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Adjuvant drug strategies in the treatment of recurrent respiratory papillomatosis
Otolaryngology Head and Neck Surgery FEBRUARY 1995
VOLUME 112
NUMBER 2
ORIGINAL ARTICLES
Adjuvant drug strategies in the treatment of recurrent respiratory papillomatosis MICHAEL A. AVlDANO, MD, and GEORGE T. SINGLETON, MD, Gainesville, Florida
The purpose of this study was to evaluate adjuvant drug therapies combined with standard laser excision in the treatment of recurrent respiratory papillomatosis. Previous studies have presented conflicting data on the efficacy of various treatments, including interferon and isotretinoin. A retrospective study of 34 patients with moderate to severe papillomatosis who underwent both laser surgery and adjuvant therapy was therefore performed. All patients were treated with interferon. Five interferon failures received isotretinoin, and three with recalcitrant disease received methotrexate. Interferon produced a complete response in 16 patients and partial response in 12 patients. Juvenile-onset disease had a slightly higher response to interferon than adult-onset disease. Isotretinoin produced no response in all five patients. Methotrexate demonstrated a marked improvement in both severity of disease and treatment interval in all three patients. Serious side effects were limited to one interferon patient with febrile seizures, which resolved with discontinuation of therapy. We conclude that adjuvant therapy including interferon and methotrexate is clearly of benefit in the treatment of patients with respiratory papillomatosis. A detailed approach to surgery combined with an interferon dosing regimen is presented. Further study of methotrexate appears warranted. [OTOLARYNGOL HEADNECKSURG1995;I 12:197-202,}
Recurrent respiratory papillomatosis (RRP) is an uncommon disease characterized by the recurrent growth of benign papillomas along the epithelium of the respiratory tract. Most commonly the larynx is involved, although the disease may also involve the trachea, bronchi, and oropharynx. Histologically, papillomas appear as benign squamous lesions with
From the Department of Otolaryngology-Head and Neck Surgery, University of Florida College of Medicine. Presented at the Annual Meeting of the American Academy of Otolaryngology-Head and Neck Surgery, Minneapolis, Minn., Oct. 2-6, 1993. Received for publication Oct. 4, 1993; revision received April 21, 1994; accepted April 22, 1994. Reprint requests: George T. Singleton, MD, Department of Otolaryngology, University of Florida, Box 100264, Gainesville, FL 32601. Copyright © 1995 by the American Academy of OtolaryngologyHead and Neck Surgery Foundation, Inc. 0194-5998/95/$3.00 + 0 23/1/56926
an arborizing core of highly vascular connective tissue surrounded by an outer layer of nonkeratinized stratified squamous epithelium) Cellular differentiation of laryngeal papillomas appears to be abnormal, with altered expression and production of keratins, related in part to high levels of epidermal growth factor receptors present on affected cells. 2,3 A bimodal age distribution is seen with both juvenile-onset ( < 5 years) and adult-onset ( > 20 years) forms of the disease, with the juvenile-onset form being more aggressive in most cases. 4The presence of human papillomavirus (HPV) DNA types 6 and 11 has been demonstrated in these lesions, which are the same viral types associated with genital condylomata2 The genital tract appears to act as the reservoir for transmission of HPV to the respiratory tract, although R R P is relatively rare compared with genital condylomata. Risk factors and method of transmission appear to differ between the juvenile and adult types of disease. 6 The triad of firstborn 197
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child, vaginal delivery, and a teenage mother is significantly more common in juvenile-onset RRP, whereas more lifetime sexual partners and higher frequency of oral sex is associated with adult-onset RRP. Transmission of RRP has been reported despite cesarean section, and blood-borne exposure remains a possible route of transmission in children.7 Standard treatment now consists of endoscopic carbon dioxide laser excision of all visible papilloma from affected areas of the respiratory tract, as warranted by the patient's symptoms. Still, removal of visible disease leaves behind normal-appearing epithelium harboring viral DNA, which leads to recurrence, s The disease is noted for its highly unpredictable course, with rapid growth, spread within the respiratory tract, spontaneous resolution, and the constant possibility of airway obstruction requiring urgent intervention to maintain patency. Because of the often relentless course and need for frequent surgical intervention, the disease imposes a significant emotional and financial burden on the patient and family, indicating the need for more effective therapies. Several studies have demonstrated that adjuvant therapy with interferon-a n-1 (IF) produces a longterm beneficial response in the majority of patients treated. 9-11Two studies exist on the efficacy of isotretinoin (Accutane) in RRP with differing results, m3 Other adjuvant therapies, including hormones, cytotoxic agents, antimetabolites, and photodynamic therapy, have all been tried with variable success, m5 At the University of Florida we have had numerous patients with RRP undergo treatment with three types of adjuvant therapy. Thirty-four patients have undergone treatment with IF. Five IF failures were treated with isotretinoin, and most recently, three IF failures were treated with methotrexate. This article reviews our experience with IF, isotretinoin, and methotrexate; reviews the literature concerning these therapies; and presents an approach to surgery combined with adjuvant therapy in the treatment of patients with RRP. METHODS AND PATIENTS Interferon
A total of 34 patients underwent therapy with IF and were available for evaluation. All patients had moderate to severe disease and were initially treated with endoscopic examination and carbon dioxide laser excision of disease for a minimum of five times, or three times within 1 year, before starting IF. Further endoscopy and laser ablation of disease were carried out as warranted by the patient's symptoms and findings on laryngoscopy. All IF used was
produced by recombinant DNA methods from differing manufacturers based on availability. Six patients were part of a randomized double-blind multicenter clinical trial and have previously been reported by Leventhal et al. 1° Dosing was 5 megaunits (MU) IF per meter squared body surface area, given for a 21- or 28-day loading period for all patients. This was followed by a maintenance dose of 5 MU/m 2 given three times per week for at least 6 months in 21 patients. Thirteen patients were treated with 21- or 28-day pulses of IF at 4- to 6-month intervals. Treatment was not randomized or blinded except for the six patients from the multicenter study.1° Dosing was decreased or withheld for i to 2 weeks for significant side effects and then returned to the maximum dose tolerated, between 3 and 5 MU/m 2. Clinical response was measured by the volume and areas of airway involvement with papilloma on endoscopic examination. Carbon dioxide laser surgery was performed when clinically required for increased airway compromise. Partial response is defined as any improvement in the extent of disease present on serial flexible endoscopic examination. Complete response denotes no evidence of disease on evaluation for at least 6 months of follow-up. For a partial clinical response, treatment was continued as long as the response was maintained. For a complete clinical response in patients receiving three times weekly dosing, treatment was discontinued after 6 months. For 21- or 28-day courses, treatment was discontinued after the last course for a complete clinical response. Patients with no response continued therapy for 1 year to allow time for a possible response to be observed. Injections were given by the patient or family in the home at bedtime, Liver function testing was performed weekly during the loading period and monthly thereafter. Complete blood count was also performed monthly. Isotretinoin (13-cis-Retinoic Acid)
Five patients with severe disease and poor responses to standard laser excision and IF were further treated with isotretinoin. Dosing was 1 mg/kg/day orally, divided twice daily, for a period of 6 to 12 months. One patient was simultaneously treated with IF. Clinical response was measured by changes found at examination and surgery, as previously defined for IF therapy. Methotrexate
Three patients with severe disease requiring surgery approximately once per month were treated
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Table I. Response to IF therapy according to treatment regimen Response to IF Treatment regimen
28 Day-3 x / w k 21/28 day pulse TOTAL
Complete
Partial
None
TOTAL
12 4 16
6 6 12
3 3 6
21 13 34
with methotrexate. All had undergone previous treatment with 1F with minimal improvement, but not enough to warrant further therapy. Because of the potential toxicity of methotrexate, administration was performed in consultation with our pediatric hematology-oncology service. Liver and renal functions, complete blood counts, and platelet counts were monitored on each patient. Oral dosing started at 1 mg/kg given once or twice weekly and was adjusted as dictated by side effects and efficacy. Clinical response was again measured by changes seen at flexible endoscopic examination and surgery. RESULTS Interferon
Thirty-four patients underwent treatment with IF. Age at the start of therapy ranged from 2 years to 68 years, with a median age of 6 years and equal numbers of male and female patients. Twenty-four patients had juvenile-onset disease, and 10 patients had adult-onset disease. All 34 patients had laryngeal disease, and 9 also had tracheal involvement. No patients had pulmonary or pharyngeal disease. Five patients required a tracheotomy during therapy for airway management. Two of these were cured of disease and later decannulated. A positive response to treatment was achieved in 28 of 34 patients (82%). Sixteen patients had a complete response with resolution of papilloma for at least 6 months (47%). Only one patient with a complete response had recurrence of disease and was treated a second time with a complete response 3 years later. Twelve patients had a partial response to treatment (35%). One patient with juvenile-onset disease had progression despite treatment and died of airway obstruction. Treatment results are summarized in Table 1. When examining different treatment regimens, the 28-day loading dose followed by three times weekly dosing produced the highest percentage of positive responses to therapy (86%) and a high complete response rate (57%). A similar overall positive response rate (76%) was obtained for 21- or 28-day pulse therapy, with a lower complete re-
sponse rate (31%). No difference was observed between the 21- and 28-day pulse therapies. Data were also analyzed for differences between juvenile- and adult-onset disease. Complete response rates were slightly higher for juvenile-onset (54%) compared with adult-onset disease (30%). No response to therapy was observed more frequently in adult-onset (30%) compared with juvenile-onset disease (13%). These results are summarized in Table 2. Complications of treatment included mild lethargy, fatigue, headache, and low-grade fevers in over half the patients. Nine patients with transient elevations of liver function test results (greater than twice normal) were treated with a temporary decrease or discontinuation of therapy until testing returned to normal. Mild alopecia occurred in four patients, and skin rash occurred in one. A single patient had a decreased white blood cell count (less than 3000 cells/mm3), which returned to normal with a temporary decrease in dosage. One patient had to completely discontinue therapy because of febrile seizures. No severe long-term side effects were observed. Isotretinoin
Five patients with juvenile-onset disease were treated with isotretinoin. Four received isotretinoin after a poor response to IF. One was treated simultaneously with IF. No significant clinical response was observed in any patient treated with isotretinoin. Side effects included severe dryness of the skin and lips. No discontinuation of therapy was required because of side effects. Methotrexate
Three of the above patients with the most severe juvenile-onset disease, all of whom were tracheotomy dependent and required surgical intervention at least once a month, were treated with methotrexate. All three patients had a significant clinical response to methotrexate within 3 to 6 months of initiating therapy. The average interval between surgical interventions increased twofold to three-
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Table 2. Response to IF therapy by disease onset Response to IF Disease onset
Complete
Partial
None
TOTAL
8 4 12
3 3 6
24 10 34
i
Juvenile Adult TOTAL
13 3 16
fold, and the amount of disease present on each surgical intervention was also significantly diminished. None had a complete response. One patient was unable to tolerate the oral form of methotrexate because of severe nausea and emesis and received 170 mg intravenously followed by leucovorin rescue 24 hours after the methotrexate dose, repeated every other week for 1 year. A Hickman central-line catheter was placed for this purpose. No other complications have been noted. DISCUSSION
Numerous clinical trials have shown that IF is an effective adjuvant treatment for RRP. Long-term follow-up in the multicenter study by Leventhal et al. 1°revealed that treatment with IF produced a 79% overall response rate with 37% complete remission. An earlier study by Lusk et al." presented similar data with a 75% overall response and 25% cure. Our data are in good accordance with these studies for an overall response rate of 82% and a slightly higher complete response rate of 47%. These studies all used IF produced by recombinant DNA techniques. These results are in marked contrast to those obtained by Healy et al. a6using pooled, blood bankharvested IF, given in doses of 2 MU/m z for 7 days and then three times weekly. Improvement was seen in the first 6 months of the study, but there was no significant improvement at 1 year. The discrepancy in results between these studies might be attributed to both the lower dosing regimen and the source of IF. Leventhal et al. 1° have demonstrated significant long-term improvement with a higher and more frequent dosing regimen. Many authors have implicated a difference in both the side effects and efficacy on the basis of the source of IF production. IF produced by recombinant DNA techniques has fewer side effects and a higher response rate than blood bank-harvested IF, although no statistically significant difference has been proved? 7 Currently we are using Roferon (Roche Laboratories, Nutley, N.J.), which is well tolerated with a favorable sideeffect profile.
•
The exact mechanism by which IF exerts its effect is not well understood. It is believed that there is modulation of the host immune response with production of a protein kinase and endonuclease, which results in both the inhibition of viral protein synthesis and breakdown of viral RNA. TM Several other cellular genes are also modulated by IF with varying effects, and these regulatory mechanisms remain to be discovered. The difference in response between juvenile- and adult-onset RRP to IF therapy has not been examined before. We found that juvenile-onset disease had a higher complete response rate, and adultonset disease had a higher rate of treatment failures, although overall positive response rates were similar. This finding may be explained by the fact that juvenile-onset RRP tends to be a more aggressive disease with more rapid growth of papillomas4 and therefore may be more sensitive to the antiviral effects of IF. Further study of the differences in IF efficacy between adult- and juvenile-onset forms of RRP is warranted. The side-effect profile of IF has been well established. 19All side effects observed in our study were minor, with the exception of febrile seizures in one patient, who required discontinuation of therapy. These side effects are consistent with those previously described. Injections are given at bedtime to minimize the symptoms of headache, fever, and lethargy. Elevated transaminase levels and leukopenia can be easily managed with a decreased dosage for a short period of time and rarely require discontinuation of therapy. For relief of pain or fevers, only acetaminophen should be used because aspirin and other nonsteroidal antinflammatory drugs interact with IF and diminish its effectiveness. DNA typing of HPV from previous studies has identified HPV types 6 and 11 as being responsible for infection in RRP. 5,9 Six of our patients were included in the study by Leventhal et al., 9 which identified no significant difference in clinical outcome and response to IF based on HPV type. We did not analyze HPV DNA typing any further in our
Otolaryngology Head and Neck Surgery Volume t12 Number 2
study because it appears that the type of HPV DNA virus is not predictive of response to IF therapy. Various dosing regimens for IF therapy have been presented in the literature. Most of our patients were treated with 5 MU/m2/day for 28 days, followed by three times weekly dosing for at least 6 months, which produced a high overall rate of positive response (86%) and high complete response rate (57%). Leventhal et al. ~° have recommended that patients with disease requiring surgical intervention every 2 to 3 months be treated with a 6-month trial of IF dosed 5 MU/m 2 for 28 days, followed by 2 MU once a day or 4 MU every other day. Clinical response is expected within 1 month, with treatment continuing as long as a partial response is maintained without significant side effects. Treatment is discontinued when a complete response is confirmed. Before instituting adjuvant therapy, we perform aggressive surgical intervention on all our newly diagnosed RRP patients. Carbon dioxide laser ablation of disease is performed at 4- to 6-week intervals for at least four consecutive treatments, and the patient's disease status is then reevaluated. We have found that many patients will resolve their disease or greatly improve with this surgical regimen. Patients who do not show a decrease in disease volume are then considered for IF adjuvant therapy. IF treatment is effective in the majority of patients with recurrent respiratory papillomatosis who do not improve with aggressive surgical therapy. We recommend a regimen starting with a loading dose of 5 MU/m 2 for 28 days, followed by 5 MU/m 2 three times per week for at least 6 months, as the most effective in eliciting a complete or partial response. This regimen may be continued as long as a positive clinical response is maintained. Long-term treatment should attempt to use the lowest effective dose for the individual patient as measured by clinical evaluation. Once a complete response has been obtained, therapy may be discontinued. Follow-up for recurrent disease should be continued for at least 1 year after complete remission. Recurrent disease may be retreated with IF, again obtaining a complete response. Isotretinoin, a retinoid compound, is primarily used in the treatment of severe cystic ache. Retinoids reverse abnormal differentiation of epithelial cells in part by controlling the expression of keratin genes and subsequent keratin production. 2° They have no known direct antiviral properties. In the treatment of RRP it was hypothesized that isotretinoin would allow for normalized epithelialization of
AVIDANO a n d SINGLETON 2 0 t
the mucosa, thereby decreasing the viral effects and papillomatous changes. Alberts et al. 12 treated five patients with isotretinoin, with dosing of 1 to 2 mg/kg/day. Two had complete responses, and one had a partial response lasting up to 24 months. Two had no response to therapy. Minimal side effects were observed, which responded to a decrease in dosage. Bell et al., I3in an attempted randomized study, found no significant clinical improvement in treatment with isotretinoin over placebo, along with an unfavorable side-effect profile requiring decreased dosage or discontinuation in most patients. Our group of patients treated with isotretinoin is somewhat biased because only those with more severe disease and a poor response to IF were treated with isotretinoin. Our data suggest that isotretinoin therapy is of no benefit in the treatment of severe respiratory papillomatosis. A subset of patients may exist that will benefit from isotretinoin therapy, as seen in the study by Alberts et al. The role of isotretinoin in the treatment of mild RRP remains undefined. Methotrexate is an antimetabolite used in the treatment of neoplastic diseases. It acts by the inhibition of dihydrofolic acid reductase, which blocks the synthesis of purine nucleotides and thymidylate, subsequently interfering with DNA synthesis and repair. Actively proliferating cells and DNA are more sensitive to the effects of methotrexate than normal cells. The rationale in the treatment of RRP with methotrexate is that the more rapidly proliferating viral-containing epithelial ceils will be preferentially affected, leaving the normal epithelium intact. Little is reported in the literature concerning methotrexate therapy for RRP. Treatment of nine children with severe disease using adenine arabinoside, another DNA antimetabolite, was performed by Hendrickse et al. a5Three patients had resolution of disease, and six had a minimal response, all without side effects. These findings suggest that antimetabolite therapy might be effective in some patients with severe disease. After treatment with methotrexate all three of our patients have had a dramatic improvement in their clinical course, with at least a doubling of the surgical interval and a large decrease in the amount of disease present. No complete remissions have been noted, although all patients have been treated for less than 1 year. No complications have been noted. On the basis of the known mechanism of action of methotrexate, we predict that patients with the most severe and rapidly recurring disease would receive the most benefit
202
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from methotrexate therapy. These preliminary data on treatment with methotrexate are promising for those patients with recalcitrant disease. Larger trials and long-term follow-up will be required to determine whether methotrexate is as beneficial in the treatment of recurrent respiratory papillomatosis as it appears to be. SUMMARY
We have found adjuvant therapy with IF and methotrexate to be beneficial in the treatment of recurrent respiratory papillomatosis. Isotretinoin appears ineffective in patients with severe disease. The standard of care remains aggressive surgical intervention with the carbon dioxide laser to remove all visible papillomas from the airway. In patients with severe disease not responsive to surgery alone, adjunctive therapy with IF should be carried out in a dosing regimen of 5 MU/m 2 for 28 days followed by three times weekly doses for at least 6 months. This is continued on the basis of clinical response, in an attempt to obtain complete resolution of disease. Methotrexate may be added for patients with severe disease who are not responding to these treatments, although the full role of methotrexate needs to be studied further. REFERENCES
1. Irwin BC, Hendrickse WA, Pincott JR, Bailey CM, Evans JN. Juvenile laryngeal papillomatosis. J Laryngol Otol 1986;100: 435 -45. 2. Steinberg BM. Laryngeal papillomatosis is associated with a defect in cellular differentiation. Ciba Found Symp 1986;120: 208-220. 3. Vambutas A, Di Lorenzo TP, Steinberg BM, Laryngeal papilloma cells have high levels of epidermal growth factor receptor and respond to epidermal growth factor by a decrease in epithelial differentiation. Cancer Res 1993;53: 910-4. 4. Strong MS, Vaughan CW, Healy GB. Recurrent respiratory papillomatosis: management with the CO2 laser. Ann Otol Rhinol Laryngol 1982;89:472-8. 5. Mounts P, Shah KV. Respiratory papillomatosis: etiological relationship to genital tract papillomaviruses. Prog Med Virol 1984;29:90-114.
Otolaryngology Head and Neck Surgery February 1995
6. Kashima HK, Shah F, Lyles A, et al. A comparison of risk factors in juvenile-onset and adult-onset recurrent respiratory papillomatosis. Laryngoscope 1992;102:9-13. 7. Shah K, Kashima H, Polk F, Shah F, Abbey H, Abramson A. Rarity of cesarean delivery in cases of juvenile-onset respiratory papillomatosis. Obstet Gynecol 1986;68:795-9. 8. Steinberg BM, Topp WC, Schneider PS, Abramson AL. Laryngeal papillomavirus infection during clinical remission. N Engl J Med 1983;308:1261-4. 9. Leventhal BG, Kashima HK, Weck PW, et al. Randomized surgical adjuvant trial of interferon alfa-nl in recurrent papiUomatosis. Arch Otolaryngol Head Neck Surg 1988;114: 1163-9. 10. Leventhal GB, Kashima HK, Mounts P, et al. Long-term response of recurrent respiratory papillomatosis to treatment with lymphoblastoid interferon alfa-nl. N Engl J Med 1991; 325:613-7. 11. Lusk RP, McCabe BF, Mixon JH. Three year experience of treating recurrent respiratory papilloma with interferon. Ann Otol Rhinol Laryngol 1987;96:158-62. 12. Alberts DS, Coulthard SW, Meyskens FL. Regression of aggressive laryngeal papillomatosis with 13-cis-retinoic acid. J Biol Response Mod 1986;5:124-8. 13. Bell R, Hong WK, Itri LM, McDonald G, Strong MS. The use of cis-retinoic acid in recurrent respiratory papillomatosis of the larynx: a randomized pilot study. Am J Otolaryngol 1988;9:161-4. 14. Smith HG, Healy GB, Vaughan CW, Strong MS. Topical chemotherapy of recurrent respiratory papillomatosis: a preliminary report. Ann Otol Rhinol Laryngol 1980;89:472-8. 15. Hendrickse WA, Irwin BC, Levinsky RJ, Bailey CM, Tymm G, Evans JNG. Treatment of respiratory papillomatosis with adenine arabinoside. Arch Dis Child 1985;60:374-6. 16. Healy GB, Gelber RD, Trowbridge AL, Grundfast KM, Ruben RJ, Price KN. Treatment of recurrent respiratory papillomatosis with human leukocyte interferon: results of a multicenter randomized clinical trial. N Engl J Med 1988; 319:401-7. 17. Sessions RB, Goepfert H, Donovan DT, Dichtel WJ, Gutterman JU. Further observations on the treatment of recurrent respiratory papillomatosis with interferon: a comparison of sources. Ann Otol Rhinol Laryngol 1983;92:456-61. 18. Androphy EJ, Papillomaviruses and interferon. Ciba Found Symp 1986;120:221-34. 19. Crockett DM, McCabe BF, Lusk RP, Mixon JH. Side effects and toxicity of interferon in the treatment of recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol 1987; 96:601-7. 20. Jetten AM, Smits H. Regulation of differentiation of tracheal epithelial cells by retinoids. Ciba Found Syrup 1985;113:6176.
VOLUME 112
NUMBER 2
ORIGINAL ARTICLES
Adjuvant drug strategies in the treatment of recurrent respiratory papillomatosis MICHAEL A. AVlDANO, MD, and GEORGE T. SINGLETON, MD, Gainesville, Florida
The purpose of this study was to evaluate adjuvant drug therapies combined with standard laser excision in the treatment of recurrent respiratory papillomatosis. Previous studies have presented conflicting data on the efficacy of various treatments, including interferon and isotretinoin. A retrospective study of 34 patients with moderate to severe papillomatosis who underwent both laser surgery and adjuvant therapy was therefore performed. All patients were treated with interferon. Five interferon failures received isotretinoin, and three with recalcitrant disease received methotrexate. Interferon produced a complete response in 16 patients and partial response in 12 patients. Juvenile-onset disease had a slightly higher response to interferon than adult-onset disease. Isotretinoin produced no response in all five patients. Methotrexate demonstrated a marked improvement in both severity of disease and treatment interval in all three patients. Serious side effects were limited to one interferon patient with febrile seizures, which resolved with discontinuation of therapy. We conclude that adjuvant therapy including interferon and methotrexate is clearly of benefit in the treatment of patients with respiratory papillomatosis. A detailed approach to surgery combined with an interferon dosing regimen is presented. Further study of methotrexate appears warranted. [OTOLARYNGOL HEADNECKSURG1995;I 12:197-202,}
Recurrent respiratory papillomatosis (RRP) is an uncommon disease characterized by the recurrent growth of benign papillomas along the epithelium of the respiratory tract. Most commonly the larynx is involved, although the disease may also involve the trachea, bronchi, and oropharynx. Histologically, papillomas appear as benign squamous lesions with
From the Department of Otolaryngology-Head and Neck Surgery, University of Florida College of Medicine. Presented at the Annual Meeting of the American Academy of Otolaryngology-Head and Neck Surgery, Minneapolis, Minn., Oct. 2-6, 1993. Received for publication Oct. 4, 1993; revision received April 21, 1994; accepted April 22, 1994. Reprint requests: George T. Singleton, MD, Department of Otolaryngology, University of Florida, Box 100264, Gainesville, FL 32601. Copyright © 1995 by the American Academy of OtolaryngologyHead and Neck Surgery Foundation, Inc. 0194-5998/95/$3.00 + 0 23/1/56926
an arborizing core of highly vascular connective tissue surrounded by an outer layer of nonkeratinized stratified squamous epithelium) Cellular differentiation of laryngeal papillomas appears to be abnormal, with altered expression and production of keratins, related in part to high levels of epidermal growth factor receptors present on affected cells. 2,3 A bimodal age distribution is seen with both juvenile-onset ( < 5 years) and adult-onset ( > 20 years) forms of the disease, with the juvenile-onset form being more aggressive in most cases. 4The presence of human papillomavirus (HPV) DNA types 6 and 11 has been demonstrated in these lesions, which are the same viral types associated with genital condylomata2 The genital tract appears to act as the reservoir for transmission of HPV to the respiratory tract, although R R P is relatively rare compared with genital condylomata. Risk factors and method of transmission appear to differ between the juvenile and adult types of disease. 6 The triad of firstborn 197
198
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child, vaginal delivery, and a teenage mother is significantly more common in juvenile-onset RRP, whereas more lifetime sexual partners and higher frequency of oral sex is associated with adult-onset RRP. Transmission of RRP has been reported despite cesarean section, and blood-borne exposure remains a possible route of transmission in children.7 Standard treatment now consists of endoscopic carbon dioxide laser excision of all visible papilloma from affected areas of the respiratory tract, as warranted by the patient's symptoms. Still, removal of visible disease leaves behind normal-appearing epithelium harboring viral DNA, which leads to recurrence, s The disease is noted for its highly unpredictable course, with rapid growth, spread within the respiratory tract, spontaneous resolution, and the constant possibility of airway obstruction requiring urgent intervention to maintain patency. Because of the often relentless course and need for frequent surgical intervention, the disease imposes a significant emotional and financial burden on the patient and family, indicating the need for more effective therapies. Several studies have demonstrated that adjuvant therapy with interferon-a n-1 (IF) produces a longterm beneficial response in the majority of patients treated. 9-11Two studies exist on the efficacy of isotretinoin (Accutane) in RRP with differing results, m3 Other adjuvant therapies, including hormones, cytotoxic agents, antimetabolites, and photodynamic therapy, have all been tried with variable success, m5 At the University of Florida we have had numerous patients with RRP undergo treatment with three types of adjuvant therapy. Thirty-four patients have undergone treatment with IF. Five IF failures were treated with isotretinoin, and most recently, three IF failures were treated with methotrexate. This article reviews our experience with IF, isotretinoin, and methotrexate; reviews the literature concerning these therapies; and presents an approach to surgery combined with adjuvant therapy in the treatment of patients with RRP. METHODS AND PATIENTS Interferon
A total of 34 patients underwent therapy with IF and were available for evaluation. All patients had moderate to severe disease and were initially treated with endoscopic examination and carbon dioxide laser excision of disease for a minimum of five times, or three times within 1 year, before starting IF. Further endoscopy and laser ablation of disease were carried out as warranted by the patient's symptoms and findings on laryngoscopy. All IF used was
produced by recombinant DNA methods from differing manufacturers based on availability. Six patients were part of a randomized double-blind multicenter clinical trial and have previously been reported by Leventhal et al. 1° Dosing was 5 megaunits (MU) IF per meter squared body surface area, given for a 21- or 28-day loading period for all patients. This was followed by a maintenance dose of 5 MU/m 2 given three times per week for at least 6 months in 21 patients. Thirteen patients were treated with 21- or 28-day pulses of IF at 4- to 6-month intervals. Treatment was not randomized or blinded except for the six patients from the multicenter study.1° Dosing was decreased or withheld for i to 2 weeks for significant side effects and then returned to the maximum dose tolerated, between 3 and 5 MU/m 2. Clinical response was measured by the volume and areas of airway involvement with papilloma on endoscopic examination. Carbon dioxide laser surgery was performed when clinically required for increased airway compromise. Partial response is defined as any improvement in the extent of disease present on serial flexible endoscopic examination. Complete response denotes no evidence of disease on evaluation for at least 6 months of follow-up. For a partial clinical response, treatment was continued as long as the response was maintained. For a complete clinical response in patients receiving three times weekly dosing, treatment was discontinued after 6 months. For 21- or 28-day courses, treatment was discontinued after the last course for a complete clinical response. Patients with no response continued therapy for 1 year to allow time for a possible response to be observed. Injections were given by the patient or family in the home at bedtime, Liver function testing was performed weekly during the loading period and monthly thereafter. Complete blood count was also performed monthly. Isotretinoin (13-cis-Retinoic Acid)
Five patients with severe disease and poor responses to standard laser excision and IF were further treated with isotretinoin. Dosing was 1 mg/kg/day orally, divided twice daily, for a period of 6 to 12 months. One patient was simultaneously treated with IF. Clinical response was measured by changes found at examination and surgery, as previously defined for IF therapy. Methotrexate
Three patients with severe disease requiring surgery approximately once per month were treated
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Number 2
199
Table I. Response to IF therapy according to treatment regimen Response to IF Treatment regimen
28 Day-3 x / w k 21/28 day pulse TOTAL
Complete
Partial
None
TOTAL
12 4 16
6 6 12
3 3 6
21 13 34
with methotrexate. All had undergone previous treatment with 1F with minimal improvement, but not enough to warrant further therapy. Because of the potential toxicity of methotrexate, administration was performed in consultation with our pediatric hematology-oncology service. Liver and renal functions, complete blood counts, and platelet counts were monitored on each patient. Oral dosing started at 1 mg/kg given once or twice weekly and was adjusted as dictated by side effects and efficacy. Clinical response was again measured by changes seen at flexible endoscopic examination and surgery. RESULTS Interferon
Thirty-four patients underwent treatment with IF. Age at the start of therapy ranged from 2 years to 68 years, with a median age of 6 years and equal numbers of male and female patients. Twenty-four patients had juvenile-onset disease, and 10 patients had adult-onset disease. All 34 patients had laryngeal disease, and 9 also had tracheal involvement. No patients had pulmonary or pharyngeal disease. Five patients required a tracheotomy during therapy for airway management. Two of these were cured of disease and later decannulated. A positive response to treatment was achieved in 28 of 34 patients (82%). Sixteen patients had a complete response with resolution of papilloma for at least 6 months (47%). Only one patient with a complete response had recurrence of disease and was treated a second time with a complete response 3 years later. Twelve patients had a partial response to treatment (35%). One patient with juvenile-onset disease had progression despite treatment and died of airway obstruction. Treatment results are summarized in Table 1. When examining different treatment regimens, the 28-day loading dose followed by three times weekly dosing produced the highest percentage of positive responses to therapy (86%) and a high complete response rate (57%). A similar overall positive response rate (76%) was obtained for 21- or 28-day pulse therapy, with a lower complete re-
sponse rate (31%). No difference was observed between the 21- and 28-day pulse therapies. Data were also analyzed for differences between juvenile- and adult-onset disease. Complete response rates were slightly higher for juvenile-onset (54%) compared with adult-onset disease (30%). No response to therapy was observed more frequently in adult-onset (30%) compared with juvenile-onset disease (13%). These results are summarized in Table 2. Complications of treatment included mild lethargy, fatigue, headache, and low-grade fevers in over half the patients. Nine patients with transient elevations of liver function test results (greater than twice normal) were treated with a temporary decrease or discontinuation of therapy until testing returned to normal. Mild alopecia occurred in four patients, and skin rash occurred in one. A single patient had a decreased white blood cell count (less than 3000 cells/mm3), which returned to normal with a temporary decrease in dosage. One patient had to completely discontinue therapy because of febrile seizures. No severe long-term side effects were observed. Isotretinoin
Five patients with juvenile-onset disease were treated with isotretinoin. Four received isotretinoin after a poor response to IF. One was treated simultaneously with IF. No significant clinical response was observed in any patient treated with isotretinoin. Side effects included severe dryness of the skin and lips. No discontinuation of therapy was required because of side effects. Methotrexate
Three of the above patients with the most severe juvenile-onset disease, all of whom were tracheotomy dependent and required surgical intervention at least once a month, were treated with methotrexate. All three patients had a significant clinical response to methotrexate within 3 to 6 months of initiating therapy. The average interval between surgical interventions increased twofold to three-
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Table 2. Response to IF therapy by disease onset Response to IF Disease onset
Complete
Partial
None
TOTAL
8 4 12
3 3 6
24 10 34
i
Juvenile Adult TOTAL
13 3 16
fold, and the amount of disease present on each surgical intervention was also significantly diminished. None had a complete response. One patient was unable to tolerate the oral form of methotrexate because of severe nausea and emesis and received 170 mg intravenously followed by leucovorin rescue 24 hours after the methotrexate dose, repeated every other week for 1 year. A Hickman central-line catheter was placed for this purpose. No other complications have been noted. DISCUSSION
Numerous clinical trials have shown that IF is an effective adjuvant treatment for RRP. Long-term follow-up in the multicenter study by Leventhal et al. 1°revealed that treatment with IF produced a 79% overall response rate with 37% complete remission. An earlier study by Lusk et al." presented similar data with a 75% overall response and 25% cure. Our data are in good accordance with these studies for an overall response rate of 82% and a slightly higher complete response rate of 47%. These studies all used IF produced by recombinant DNA techniques. These results are in marked contrast to those obtained by Healy et al. a6using pooled, blood bankharvested IF, given in doses of 2 MU/m z for 7 days and then three times weekly. Improvement was seen in the first 6 months of the study, but there was no significant improvement at 1 year. The discrepancy in results between these studies might be attributed to both the lower dosing regimen and the source of IF. Leventhal et al. 1° have demonstrated significant long-term improvement with a higher and more frequent dosing regimen. Many authors have implicated a difference in both the side effects and efficacy on the basis of the source of IF production. IF produced by recombinant DNA techniques has fewer side effects and a higher response rate than blood bank-harvested IF, although no statistically significant difference has been proved? 7 Currently we are using Roferon (Roche Laboratories, Nutley, N.J.), which is well tolerated with a favorable sideeffect profile.
•
The exact mechanism by which IF exerts its effect is not well understood. It is believed that there is modulation of the host immune response with production of a protein kinase and endonuclease, which results in both the inhibition of viral protein synthesis and breakdown of viral RNA. TM Several other cellular genes are also modulated by IF with varying effects, and these regulatory mechanisms remain to be discovered. The difference in response between juvenile- and adult-onset RRP to IF therapy has not been examined before. We found that juvenile-onset disease had a higher complete response rate, and adultonset disease had a higher rate of treatment failures, although overall positive response rates were similar. This finding may be explained by the fact that juvenile-onset RRP tends to be a more aggressive disease with more rapid growth of papillomas4 and therefore may be more sensitive to the antiviral effects of IF. Further study of the differences in IF efficacy between adult- and juvenile-onset forms of RRP is warranted. The side-effect profile of IF has been well established. 19All side effects observed in our study were minor, with the exception of febrile seizures in one patient, who required discontinuation of therapy. These side effects are consistent with those previously described. Injections are given at bedtime to minimize the symptoms of headache, fever, and lethargy. Elevated transaminase levels and leukopenia can be easily managed with a decreased dosage for a short period of time and rarely require discontinuation of therapy. For relief of pain or fevers, only acetaminophen should be used because aspirin and other nonsteroidal antinflammatory drugs interact with IF and diminish its effectiveness. DNA typing of HPV from previous studies has identified HPV types 6 and 11 as being responsible for infection in RRP. 5,9 Six of our patients were included in the study by Leventhal et al., 9 which identified no significant difference in clinical outcome and response to IF based on HPV type. We did not analyze HPV DNA typing any further in our
Otolaryngology Head and Neck Surgery Volume t12 Number 2
study because it appears that the type of HPV DNA virus is not predictive of response to IF therapy. Various dosing regimens for IF therapy have been presented in the literature. Most of our patients were treated with 5 MU/m2/day for 28 days, followed by three times weekly dosing for at least 6 months, which produced a high overall rate of positive response (86%) and high complete response rate (57%). Leventhal et al. ~° have recommended that patients with disease requiring surgical intervention every 2 to 3 months be treated with a 6-month trial of IF dosed 5 MU/m 2 for 28 days, followed by 2 MU once a day or 4 MU every other day. Clinical response is expected within 1 month, with treatment continuing as long as a partial response is maintained without significant side effects. Treatment is discontinued when a complete response is confirmed. Before instituting adjuvant therapy, we perform aggressive surgical intervention on all our newly diagnosed RRP patients. Carbon dioxide laser ablation of disease is performed at 4- to 6-week intervals for at least four consecutive treatments, and the patient's disease status is then reevaluated. We have found that many patients will resolve their disease or greatly improve with this surgical regimen. Patients who do not show a decrease in disease volume are then considered for IF adjuvant therapy. IF treatment is effective in the majority of patients with recurrent respiratory papillomatosis who do not improve with aggressive surgical therapy. We recommend a regimen starting with a loading dose of 5 MU/m 2 for 28 days, followed by 5 MU/m 2 three times per week for at least 6 months, as the most effective in eliciting a complete or partial response. This regimen may be continued as long as a positive clinical response is maintained. Long-term treatment should attempt to use the lowest effective dose for the individual patient as measured by clinical evaluation. Once a complete response has been obtained, therapy may be discontinued. Follow-up for recurrent disease should be continued for at least 1 year after complete remission. Recurrent disease may be retreated with IF, again obtaining a complete response. Isotretinoin, a retinoid compound, is primarily used in the treatment of severe cystic ache. Retinoids reverse abnormal differentiation of epithelial cells in part by controlling the expression of keratin genes and subsequent keratin production. 2° They have no known direct antiviral properties. In the treatment of RRP it was hypothesized that isotretinoin would allow for normalized epithelialization of
AVIDANO a n d SINGLETON 2 0 t
the mucosa, thereby decreasing the viral effects and papillomatous changes. Alberts et al. 12 treated five patients with isotretinoin, with dosing of 1 to 2 mg/kg/day. Two had complete responses, and one had a partial response lasting up to 24 months. Two had no response to therapy. Minimal side effects were observed, which responded to a decrease in dosage. Bell et al., I3in an attempted randomized study, found no significant clinical improvement in treatment with isotretinoin over placebo, along with an unfavorable side-effect profile requiring decreased dosage or discontinuation in most patients. Our group of patients treated with isotretinoin is somewhat biased because only those with more severe disease and a poor response to IF were treated with isotretinoin. Our data suggest that isotretinoin therapy is of no benefit in the treatment of severe respiratory papillomatosis. A subset of patients may exist that will benefit from isotretinoin therapy, as seen in the study by Alberts et al. The role of isotretinoin in the treatment of mild RRP remains undefined. Methotrexate is an antimetabolite used in the treatment of neoplastic diseases. It acts by the inhibition of dihydrofolic acid reductase, which blocks the synthesis of purine nucleotides and thymidylate, subsequently interfering with DNA synthesis and repair. Actively proliferating cells and DNA are more sensitive to the effects of methotrexate than normal cells. The rationale in the treatment of RRP with methotrexate is that the more rapidly proliferating viral-containing epithelial ceils will be preferentially affected, leaving the normal epithelium intact. Little is reported in the literature concerning methotrexate therapy for RRP. Treatment of nine children with severe disease using adenine arabinoside, another DNA antimetabolite, was performed by Hendrickse et al. a5Three patients had resolution of disease, and six had a minimal response, all without side effects. These findings suggest that antimetabolite therapy might be effective in some patients with severe disease. After treatment with methotrexate all three of our patients have had a dramatic improvement in their clinical course, with at least a doubling of the surgical interval and a large decrease in the amount of disease present. No complete remissions have been noted, although all patients have been treated for less than 1 year. No complications have been noted. On the basis of the known mechanism of action of methotrexate, we predict that patients with the most severe and rapidly recurring disease would receive the most benefit
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from methotrexate therapy. These preliminary data on treatment with methotrexate are promising for those patients with recalcitrant disease. Larger trials and long-term follow-up will be required to determine whether methotrexate is as beneficial in the treatment of recurrent respiratory papillomatosis as it appears to be. SUMMARY
We have found adjuvant therapy with IF and methotrexate to be beneficial in the treatment of recurrent respiratory papillomatosis. Isotretinoin appears ineffective in patients with severe disease. The standard of care remains aggressive surgical intervention with the carbon dioxide laser to remove all visible papillomas from the airway. In patients with severe disease not responsive to surgery alone, adjunctive therapy with IF should be carried out in a dosing regimen of 5 MU/m 2 for 28 days followed by three times weekly doses for at least 6 months. This is continued on the basis of clinical response, in an attempt to obtain complete resolution of disease. Methotrexate may be added for patients with severe disease who are not responding to these treatments, although the full role of methotrexate needs to be studied further. REFERENCES
1. Irwin BC, Hendrickse WA, Pincott JR, Bailey CM, Evans JN. Juvenile laryngeal papillomatosis. J Laryngol Otol 1986;100: 435 -45. 2. Steinberg BM. Laryngeal papillomatosis is associated with a defect in cellular differentiation. Ciba Found Symp 1986;120: 208-220. 3. Vambutas A, Di Lorenzo TP, Steinberg BM, Laryngeal papilloma cells have high levels of epidermal growth factor receptor and respond to epidermal growth factor by a decrease in epithelial differentiation. Cancer Res 1993;53: 910-4. 4. Strong MS, Vaughan CW, Healy GB. Recurrent respiratory papillomatosis: management with the CO2 laser. Ann Otol Rhinol Laryngol 1982;89:472-8. 5. Mounts P, Shah KV. Respiratory papillomatosis: etiological relationship to genital tract papillomaviruses. Prog Med Virol 1984;29:90-114.
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6. Kashima HK, Shah F, Lyles A, et al. A comparison of risk factors in juvenile-onset and adult-onset recurrent respiratory papillomatosis. Laryngoscope 1992;102:9-13. 7. Shah K, Kashima H, Polk F, Shah F, Abbey H, Abramson A. Rarity of cesarean delivery in cases of juvenile-onset respiratory papillomatosis. Obstet Gynecol 1986;68:795-9. 8. Steinberg BM, Topp WC, Schneider PS, Abramson AL. Laryngeal papillomavirus infection during clinical remission. N Engl J Med 1983;308:1261-4. 9. Leventhal BG, Kashima HK, Weck PW, et al. Randomized surgical adjuvant trial of interferon alfa-nl in recurrent papiUomatosis. Arch Otolaryngol Head Neck Surg 1988;114: 1163-9. 10. Leventhal GB, Kashima HK, Mounts P, et al. Long-term response of recurrent respiratory papillomatosis to treatment with lymphoblastoid interferon alfa-nl. N Engl J Med 1991; 325:613-7. 11. Lusk RP, McCabe BF, Mixon JH. Three year experience of treating recurrent respiratory papilloma with interferon. Ann Otol Rhinol Laryngol 1987;96:158-62. 12. Alberts DS, Coulthard SW, Meyskens FL. Regression of aggressive laryngeal papillomatosis with 13-cis-retinoic acid. J Biol Response Mod 1986;5:124-8. 13. Bell R, Hong WK, Itri LM, McDonald G, Strong MS. The use of cis-retinoic acid in recurrent respiratory papillomatosis of the larynx: a randomized pilot study. Am J Otolaryngol 1988;9:161-4. 14. Smith HG, Healy GB, Vaughan CW, Strong MS. Topical chemotherapy of recurrent respiratory papillomatosis: a preliminary report. Ann Otol Rhinol Laryngol 1980;89:472-8. 15. Hendrickse WA, Irwin BC, Levinsky RJ, Bailey CM, Tymm G, Evans JNG. Treatment of respiratory papillomatosis with adenine arabinoside. Arch Dis Child 1985;60:374-6. 16. Healy GB, Gelber RD, Trowbridge AL, Grundfast KM, Ruben RJ, Price KN. Treatment of recurrent respiratory papillomatosis with human leukocyte interferon: results of a multicenter randomized clinical trial. N Engl J Med 1988; 319:401-7. 17. Sessions RB, Goepfert H, Donovan DT, Dichtel WJ, Gutterman JU. Further observations on the treatment of recurrent respiratory papillomatosis with interferon: a comparison of sources. Ann Otol Rhinol Laryngol 1983;92:456-61. 18. Androphy EJ, Papillomaviruses and interferon. Ciba Found Symp 1986;120:221-34. 19. Crockett DM, McCabe BF, Lusk RP, Mixon JH. Side effects and toxicity of interferon in the treatment of recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol 1987; 96:601-7. 20. Jetten AM, Smits H. Regulation of differentiation of tracheal epithelial cells by retinoids. Ciba Found Syrup 1985;113:6176.