizes in neoplastic toxicity. More hydrophilic agents do not accu­ and dysplastic tissues while at the same time mulate well and therefore are very poor photo­ rapidly clearing from normal tissues. Illumina­ sensitizers of intact cells. The porphyrin struc­ tion with red light electronically excites the ture also affects the toxic products formed and compound in the malignant tissue; energy is the speed of their formation. Studies showed released, cell components oxidize and cell that hematoporphyrin has difficulty crossing death occurs. Normal tissue is thus spared cell membranes; localization in malignant tis= while malignant tissue is destroyed.1 sues occurs as a result of intercellular conver­ sion of a permeable derivative to hemato­ History porphyrin or another poorly diffusible The theory that drugs cause a photosensitiv­ component.6 ity reaction in tissues is not new.2Thirty years How are such toxic compounds formed and ago it was noted that hematoporphyrins accu­ how do they destroy the tissues? The reaction mulated in embryonic, neoplastic, and re­ is a photo-initiated oxidation in which energy generating tissues, and in lymph nodes. Tu­ is transferred from the Hpd to tissue oxygen, mors fluoresced a red color when illuminated forming singlet oxygen: with ultraviolet light after injection of a crude hematoporphyrin compound. In 1960 a puri­ fied compound, hematoporphyrin derivative Hpd + hv - 1Hpd* 1Hpd*- 3Hpd* *·Ms. IWe is a fourth-year student in the College of 3Hpd* 30 - 10 Hpd Veterinary Medicine at Iowa State University. + 2 2 + **Dr. Grier is a professor of Veterinary Clinical 102 + substrate - oxidation - Sciences at Iowa State University. 102 302

4 Iowa State Veterinarian In this reaction 1H pd* is the excited state of curred with many types of neoplasia and in Hpd, 3Hpd* is the excited triplet state of Hpd, numerous anatomical locations. PRT has also

302 is ground state triplet oxygen and 102 is the been shown to be effective in localization of 7 excited triplet state of oxygen. ,8 some malignancies. The occurrence of such a reaction has been PRT has been used to treat squamous cell inferred from the protective effect provided by carcinoma of the tracheobronchial tree in 10 the presence of natural or added carotenoids patients. 11 Laser beams were used to deliver which are well-established quenchers of singlet light through a bronchoscope. Complete re­ oxygen. Using 1,3-diphenylisobenzofuran as a sponse (no tumor demonstrable in a biopsy or quencher of photoactivation, studies have con­ brush preparation) was seen in four cases, and firmed that singlet oxygen is the likely cytotox­ a partial response (greater than 50% decrease ic agent with this type of therapy.8 Immediately in tumor size) occurred in five patients. All after exposure to PRT, coagulation of erythro­ masses had been small superficial tumors. The cytes occurs in tumor vessels where the por­ remaining patient died from hemorrhage and phyrin levels are highest. Death of nearby cells cardiac arrest secondary to the neoplasm erod­ occurs and more distant cells become less ing the wall of a major bronchus.ll tightly packed. Electron microscopy shows that In Australia, researchers used Hpd and a cells nearest the vessels are actually emptied of laser/fiberoptic system to treat 20 superficial cytoplasmic contents which have leaked into and seven deeper tumors which included mam­ the interstitium. Within three hours gross ne­ mary carcinoma and other carcinomas, malig­ crosis and massive cell destruction are seen. nant melanoma, chondrosarcoma and glioma. This is a manifestation of inhibition of mem­ The best clinical results were seen with superfi­ brane transport, membrane damage due to cial tumors, with a positive response in 17 of 20 photodynamic crosslinking of membrane pro­ cases. Complete tumor necrosis occurred in teins and lipids, and damage to DNA and lyso­ five. There was no response in two malignant somes. Survival curves for cells containing melanomas and a metastatic chondrosarcoma. H pd are similar to those resulting from ioniz­ Of the seven tumors, only the glioma showed ing radiation. 7 any response (See Table 1). Having established that such a reaction oc­ Two studies with PRT have been done at the curs, it was desirable to find a light source pro­ University of California on dermal breast can­ ducing wavelengths of 620-640 nanometers. cer recurrence, local recurrence of head and This range was found to produce optimal re­ neck squamous cell carcinoma, and other car­ sults since visible wavelengths greater than 600 cinomas. One study reported a 67 % favorable nm are least absorbed by skin and other tis­ response involving treatment of 128 sites. The sues, and porphryrins show weak absorption in best response was against local recurrence of this part of the spectrum. Arc lamps, fluores­ head and neck squamous cell carcinoma and cent lights and other strong light sources will recurrence of breast cancer with an 85 % and deliver enough light to treat superficial tumors 70% response rate respectively. A lesser re­ when fitted with appropriate filters. 9 Deeper sponse was seen with metastatic squamous cell tumors require a different method of light de­ carcinoma in which the tumors were usually livery. New developments in lasers and fi­ larger, ulcerated and more severe at the time of beroptics can be used to allow illumination of treatment. Response was evaluated 30 days nearly any portion of the body without major post-treatment; a positive response was defined surgery. In man, tumors up to 5cm X 5cm as either complete or partial. 12 In another study have been destroyed by use of multiple fiber from the University of California, PRTwas techniques. 10 used on 267 tumor sites which included dermal breast carcinoma recurrence, head and neck Human Medicine Applications squamous cell carcinoma recurrence and cuta­ Many preclinical tests and trials of PRT neous metastasis. An 81 % postitive response have been done in man. In all cases the lesions rate was seen (complete and partial response). treated have been inoperable and have failed to Some patients with recurrent breast cancer ex­ respond to conventional therapy. The amount perienced significant pain for up to three weeks of Hpd used, the wavelength and duration of following treatment. Interestingly, while 84 tu­ light exposure and many other parameters mors responded favorably, only 25 % of 'these have been studied. Favorable response oc- had an effect on the course of the disease.

VOl. 46) No. 1 5 TABLE 1 Current statistics for tumor responses to phototherapy (6/1/83) Response Tumor No. Complete* Partial None No Follow-up Adenocarcinoma (Mammary- Cat) 5 5 Adenocarcinoma (Undifferentiated) 3 1 2 Adamantinoma 4 4(3)" Eosinophilic Granuloma 1 Fibromatous Epulus 2 1(1)" Acanthomatous Epulus 1 1 Fibroma 1 1 Fibrosarcoma 7 2(2)" 4 Hemangiopericytoma 1 1 Hemangiosarcoma 1 Leiomyosarcoma 1 Liposarcoma 1 1 Malignant Mast Cell 12 9(2)" 2 Malignant Melanoma (Melanotic) 4 3(2)" 1 Malignant Melanoma (Amelanotic) 3 2(1)" 1 Mastocytoma 1 1 Myxoma 2 1 1 Osteosarcoma (Head) 6 3(3)- 2 1 Osteusarcoma (Limb) 3 1~ 2 Perianal Gland Sarcoma 1 1 Sarcoma (Undifferentiated) 2 2 Sebacious Gland Sarcoma 1 1(1)- Sebacious Gland Carcinoma 1 1 Squamous Cell Carcinoma 8 3(1)- 4 Synovial Cell Sarcoma 3 1 2 Total types: 25 75 44 23 5 3 or or or or 59% 31 % 7% 4% 90% Total positive response

(*Number in parentheses are those in complete remission for more than one year.) [Thoma, Stein, Weishaupt, and Dougherty: Phototherapy: a promising cancer therapy. VMISAC 78:1965, 1983.]

Many patients developed new lesions in un­ chial and lung cancer. In the past when sputum treated areas. Patients with cutaneous metas­ cytology suggested neoplasia, a brush biopsy or tatic head and neck tumors did not do well, but tissue biopsy had to be prepared. These proce­ those with local recurrence benefitted consider­ dures were often difficult to perform if the le­ ably with a major change in disease progres­ sion could not be visibly differentiated from the sion. 12 ,13 surrounding tissue. With PRT, Hpd was given Several other anatomical locations and tu­ intravenously and the areas were checked three mors have been treated with PRT. The Japa­ hours later for fluorescence. The results were nese have reported complete regression ofearly quite favorable with fluorescence seen in 32 of vaginal carcinomas with PRT treatment, with 34 malignancies. No false positives were seen no recurrence at one-year follow-up.14 Hpd in the eight benign lesions. A few false positives and a laser light source have been used to treat were seen in areas of lymphoid tissue, but this retinoblastomas and intraocular malignant me­ was not a problem since all true positives were lanoma of the choroid. Treatment in this area later confirmed by biopsy. False negatives are is normally difficult, as adjacent normal tissue more of a problem since the lesion could then 17 must be spared. Radiation therapy results in be missed. ,18,19 This same technique for locali- radiation burn of nearby tissue. This problem zation of neoplasia has been used on bladder does not occur with PRT if the light intensity carcinoma. Biopsies ofvisually suspicious areas 2 15 remains less than 200 milliwatts/cm • PRT is have previously been the primary method of also being considered for malignant brain tu­ confirming positive urine cytology. Subtle or mors. Some work has been done in this area, diffuse disease was often missed by this but conclusions cannot be drawn at this time. 16 method, however. Hpd given intravenously An interesting facet ofcurrent PRT research two hours pre-surgery will localize in dysplastic is the use of Hpd and fluorescence bronchosco­ and neoplastic transitional cells and be detected py for the detection and localization of bron- by subsequent fluorescence. 20

6 Iowa State Veterinarian Side effects have been relatively mild. Slight At the time of light treatment the ~nimals pain has been experienced in a few cases and were anesthetized with thiamylal sodium and some discomfort has been associated with re­ halothane, or xylazine and ketamine. The area sultant tumor necrosis. The main complication of the tumor was clipped and prepped for sur­ is photosensitivity for 2-4 weeks post-treat­ gery. The treatment light source was produced ment. This can be prevented however, if the by an argon ion laser. This produced enough patient avoids exposure to sun during this light energy to pump a Rhodamine B dye laser time. A few patients who have ignored this ad­ operating without the tuning element. A broad vice have incurred skin burns. output spectrum between 625 and 640 nm re­ sulted which was then narrowed to 630 ± 2 Veterinary Medicine Applications nm with a birefringent filter. The beam was PRT has been used in pet dogs and cats in split into four beams and coupled with fiberop­ the past few years. The animals used in this tics. Coupling efficiency was greater than 70% ongoing study were chosen because of their within the fiber lengths used. The ends of the failure to respond to conventional therapy or fibers were cut optically flat after stripping because they could not tolerate therapy. Some back 1-2 cm of the protective teflon coating. pets had surgical excision of tumor with PRT If the mass was less than 1.0-1.Scm in used as adjunct therapy. The pets were ob­ diameter, four 18-gauge needles were inserted tained directly from their owners after having in the tumor in a tetrahedral pattern with lcm discussed all treatment alternatives and the in­ sides. The optical fibers, having been cold vestigational status of Hpd/PRT. The animals sterilized and cleaned with 70% ethanol, were were returned to their owners following treat­ inserted through the needles to a distance Imm ment. Radiology was used to determine the beyond the needle tips. If excessive bleeding size and extent of the mass, presence of metas­ occurred through the needle, the needle and tasis and to aid in fiberoptic placement in tu­ fiber were withdrawn and reinserted a short mors to be treated. All lesions were confirmed distance away. This was necessary since hemo­ by biopsy and histopathology. 10,21 Other tests globin absorbs light slightly at 630nm. such as electrocardiograms, urinalyses, and If the tumor was greater than 2cm in diame­ microbial cultures were performed if deemed ter, the fibers were implanted in several areas necessary. 10,21 sequentially to ensure light delivery throughout a The Hpd used was Photofrin-V , which is the mass and the most adjacent normal tissue. produced by dissolving hematoporphryin in Treatment times ranged from 15-30 minutes glacial acetic acid and sulphuric acid. The solu­ at 120-900 milliwatts/fiber but was deter­ tion was filtered and neutralization with so­ mined to be optimal at 20 minutes at 250mW/ dium acetate formed a precipitate. The precip­ fiber. This delivered 300 Joules/fibyr/insertion. itate was washed and stored at - 20°C until Total time for a treatment session was usually 2 needed. For injection, one part Hpd was mix­ hours. With large tumors surgical debulking ed with sodium hydroxide, neutralized with was performed one week prior to phototherapy hydrochloric acid, and diluted with sodium to lessen treatment time and decrease the chloride to a final concentration of 5mg/ml. amount of necrotic tissue. During treatment, Millipore filtration rendered the solution power was increased slowly and the light sterile. 1 emanating from the tumor was observed to en­ Two to three days prior to light treatment, sure proper light levels and adequate fiber posi­ 3.0 to 5.0 mg/kg Hpd was injected intrave­ tioning. nously. This allowed adequate drug concentra­ As PRT proceeded, the tumor increased in tion in the tumor and clearance by normal tis­ size due to edema and cell necrosis; some tu­ sues. During this time the animals were kept mors also appeared dark or discolored due to out of sunlight or bright light to minimize pho­ necrosis. The edema usually regressed in 48 tosensitivity reactions. Photosensitivity appears hours. Tissue response ranged from fluid as a transient sunburn/edema/erythema reac­ drainage to severe frank necrosis and tion that is reversible with antihistamines. sloughing. Granulation and healing occurred Minimal problems have been observed in ani­ at a normal rate, and by three weeks, deter­ mals ~ue to their pigmentation and hair coat. mination of tumor regrowth was possible. aOncology Research and Development, Inc., Cheekto­ There are no contraindications to repeated waga, NY. treatments as long as it is safe for the animal to

VOl. 46, No. 1 7 again be anesthetized. Large tumors that could new development in the field of oncology and not be surgically reduced prior to PRT were the treatment of discrete solid tissue tumors. It retreated at close intervals; with such a treat­ is showing itself to be very effective and reliable ment schedule the dose of Hpd should be de­ for several histopathologic types of tumors creased by one-third or one-half if given within which do not respond well to presently avail­ four to six days of the previous injection. able modalities. One such tumor is the os­ Post-treatment care was similar to that for teogenic sarcoma of the head. Not only has any surgical procedure. Doxorubicin HCl photoradiation therapy eradicated some tu­ (Adriamycin®) is the only known drug to be mors, but it does so without damage to adja­ contraindicated. Antibiotics, steroids, fluids, cent healthy tissue. This allows the healthy tis­ cleansing of the sloughing tissue, diuretics, and sues to fill-in the defect and remodel the bone. other compounds all were used as needed. The Good results (complete remission) were also patients were rechecked weekly for at least one seen with mammary adenocarcinomas in the month and then monthly if all seemed to be cat. This highly malignant neoplasia pre­ progressing well. Chemotherapy other than viously carried a poor prognosis even with sur­ doxorubicin may be used in an effort to control gery. 5 micrometastasis. ,6,21 The ability to deliver light directly to the The results of PRT on pets have been very tumor via fiberoptics extends the use of PRT encouraging for certain types of solid malig­ to any site reached by needles or an endoscope. nant tumors. Table 1 gives the results of PRT Previously, chemotherapy or surgery were the in 75 animals with 25 histological tumor types. main alternatives for neoplasia of the lungs, Seventeen have been in remission for over a throat, bladder, vagina, and colon. PRT may year and 44 (59%) are in complete remission. be a safer, less-invasive alternative. Partial response was seen in an additional 23 The technique is a simple one, making it a cases. Those tumors unresponsive to the thera­ good procedure for the practitioner. The cost of py were in the long bones of the extremities the equipment is prohibitive at the current (two osteosarcomas, one myxoma, and one fi­ time, but it has been proposed that a metropol­ brosarcoma). Three animals were lost to fol­ itan area with a population of greater than low-up. The longest follow-up is of a cat 750,000 could produce enough cases to justify treated for osteogenic sarcoma of the mandible a regional unit. 5 Furthern10re, as lower cost SIX years ago. light sources are developed, PRT could be put Favorable response was seen with osteosar­ into even more widespread use. con1a of the head, malignant melanoma, fibro­ Problems remain to be further investigated. sarcoma, malignant mast cell sarcoma, ada­ More work is needed to determine exactly why mantinoma and synovial cell carcinoma. Both some types of neoplasia do not respond to favorable and unfavorable responses were seen treatment. The recurrence of new squamous with squamous cell carcinoma, adenocarcino­ cell lesions adjacent to the site of previous ma, leiomyosarcoma, and hemangiopericyto­ treatment points to the need to develop better rna. The differences in response have not been ways to initially evaluate the extent of the le­ explained but are similar to those being seen in sions. It would be helpful to be able to assay for human medicine. Many variables can affect Hpd levels to predict response to treatment and the response of the tumor to therapy. Altera­ plan further therapy; currently no such assay is tion ofthe circulation to the tumor may change available. 21 Lastly, large tumors require long the amount of Hpd being delivered to the and/or repeated periods of anesthesia which mass. Passage of the drug into the tumor cells may not be well tolerated by some patients; a and surrounding tissue are dependent on the larger dose of Hpd to increase the effective permeability of the tumor vessels. Tissue den­ treatment volume and the coupling of multiple sity (e.g. bone or melanin granules) can alter fibers to the laser are being investigated. 21 the penetrating ability of light. Less under­ As with any tumor treatment protocol, PRT stood variables, such as the fact that osteogenic has its advantages and disadvantages. Its sarcoma of the head is more osteoblastic while adaptability, however, allows it to be effectively osteogenic sarcoma of the limbs is more lytic, used as a primary treatment or as an adjuvant 5 also may playa part. ,6 to surgery or as an alternative to radiation and Summary chemotherapy. With time and further study Phototherapy looks to be a very promising and development, its benefits are increasing

8 Iowa State Veterinarian and its limitations are decreasing. The clinical 17. Cortese, DA: Hematoporphyrin derivative in the de­ simplicity and apparent safety of this therapy tection and localization of radiographically occult lung cancer. Am Rev Respir Dis 126:1087-1088, 1982. n~ay makes it possible that PRT soon take a 18. Hayata Y, Kato H, Konaka C, OnoJ, Matsushima place alongside the more conventional tumor Y, Yoneyama K, Nishimiya K. Fiberoptic bronchos­ therapies. copic laser photoradiation for tumor localization in lung cancer. Chest 82:10-14, 1982. 19. Cortese DA, Kinsey JH: Endoscopic management of References lung cancer with hematoporphyrin derivative pho­ 1. Forbes IJ, Cowled PA, Leong AS-Y, Ward AD, totherapy. Mayo Clin Proc 57:543-547, 1982. Bleack RB, Blake AJ, Jacka FJ: Phototherapy of hu­ 20. Benson RC, Farrow GM, Kinsey JH, Cortese DA, man tumors using haematoporphyrin derivative. Zincke H, U tz DC: Detection and localization of in MedJ Aust 2:489-493, 1980. situ carcinoma of the bladder with hematoporphyrin 2. Doiron DR, Profio E, Vincent RC, Dougherty TJ: derivative. Mayo Clin Proc 57:548-555, 1982. Fluorescence bronchoscopy for detection of lung can­ 21. Dougherty TJ, Thoma RE, Boyle DG, Weishaupt cer. Chest 76:27 -32, 1979. KR: Interstitial photoradiation therapy for primary 3. Lipson RL, Baldes EJ, Olsen AM: The use of a solid tumors in pet cats and dogs. Can Res 41: 401­ derivative of hematoporphyrin in tumor detection. J 404, 1981. Nat! Cancer Inst 26: 1-8, 1961. 4. Kelly JF, Snell ME: Hematoporphyrin derivative: A possible aid in the diagnosis and therapy of carcino­ ma of the bladder. J Urol 115: 150-151, 1976. 5. Gomer CJ, Dougherty TJ: Determination of CH)­ and C4C)-hematoporphyrin derivative distribution in malignant and normal tissues. Can Res 39:146-151, 1979. 6. Kessel D, Chou T-H: Tumor-localizing components of the porphyrin preparation hematoporphyrin de­ rivative. Can Res 43:1994-1999, 1983. 7. Dougherty TJ, Gomer CJ, Weishaupt KR: Ener­ getics and efficiency of photoinactivation of murine tumor cells containing hematoporphyrin. Can Res 36:2330-2333, 1976. 8. Weishaupt KR, Gomer CJ, Dougherty TJ: Identifi­ cation of singlet oxygen as the cytotoxic agent in pho­ toinactivation of a murine tumor. Can Res 36:2326­ 2329, 1976. 9. Thoma RE: Phototherapy, in Kirk R (ed): Current veterinary Therapy VIII. Philadelphia, W.B. Saunders Co., pp 438-441, 1983. 10. Thoma RE, Stein RM, Wishaupt KR, Dougherty TJ: Phototherapy: a promising cancer therapy. VMI SAC 78:1693-1699, 1983. 11. Cortese DA, Kinsey JH: Hematoporphyrin deriva­ tive phototherapy for local treatment of cancer of the tracheobronchial tree. Ann Otol Rhinol Laryngol 91:652-655,1982. 12. Dahlman A, Wile AG, Burns RG, Mason GR, Johnson FM, Berns MW: Laser photoradiation therapy of cancer. Can Res 43:430-434, 1983. 13. Wile AG, Dahlman A, Burns RG, Berns MW: Laser photoradiation therapy of cancer following hemato­ porphyrin sensitization. Laser in Surgery and Medicine 2: 163-168, 1982. 14. Soma H, Akiya K, Nutahara S, Kato H, Hayata Y: Treatment of vaginal carcinoma with laser photoirra­ 01S Seminar diation following administration of hematoporphryin derivative. Annales Chirurgiae et Gynaecologiae 71:133­ Omega Tau Sigma will host a practitioner's 136, 1982. seminar on October 27, 1984. Topics of the 15. Gomer CJ, Doiron DR, Jester JV, Szirth BC, seminar will be Computers and the Veterinarian) Murphree AL: Hematoporphyrin derivative pho­ toradiation therapy for the treatment of intraocular arid New Aspects of Diagnosis and Treatment of tumors: examination of acute normal ocular tissue Heart Disease. For more information contact: toxicity. Can Res 43:721-727,1983. Omega Tau Sigma 16. Laws ER, Cortese DA, Kinsey JH, Eagan RT, An­ Practitioner's Sen~inar derson RE: Photoradiation therapy in the treatment 300 Wellons of malignant brain tumors: a phase I (feasibility) stu­ dy. Neurosurgery 9:672-678, 1981. Ames, IA 50010

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