- Email: [email protected]
Pulsed-dye laser therapy for cutaneous Kaposi's sarcoma associated with acquired immunodeficiency syndrome
Journal of the American Academy of Dermatology
BOhler-Sommeregger et al. ity of pigmented mucosa and skin to freezing injury. Cryobiology 1979;16:348-61. 11. Breathnach AS. Melanocytes in early regenerated human epidermis. J Invest Dermatol 1960;32:245-51. 12. Burger SM, Jones RL, MiUard PR, et al. Pigment change and melanocyte distribution on guinea pig skin after cataneous freeze injury. J Invest Dermatol 1987;88:136-40. II I I
13. Snell RS. A study of the melanocytes and melanin in a healing deep wound. J Anat 1963;97:243-53. 14. Green A, Bain C, McLennan R, et al. Risk factors for cutaneous melanoma in Queensland. In: Gallagher RP, ed. Recent results in cancer research: epidemiologyof malignant melanoma. New York: Springer-Veriag, 1985:76-97.
I
Pulsed-dye laser therapy for cutaneous Kaposi's sarcoma associated with acquired immunodeficiency syndrome Jordan W. Tappero, M D , M P H , Roy C. Grekin, M D , G u y A. Zanelli, M D , and Timothy G. Berger, M D San Francisco, California
Background: Cutaneous lesions of Kaposi's sarcoma associated with acquired immunodeficiency syndrome (AIDS-KS) are disfiguring. Objective:This study assesses the response of AIDS-KS to pulsed-dye laser (PDL) therapy. Methods: The PDL was used to treat 15 AIDS-KS patients. Treatment was repeated at 4-week intervals. On average, patients received three treatments per treated lesion. Results: At 6 weeks' follow-up, the patients' treated lesions were reduced in size when compared with their matched control lesions (p < 0.002). A complete or partial clinical response occurred in 44% of treated lesions (17 of 39) compared with 18% of matched control lesions (17 of 39). Patients experienced limited pain, infrequent blistering, and no scarring. However, histopathologic findings of treated lesions throughout therapy correlated poorly with clinical response. At 12 weeks, all treated lesions had recurred. Conclusion." PDL therapy for AIDS-KS is not recommended. Although safe, the rapid recurrence of disease at initially responsive sites would require costly, long-term therapy to maintain cosmetic improvement. (J AM ACAD DEm~ATOL 1992;27:526-30.) Kaposi's sarcoma ( K S ) remains the most common tumor associated with h u m a n immunodeficiency virus (HIV) infection. 1 A m o n g homosexual men in the United States, approximately 18% have KS as their acquired immunodeficiency syndrome (AIDS)--defining illness. 1 In this population, the incidence of KS continues to increase. 2, 3 For AIDSassociated KS ( A I D S - K S ) , antiviral therapy with zidovudine has no beneficial effect on the extent of KS or on immune function. 4 Neither local nor systemic therapies for A I D S - K S have been shown to prolong survival. 57 From the Departmentof Dermatology,Universityof California,San Francisco. Supported by a research fellowshipaward from the Dermatology Foundation to the University of California, San Francisco (to J. W. T.). Accepted t'or publicationMarch 30, 1992. No reprints available. ]~/1/38242 526
The primary objective of local therapy is the cosmetic control of disfiguring AIDS-KS. Several modalities have been evaluated in patients with localized disease and/or a limited number of cutaneous lesions. Radiation therapy is best suited for the control of pain and symptoms caused by mass effects because lesions irradiated solely for cosmetic purposes have less than a 50% reduction in size in most patients.7, 8 Intralesional vinblastine has an initial complete or partial response rate of more t h a n 60%, but healing is often associated with significant hyperpigmentation. 9, * Cryotherapy was found to have an 85% complete or partial clinical response rate at 11 weeks after therapy, independent of the CD4 cell count. This lasts up to 6 months in most *Newman SB. Treatment of epidemic Kaposi's sarcoma (KS) with intralesional vinblastine injection (IL-VLB). Seventh Proceedings of the American Society ot"Clinical Oncology, New Orleans, May 2224, 1988.
Volume 27 Number 4 October 1992
patients, to However, biopsy specimens of liquid nitrogen-treated lesions often revealed persistent KS in the deep reticular dermis. The pulsed-dye laser (PDL) can successfully treat benign cutaneous vascular lesions. 11-18 Because KS is a vascular proliferation in its macular, papular, and plaque stages,19 the P D L became a logical candidate for its treatment. In addition, complications of local KS therapy, such as hyperpigmentation and/or scarring, have rarely been reported after PDL treatment. 11-t8 Finally, P D L therapy is safe, easily administered, and noninvasive, thereby limiting physician exposure to blood products. Set at an emission wavelength of 585 nm, the PDL penetrates to a depth of 1.0 to 1.3 ram, a distance roughly equivalent to. the mid reticular dermis for adult human nonfaeial skin. 2~ 21 For KS, the depth of the abnormal vascular proliferation often extends to the subcutaneous fat. 19In addition, unlike port-wine stains (PWS), 22 the lesions of AIDS-KS do not have a predilection for the face but are widely distributed and occur in areas in which the thickness of the dermis is greater than that of the face. Despite this, it was hypothesized that laser-induced changes to a depth of 1.0 to 1.3 mm for both facial and nonfacial lesions of KS might be cosmetically beneficial, as seen with PDL-treated PWS. 11-15 This study was initiated to determine whether P D L therapy would show superior cosmetic results over cryotherapy, analogous to the superior results with PDL for the treatment of P W S compared with cryotherapy. 23 In addition, unlike cryotherapy, PDL-treated skin rarely blisters, thereby reducing the potential for contact with HIV-containing blister fluid. 24 The carbon dioxide (CO2) and argon lasers have been successfully used for palliative treatment of large oropharyngeal lesions of AIDS-KS, 25 but this is the first report on the use of the PDL for cutaneous lesions. METHODS
Subject population Fifteen white patients participated in this study. All met the following entry criteria: older than 17 years of age, established HIV infection, Karnofsky performance status of at least 70%, life expectancy of at least 2 months, biopsy-proven KS, and at least six measurable cutaneous lesions of KS that had never been subjected to biopsy or treated locally. Patients were allowed concurrent treatment with systemic chemotherapy and/or zidovudine at any time during the study. All patients signed informed consent before enrollment in this study, which was approved by the Committee on Human Research at the University of California, San Francisco.
Pulsed-dye laser for AIDS-KS 527 Laser The Candela SPTL- 1 flashlamp-PDL (Candela Laser, Wayland, Mass.) was used, with rhodamine in ethylene glycol as the dye. Treated lesions received an average of 9.0 joules/era 2, with an emission wavelength of 585 nm, and a pulse duration of 450 #sec transmitted down a 1 mm fiber and focused as a 5 mm diameter beam with a planoconvex lens. Energy densities were measured with an Ophir Meter calibrated to _+0.25 joule/cm 2. A vacuum smokeevacuator was used during each treatment session to remove the occasional faint smoke plume from the treatment site. Laser safety glasses were worn by all persons in the treatment room and filtration masks with a pore size of 0.3 #m were worn by all investigators during a treatment session.
Treatment regimen Randomly selected cutaneous lesions of KS were exposed to PDL energy. Multiple laser pulses were directed at each KS lesion until the entke lesion was covered with minimally overlapping circular areas. The patients' treated lesions were reevaluated every 4 to 6 weeks and their treatments were repeated every visit for a maximum of four treatments per lesion. Patients were instructed to apply ice to the treated area for i5 minutes every hour for 8 hours after each treatment session and to apply polysporin ointment to each lesion in the event of blistering. Lesions with visible progression were not treated again. Patients were given the option of premedication with 600 mg of acetaminophen with or without 60 mg of codeine 1 hour before laser treatment and after therapy as needed.
Monitoring and criteria A brief medical history was obtained and a complete physical examination was performed before initial therapy. Patients were staged at the beginning and at the completion of study by the AIDS Clinical Trials Group (ACTG) classification system. 26 All visible KS lesions were counted and six KS indicator lesions, roughly equivalent in size, were selected. These six indicator lesions were grouped into three pairs primarily by size and proximity. Each lesion pair was subsequently randomized by coin toss to receive either treatment with the PDL laser or to serve as a matched-pair control. All six indicator lesions were measured in two dimensions. Whole body photographs, individual lesion photographs, and crossproduct measurements of all indicator lesions were obtained before the initiation of therapy, at each follow-up visit, and at the completion of study. Lesional responses were categorized as follows: complete response (CR), complete absence of any clinically detectable residual disease for at least 4 weeks; partial response (PR), 50% or greater decrease in the sum of the product of the largest perpendicular diameter and/or complete flattening of a previously nodular or plaquelike lesion for at least 4 weeks; stable disease (SD), any
528
Journal ol the American Academy of Dermatology
Tappero et al.
Fig. 3. Lesion I0-A-L represents clinical appearaneeof PDL-treated KS lesion photographed 6 weeks after therapy. Lesion 10-A-U is the matched untreated control lesion for lesion 10-A-L.
Fig. 1. KS indicator lesion before initial PDL treatment. Fig. 2. KS indicator lesion evaluated as a complete clinical response and photographed 6 weeks after three treatments with PDL. response not meeting the criteria for disease progression or PR; and disease progression (DP), for an increase by 25% or more in the size of a treated lesion. 26 Statistical methods A matched paired t test was used to assess the significance of the difference in responses, comparing changes in the laser-treated lesions versus their matched control lesions. Histologic evaluation A sampling of biopsy specimens from indicator lesions was obtained throughout the course of therapy from consenting patients and evaluated by a dermatopathologist (T. G. B.) who was unaware of the clinical response of the lesions. Histologic findings were categorized as residual KS (throughout dermis or deep reticular dermis only), atypical vascular proliferation, scar, and normal skin. RESULTS Of the 15 homosexual men with biopsy-proven AIDS-KS enrolled in this trial, two withdrew after
their first treatment session because of the development of a new opportunistic infection. The median age was 36 years (range 26 to 45 years), and the median duration of biopsy-proven KS was 7 months (range I to 69 months). All 13 subjects remained within their same pretreatment A C T G classification stage (2 "good risk" and 1 l "poor risk") at the completion of study; in five patients further progression of their KS developed, and they received systemic chemotherapy at some point during laser therapy. Each patient received two to four treatments for each lesion. The average energy density was 9.0 joules/cm 2 (range 8.00 to 9.25 joules/cm 2) per treatment. The average size before treatment was 70 mm 2 (range of 21 to 247 mm 2) for treated lesions and 78 mm 2 (range of 21 to 320 mm 2) for control lesions. Of the 39 morphologically papular KS indicator lesions treated with laser therapy, 15 became macules at the completion of the study. In contrast, only 3 of the 39 papular control lesions were macular at the completion of the study. Lesional response Six weelcs after the last laser treatment, a C R or PR, was observed in 44% of the laser-treated lesions (17 of 39) and in 18% of the control lesions (7 of 39). A typical response is shown in Figs. 1-3. When
Volume 27 Number 4 October 1992
Pulsed-dye laser Jbr AIDS-KS 529
Fig. 4. Lesion 10-B-L represents clinical appearance at 12 weeks of the lesion shown in Fig. 5 before biopsy. Visibly recurrent KS is present. Lesion 10-B-U is the matched untreated control lesion for lesion 10-B-L. Note their different appearance.
lesions were evaluated by anatomic location (head and neck, trunk, and extremities), all three areas responded similarly. Twelve weeks after completion of therapy, all PDL-treated KS lesions that previously had a CR or PR had developed recurrent disease (Fig. 4).
Fig. 5. Histologic appearance of laser-treated lesion at 12 weeks, evaluated clinically as partial re~sponseat 6 weeks. A, Scar is present throughout papillary dermis as manifested by horizontally oriented collagen bundles with loss of normal rete ridge pattern. B, Residual KS is seen throughout deep reticular dermis extending to subcutaneous fat.
Patient response
DISCUSSION
Six weeks after the completion of therapy, the lesions of the patients treated with the laser were significantly reduced in size compared with the matched untreated lesions of the same subject (p < 0.002). This was seen for all patients, including the five patients with aggressive KS who received systemic chemotherapy. Confounding effects of chemotherapy on overall study results are unlikely as both laser-treated and control lesions were exposed to the same systemic therapy.
This study establishes that PDL therapy for cutaneous lesions of AIDS-KS produces short-lived cosmetic improvement with recurrence of the KS within 12 weeks after treatment. The CR or PR rates for the PDL (44%) rank well behind cryotherapy (85%), intralesional chemotherapy (60~ to 70%), and radiation therapy (<50%). 7-1~ * Our histologic findings suggest that the failure of laser therapy lies in its inability to penetrate deeply into the dermis. The risk of HIV exposure to the PDL operator in the treatment of AIDS-KS is unknown. An in vitro study of cultures containing live H I V has clearly shown that HIV proviral D N A is present in CO2
Histologic response Ten PDL-treated lesions from five patients were subjected to biopsy at 6 weeks. Two showed deep KS, four scar or normal skin, and four atypical vascular proliferation. Six biopsy specimens at l 2 weeks all showed residual KS (Fig. 5), correlating with clinical recurrence in all lesions.
9Newman SB. Treatment of epidemic Kaposi's sarcoma (KS) with intralesional vinblastine injection (IL-VLB). Seventh Proceedings of the American Society of Clinical Oncology, New Orleans, May 2224, 1988.
530
Tappero et al.
laser-generated smoke. 27 However, productive infection with HIV-cultured cells was not sustained beyond 14 days, which suggests that the laser energy m a y have impaired long-term replication o f HIV. Although the concentration of H I V - i n f e c t e d cells used in this study far exceeds the n u m b e r present in HIV-infected patients, laser operators should rem a i n cautious because other viruses, such as the bovine and human papillomavirus, remain intact in s m o k e vapors after the use of the CO2 laser. 28, 29 Despite the generation of only a faint smoke plume by the PDL in contrast to the CO2 laser, we recomm e n d the use of a v a c u u m smoke evacuator in conjunction with a 0.3 # m pore size aerosol particle filtration mask when the P D L is used to treat HIV-infected patients. This study establishes that P D L therapy for cutaneous lesions of A I D S - K S is safe for patients. However, the early promising results with papular lesions of A I D S - K S did not persist beyond 12 weeks. Because long-term maintenance t h e r a p y with the P D L is not cost effective, its use cannot be recommended for the treatment of p a p u l a r lesions of A/DS-KS. REFERENCES 1. Beral V, Peterman TA, Berkelman RL, et al. Kaposi's sarcoma among persons with AIDS: A sexually transmitted infection? Lancet 1990;335:123-8. 2. Chow W, Lift JM, Greenberg RS, et al. A comparison of acquired immunodeficiency syndrome and Kaposi's sarcoma incidence rates, Atlanta, 1983-86. Am J Public Health 1989;79:503-5. 3. Schrager LK, Munoz A, Vermund SH, et al. Changing frequencies of AIDS-defining conditions among HIVinfected men. Abstract MC3168. Seventh International Conference on AIDS, 1991. 4. Lane HC, Falloon J, Walker RE, et al. Zidovudine in patients with human immunodeficiencyvirus (H IV) infection and Kaposi's sarcoma: a phase II randomized, placebocontrolled trial. Ann Intern Med 1989;111:41-50. 5. Volberding PA, Cusick PS, Feigel DW. Effect of chemotherapy for H IV-associatedKaposi's sarcoma on long term survival. Proc Am Soc Clin Oncol 1989;8:3. 6. Safai B, Bason M, Freidman-Birnbaum R, et al. Interferon in the treatment of AIDS-associated Kaposi's sarcoma: the American experience. J Invest Dermatol 1990;95(suppl I ): 166-9S. 7. Hill DR. The role of radiotherapy for epidemic Kaposi's sarcoma. Semin Oncol 1987;14(suppl 3):19-22. 8. Chak LY, GiUPS, Levine AM, et al. Radiation therapy for AIDS-related Kaposi'ssarcoma. J ClinOncol 1988;5:863-7. 9. Schofer H, Ochsendorf F, Hochscheild I, et al. Facial Kaposi's sarcoma: evaluation of different palliative treatment modalities. Abstract MC2247. Seventh International Conference on AIDS, 1991.
Journal of the American Academy of Dermatology I0. Tappero JW, Berger TG, Kaplan LD, eta[. Cryotherapy for cutaneous Kaposi's sarcoma (KS) associated with acquired immune deficiencysyndrome (AIDS): a phase II trial. J Acquir Immune Defic Syndr 1991;4:839-46. 11. Tan OT, Sherwood K, Gilchrest BA. Treatment of children with port-wine stains using flashlamp-pulsed tunable dye laser. N Engl J Med 1989;320:416-21. 12. Reyes BA, Geronemus R. Treatment of port-wine stains during childhood with the flashlamp-pumped pulsed dye laser. J AM ACAD DERMATOL1990;23:1142-8. 13. Nelson JS, Applebaum J. Clinical management of portwine stain in infants and young children using the flashlamp-pulsed dye laser. Clin Pediatr 1990;29:503-8. 14. Achauer BM, Vander Kam VM, Miller SR. Clinical experience with the pulsed-dye laser in the treatment of capil. lary malformations (port-wine stains ): a preliminary report. Ann Plast Surg 1990;25:344-52. 15. Ashinoff R, Geronemus RG. Capillary hemangiomas and treatment with the flash lamp-pumped pulsed dye laser. Arch Dermatol 1991;127:202-5. 16. Wheeland RG, Appelbaum J. Flashlamp-pumped pulsed dye laser therapy for poikiloderma of Civatte. J Dermatol Surg Oncol 1990;16(1):12-6. 17. Weingold DH, White PF, Burton CS. Treatment of lymphangioma circumscriptum with tunable dye laser. Curls 1990;45(5):365-6. 18. Geronemus RG. Treatment of spider telangiectases in children using the flashlamp-pumped pulsed dye laser. Pediatr Dermatol 1991;8:61-3. 19. Silvers DN. The microscopic diagnosis of classical and epidemic Kaposi's sarcoma. In: Frcidman-Kien AE, cal. Color atlas of AIDS. Philadelphia: WB Saunders, 1989:71-82. 20. Tan OT, Morrison P, Kurban AK. 585 nm for the treatment of port-wine stains. Plast Reconstr Surg 1990; 86:1112-7. 21. Tan CY, Statham B, Marks R, et al. Skin thickness measurement by pulsed ultrasound: its reproducibility, validation and variability. Br J Dermatol 1982;106:657-67, 22. Mulliken JB, Young AE. Vascular birthmarks--hemangiomas and malformations. Philadelphia: WB Saunders, 1988. 23. Castro-Ron G. Cryosurgery of angiomas and birth defects. In: Zacarian SA, ed. Cryosurgery for skin cancer and cutaneous disorders. St. Louis: CV Mosby, 1985. 24. Supapannachart N, Breneman D, Linnemann CC. Isolation of human immunodeficiency virus type 1 in cutaneous blister fluid. Arch Dermatol 1991;127:1198-200. 25. Schweitzer VG, Visscher D. Photodynamic therapy for treatment of AIDS-related oral Kaposi's sarcoma. Otolaryngol Head Neck Surg 1990;102:639-49. 26. Krown SE, Metroka C, Wernz JC. Kaposi's sarcoma in the acquired immune deficiency syndrome: a proposal for uniform evaluation, response and staging criteria. J Clin Oncol 1989;7:1201-7. 27. Baggish MS, Poiesz BJ, Joert D, et al. Presence of human immunodeficiency virus in laser smoke. Lasers Surg Med 1991;11:197-203. 28. Garden JM, O'Banion MK, Shelnitz LS, et al. PapiLlomavirus in the vapor of carbon dioxide laser-treated verrucae. JAMA 1988;259:1199-202. 29. Sawchuck WS, Weber PJ, Lowy DR, et al. Infectious papillomavirus in the vapor of warts treated with carbon dioxide laser or electrocoagulation: detection and protection. J AM ACAD DERMATOL1989;21:41-9.
BOhler-Sommeregger et al. ity of pigmented mucosa and skin to freezing injury. Cryobiology 1979;16:348-61. 11. Breathnach AS. Melanocytes in early regenerated human epidermis. J Invest Dermatol 1960;32:245-51. 12. Burger SM, Jones RL, MiUard PR, et al. Pigment change and melanocyte distribution on guinea pig skin after cataneous freeze injury. J Invest Dermatol 1987;88:136-40. II I I
13. Snell RS. A study of the melanocytes and melanin in a healing deep wound. J Anat 1963;97:243-53. 14. Green A, Bain C, McLennan R, et al. Risk factors for cutaneous melanoma in Queensland. In: Gallagher RP, ed. Recent results in cancer research: epidemiologyof malignant melanoma. New York: Springer-Veriag, 1985:76-97.
I
Pulsed-dye laser therapy for cutaneous Kaposi's sarcoma associated with acquired immunodeficiency syndrome Jordan W. Tappero, M D , M P H , Roy C. Grekin, M D , G u y A. Zanelli, M D , and Timothy G. Berger, M D San Francisco, California
Background: Cutaneous lesions of Kaposi's sarcoma associated with acquired immunodeficiency syndrome (AIDS-KS) are disfiguring. Objective:This study assesses the response of AIDS-KS to pulsed-dye laser (PDL) therapy. Methods: The PDL was used to treat 15 AIDS-KS patients. Treatment was repeated at 4-week intervals. On average, patients received three treatments per treated lesion. Results: At 6 weeks' follow-up, the patients' treated lesions were reduced in size when compared with their matched control lesions (p < 0.002). A complete or partial clinical response occurred in 44% of treated lesions (17 of 39) compared with 18% of matched control lesions (17 of 39). Patients experienced limited pain, infrequent blistering, and no scarring. However, histopathologic findings of treated lesions throughout therapy correlated poorly with clinical response. At 12 weeks, all treated lesions had recurred. Conclusion." PDL therapy for AIDS-KS is not recommended. Although safe, the rapid recurrence of disease at initially responsive sites would require costly, long-term therapy to maintain cosmetic improvement. (J AM ACAD DEm~ATOL 1992;27:526-30.) Kaposi's sarcoma ( K S ) remains the most common tumor associated with h u m a n immunodeficiency virus (HIV) infection. 1 A m o n g homosexual men in the United States, approximately 18% have KS as their acquired immunodeficiency syndrome (AIDS)--defining illness. 1 In this population, the incidence of KS continues to increase. 2, 3 For AIDSassociated KS ( A I D S - K S ) , antiviral therapy with zidovudine has no beneficial effect on the extent of KS or on immune function. 4 Neither local nor systemic therapies for A I D S - K S have been shown to prolong survival. 57 From the Departmentof Dermatology,Universityof California,San Francisco. Supported by a research fellowshipaward from the Dermatology Foundation to the University of California, San Francisco (to J. W. T.). Accepted t'or publicationMarch 30, 1992. No reprints available. ]~/1/38242 526
The primary objective of local therapy is the cosmetic control of disfiguring AIDS-KS. Several modalities have been evaluated in patients with localized disease and/or a limited number of cutaneous lesions. Radiation therapy is best suited for the control of pain and symptoms caused by mass effects because lesions irradiated solely for cosmetic purposes have less than a 50% reduction in size in most patients.7, 8 Intralesional vinblastine has an initial complete or partial response rate of more t h a n 60%, but healing is often associated with significant hyperpigmentation. 9, * Cryotherapy was found to have an 85% complete or partial clinical response rate at 11 weeks after therapy, independent of the CD4 cell count. This lasts up to 6 months in most *Newman SB. Treatment of epidemic Kaposi's sarcoma (KS) with intralesional vinblastine injection (IL-VLB). Seventh Proceedings of the American Society ot"Clinical Oncology, New Orleans, May 2224, 1988.
Volume 27 Number 4 October 1992
patients, to However, biopsy specimens of liquid nitrogen-treated lesions often revealed persistent KS in the deep reticular dermis. The pulsed-dye laser (PDL) can successfully treat benign cutaneous vascular lesions. 11-18 Because KS is a vascular proliferation in its macular, papular, and plaque stages,19 the P D L became a logical candidate for its treatment. In addition, complications of local KS therapy, such as hyperpigmentation and/or scarring, have rarely been reported after PDL treatment. 11-t8 Finally, P D L therapy is safe, easily administered, and noninvasive, thereby limiting physician exposure to blood products. Set at an emission wavelength of 585 nm, the PDL penetrates to a depth of 1.0 to 1.3 ram, a distance roughly equivalent to. the mid reticular dermis for adult human nonfaeial skin. 2~ 21 For KS, the depth of the abnormal vascular proliferation often extends to the subcutaneous fat. 19In addition, unlike port-wine stains (PWS), 22 the lesions of AIDS-KS do not have a predilection for the face but are widely distributed and occur in areas in which the thickness of the dermis is greater than that of the face. Despite this, it was hypothesized that laser-induced changes to a depth of 1.0 to 1.3 mm for both facial and nonfacial lesions of KS might be cosmetically beneficial, as seen with PDL-treated PWS. 11-15 This study was initiated to determine whether P D L therapy would show superior cosmetic results over cryotherapy, analogous to the superior results with PDL for the treatment of P W S compared with cryotherapy. 23 In addition, unlike cryotherapy, PDL-treated skin rarely blisters, thereby reducing the potential for contact with HIV-containing blister fluid. 24 The carbon dioxide (CO2) and argon lasers have been successfully used for palliative treatment of large oropharyngeal lesions of AIDS-KS, 25 but this is the first report on the use of the PDL for cutaneous lesions. METHODS
Subject population Fifteen white patients participated in this study. All met the following entry criteria: older than 17 years of age, established HIV infection, Karnofsky performance status of at least 70%, life expectancy of at least 2 months, biopsy-proven KS, and at least six measurable cutaneous lesions of KS that had never been subjected to biopsy or treated locally. Patients were allowed concurrent treatment with systemic chemotherapy and/or zidovudine at any time during the study. All patients signed informed consent before enrollment in this study, which was approved by the Committee on Human Research at the University of California, San Francisco.
Pulsed-dye laser for AIDS-KS 527 Laser The Candela SPTL- 1 flashlamp-PDL (Candela Laser, Wayland, Mass.) was used, with rhodamine in ethylene glycol as the dye. Treated lesions received an average of 9.0 joules/era 2, with an emission wavelength of 585 nm, and a pulse duration of 450 #sec transmitted down a 1 mm fiber and focused as a 5 mm diameter beam with a planoconvex lens. Energy densities were measured with an Ophir Meter calibrated to _+0.25 joule/cm 2. A vacuum smokeevacuator was used during each treatment session to remove the occasional faint smoke plume from the treatment site. Laser safety glasses were worn by all persons in the treatment room and filtration masks with a pore size of 0.3 #m were worn by all investigators during a treatment session.
Treatment regimen Randomly selected cutaneous lesions of KS were exposed to PDL energy. Multiple laser pulses were directed at each KS lesion until the entke lesion was covered with minimally overlapping circular areas. The patients' treated lesions were reevaluated every 4 to 6 weeks and their treatments were repeated every visit for a maximum of four treatments per lesion. Patients were instructed to apply ice to the treated area for i5 minutes every hour for 8 hours after each treatment session and to apply polysporin ointment to each lesion in the event of blistering. Lesions with visible progression were not treated again. Patients were given the option of premedication with 600 mg of acetaminophen with or without 60 mg of codeine 1 hour before laser treatment and after therapy as needed.
Monitoring and criteria A brief medical history was obtained and a complete physical examination was performed before initial therapy. Patients were staged at the beginning and at the completion of study by the AIDS Clinical Trials Group (ACTG) classification system. 26 All visible KS lesions were counted and six KS indicator lesions, roughly equivalent in size, were selected. These six indicator lesions were grouped into three pairs primarily by size and proximity. Each lesion pair was subsequently randomized by coin toss to receive either treatment with the PDL laser or to serve as a matched-pair control. All six indicator lesions were measured in two dimensions. Whole body photographs, individual lesion photographs, and crossproduct measurements of all indicator lesions were obtained before the initiation of therapy, at each follow-up visit, and at the completion of study. Lesional responses were categorized as follows: complete response (CR), complete absence of any clinically detectable residual disease for at least 4 weeks; partial response (PR), 50% or greater decrease in the sum of the product of the largest perpendicular diameter and/or complete flattening of a previously nodular or plaquelike lesion for at least 4 weeks; stable disease (SD), any
528
Journal ol the American Academy of Dermatology
Tappero et al.
Fig. 3. Lesion I0-A-L represents clinical appearaneeof PDL-treated KS lesion photographed 6 weeks after therapy. Lesion 10-A-U is the matched untreated control lesion for lesion 10-A-L.
Fig. 1. KS indicator lesion before initial PDL treatment. Fig. 2. KS indicator lesion evaluated as a complete clinical response and photographed 6 weeks after three treatments with PDL. response not meeting the criteria for disease progression or PR; and disease progression (DP), for an increase by 25% or more in the size of a treated lesion. 26 Statistical methods A matched paired t test was used to assess the significance of the difference in responses, comparing changes in the laser-treated lesions versus their matched control lesions. Histologic evaluation A sampling of biopsy specimens from indicator lesions was obtained throughout the course of therapy from consenting patients and evaluated by a dermatopathologist (T. G. B.) who was unaware of the clinical response of the lesions. Histologic findings were categorized as residual KS (throughout dermis or deep reticular dermis only), atypical vascular proliferation, scar, and normal skin. RESULTS Of the 15 homosexual men with biopsy-proven AIDS-KS enrolled in this trial, two withdrew after
their first treatment session because of the development of a new opportunistic infection. The median age was 36 years (range 26 to 45 years), and the median duration of biopsy-proven KS was 7 months (range I to 69 months). All 13 subjects remained within their same pretreatment A C T G classification stage (2 "good risk" and 1 l "poor risk") at the completion of study; in five patients further progression of their KS developed, and they received systemic chemotherapy at some point during laser therapy. Each patient received two to four treatments for each lesion. The average energy density was 9.0 joules/cm 2 (range 8.00 to 9.25 joules/cm 2) per treatment. The average size before treatment was 70 mm 2 (range of 21 to 247 mm 2) for treated lesions and 78 mm 2 (range of 21 to 320 mm 2) for control lesions. Of the 39 morphologically papular KS indicator lesions treated with laser therapy, 15 became macules at the completion of the study. In contrast, only 3 of the 39 papular control lesions were macular at the completion of the study. Lesional response Six weelcs after the last laser treatment, a C R or PR, was observed in 44% of the laser-treated lesions (17 of 39) and in 18% of the control lesions (7 of 39). A typical response is shown in Figs. 1-3. When
Volume 27 Number 4 October 1992
Pulsed-dye laser Jbr AIDS-KS 529
Fig. 4. Lesion 10-B-L represents clinical appearance at 12 weeks of the lesion shown in Fig. 5 before biopsy. Visibly recurrent KS is present. Lesion 10-B-U is the matched untreated control lesion for lesion 10-B-L. Note their different appearance.
lesions were evaluated by anatomic location (head and neck, trunk, and extremities), all three areas responded similarly. Twelve weeks after completion of therapy, all PDL-treated KS lesions that previously had a CR or PR had developed recurrent disease (Fig. 4).
Fig. 5. Histologic appearance of laser-treated lesion at 12 weeks, evaluated clinically as partial re~sponseat 6 weeks. A, Scar is present throughout papillary dermis as manifested by horizontally oriented collagen bundles with loss of normal rete ridge pattern. B, Residual KS is seen throughout deep reticular dermis extending to subcutaneous fat.
Patient response
DISCUSSION
Six weeks after the completion of therapy, the lesions of the patients treated with the laser were significantly reduced in size compared with the matched untreated lesions of the same subject (p < 0.002). This was seen for all patients, including the five patients with aggressive KS who received systemic chemotherapy. Confounding effects of chemotherapy on overall study results are unlikely as both laser-treated and control lesions were exposed to the same systemic therapy.
This study establishes that PDL therapy for cutaneous lesions of AIDS-KS produces short-lived cosmetic improvement with recurrence of the KS within 12 weeks after treatment. The CR or PR rates for the PDL (44%) rank well behind cryotherapy (85%), intralesional chemotherapy (60~ to 70%), and radiation therapy (<50%). 7-1~ * Our histologic findings suggest that the failure of laser therapy lies in its inability to penetrate deeply into the dermis. The risk of HIV exposure to the PDL operator in the treatment of AIDS-KS is unknown. An in vitro study of cultures containing live H I V has clearly shown that HIV proviral D N A is present in CO2
Histologic response Ten PDL-treated lesions from five patients were subjected to biopsy at 6 weeks. Two showed deep KS, four scar or normal skin, and four atypical vascular proliferation. Six biopsy specimens at l 2 weeks all showed residual KS (Fig. 5), correlating with clinical recurrence in all lesions.
9Newman SB. Treatment of epidemic Kaposi's sarcoma (KS) with intralesional vinblastine injection (IL-VLB). Seventh Proceedings of the American Society of Clinical Oncology, New Orleans, May 2224, 1988.
530
Tappero et al.
laser-generated smoke. 27 However, productive infection with HIV-cultured cells was not sustained beyond 14 days, which suggests that the laser energy m a y have impaired long-term replication o f HIV. Although the concentration of H I V - i n f e c t e d cells used in this study far exceeds the n u m b e r present in HIV-infected patients, laser operators should rem a i n cautious because other viruses, such as the bovine and human papillomavirus, remain intact in s m o k e vapors after the use of the CO2 laser. 28, 29 Despite the generation of only a faint smoke plume by the PDL in contrast to the CO2 laser, we recomm e n d the use of a v a c u u m smoke evacuator in conjunction with a 0.3 # m pore size aerosol particle filtration mask when the P D L is used to treat HIV-infected patients. This study establishes that P D L therapy for cutaneous lesions of A I D S - K S is safe for patients. However, the early promising results with papular lesions of A I D S - K S did not persist beyond 12 weeks. Because long-term maintenance t h e r a p y with the P D L is not cost effective, its use cannot be recommended for the treatment of p a p u l a r lesions of A/DS-KS. REFERENCES 1. Beral V, Peterman TA, Berkelman RL, et al. Kaposi's sarcoma among persons with AIDS: A sexually transmitted infection? Lancet 1990;335:123-8. 2. Chow W, Lift JM, Greenberg RS, et al. A comparison of acquired immunodeficiency syndrome and Kaposi's sarcoma incidence rates, Atlanta, 1983-86. Am J Public Health 1989;79:503-5. 3. Schrager LK, Munoz A, Vermund SH, et al. Changing frequencies of AIDS-defining conditions among HIVinfected men. Abstract MC3168. Seventh International Conference on AIDS, 1991. 4. Lane HC, Falloon J, Walker RE, et al. Zidovudine in patients with human immunodeficiencyvirus (H IV) infection and Kaposi's sarcoma: a phase II randomized, placebocontrolled trial. Ann Intern Med 1989;111:41-50. 5. Volberding PA, Cusick PS, Feigel DW. Effect of chemotherapy for H IV-associatedKaposi's sarcoma on long term survival. Proc Am Soc Clin Oncol 1989;8:3. 6. Safai B, Bason M, Freidman-Birnbaum R, et al. Interferon in the treatment of AIDS-associated Kaposi's sarcoma: the American experience. J Invest Dermatol 1990;95(suppl I ): 166-9S. 7. Hill DR. The role of radiotherapy for epidemic Kaposi's sarcoma. Semin Oncol 1987;14(suppl 3):19-22. 8. Chak LY, GiUPS, Levine AM, et al. Radiation therapy for AIDS-related Kaposi'ssarcoma. J ClinOncol 1988;5:863-7. 9. Schofer H, Ochsendorf F, Hochscheild I, et al. Facial Kaposi's sarcoma: evaluation of different palliative treatment modalities. Abstract MC2247. Seventh International Conference on AIDS, 1991.
Journal of the American Academy of Dermatology I0. Tappero JW, Berger TG, Kaplan LD, eta[. Cryotherapy for cutaneous Kaposi's sarcoma (KS) associated with acquired immune deficiencysyndrome (AIDS): a phase II trial. J Acquir Immune Defic Syndr 1991;4:839-46. 11. Tan OT, Sherwood K, Gilchrest BA. Treatment of children with port-wine stains using flashlamp-pulsed tunable dye laser. N Engl J Med 1989;320:416-21. 12. Reyes BA, Geronemus R. Treatment of port-wine stains during childhood with the flashlamp-pumped pulsed dye laser. J AM ACAD DERMATOL1990;23:1142-8. 13. Nelson JS, Applebaum J. Clinical management of portwine stain in infants and young children using the flashlamp-pulsed dye laser. Clin Pediatr 1990;29:503-8. 14. Achauer BM, Vander Kam VM, Miller SR. Clinical experience with the pulsed-dye laser in the treatment of capil. lary malformations (port-wine stains ): a preliminary report. Ann Plast Surg 1990;25:344-52. 15. Ashinoff R, Geronemus RG. Capillary hemangiomas and treatment with the flash lamp-pumped pulsed dye laser. Arch Dermatol 1991;127:202-5. 16. Wheeland RG, Appelbaum J. Flashlamp-pumped pulsed dye laser therapy for poikiloderma of Civatte. J Dermatol Surg Oncol 1990;16(1):12-6. 17. Weingold DH, White PF, Burton CS. Treatment of lymphangioma circumscriptum with tunable dye laser. Curls 1990;45(5):365-6. 18. Geronemus RG. Treatment of spider telangiectases in children using the flashlamp-pumped pulsed dye laser. Pediatr Dermatol 1991;8:61-3. 19. Silvers DN. The microscopic diagnosis of classical and epidemic Kaposi's sarcoma. In: Frcidman-Kien AE, cal. Color atlas of AIDS. Philadelphia: WB Saunders, 1989:71-82. 20. Tan OT, Morrison P, Kurban AK. 585 nm for the treatment of port-wine stains. Plast Reconstr Surg 1990; 86:1112-7. 21. Tan CY, Statham B, Marks R, et al. Skin thickness measurement by pulsed ultrasound: its reproducibility, validation and variability. Br J Dermatol 1982;106:657-67, 22. Mulliken JB, Young AE. Vascular birthmarks--hemangiomas and malformations. Philadelphia: WB Saunders, 1988. 23. Castro-Ron G. Cryosurgery of angiomas and birth defects. In: Zacarian SA, ed. Cryosurgery for skin cancer and cutaneous disorders. St. Louis: CV Mosby, 1985. 24. Supapannachart N, Breneman D, Linnemann CC. Isolation of human immunodeficiency virus type 1 in cutaneous blister fluid. Arch Dermatol 1991;127:1198-200. 25. Schweitzer VG, Visscher D. Photodynamic therapy for treatment of AIDS-related oral Kaposi's sarcoma. Otolaryngol Head Neck Surg 1990;102:639-49. 26. Krown SE, Metroka C, Wernz JC. Kaposi's sarcoma in the acquired immune deficiency syndrome: a proposal for uniform evaluation, response and staging criteria. J Clin Oncol 1989;7:1201-7. 27. Baggish MS, Poiesz BJ, Joert D, et al. Presence of human immunodeficiency virus in laser smoke. Lasers Surg Med 1991;11:197-203. 28. Garden JM, O'Banion MK, Shelnitz LS, et al. PapiLlomavirus in the vapor of carbon dioxide laser-treated verrucae. JAMA 1988;259:1199-202. 29. Sawchuck WS, Weber PJ, Lowy DR, et al. Infectious papillomavirus in the vapor of warts treated with carbon dioxide laser or electrocoagulation: detection and protection. J AM ACAD DERMATOL1989;21:41-9.