Original Article
Long-Term Response of Recurrent Respiratory Papillomatosis to Treatment with Lymphoblastoid Interferon Alfa-N1
N Engl J Med 1991; 325:613-617August 29, 1991
- Abstract
- Abstract
Background.
We earlier reported that patients with recurrent respiratory papillomatosis responded to six months of treatment with lymphoblastoid interferon alfa-n1. Because another study of patients treated for one year with leukocyte interferon alfa-n3 found that the growth rate of papillomas was slowed in the first six months but returned to base line during months 7 through 12 despite persistent interferon treatment, we now report the long-term results in our original study patients who were followed for a median of four years after the original one-year crossover study.
Methods.
After the patients in our study had completed the first study year, their physicians could continue or recommence treatment with lymphoblastoid interferon alfa-n1 in a dose of either 2 MU per square meter of body-surface area per day or 4 MU per square meter every other day. The extent of disease was measured by endoscopy when clinically indicated.
Results.
Data on late-follow-up were obtained for 60 of the 66 patients. There were 22 complete remissions and 25 partial remissions; 13 patients had no response. The median duration of the complete remissions was 550 days, and 15 patients continued to be in complete remission. The median duration of partial remissions was 400 days, and seven patients were still in partial remission. Thirteen of 28 patients responded to a second course of interferon after an interruption in treatment of at least one month. The rate of response in the 11 of 53 patients who had neutralizing antibody to interferon was the same as in the patients without the antibody.
Conclusions.
Patients with severe recurrent respiratory papillomatosis may have a sustained or repeated response to treatment with lymphoblastoid interferon alfa-n1. We recommend that patients with recurrent respiratory papillomatosis who require surgery every two to three months be given a six-month trial of interferon alfa-n1. (N Engl J Med 1991; 325:613–7.)
Media in This Article
Figure 1
Percentage of Patients Responding to Interferon Therapy.Figure 2
Duration of Response in Patients with Respiratory Papillomatosis Receiving Interferon Therapy.Article Activity
- Article
RECURRENT respiratory papillomatosis is a rare disease characterized by the growth of histologically benign papillomas in the respiratory tract. The most common site of growth is the larynx, but the disease may extend throughout the airway and involve the lungs as well. The presence of human papillomavirus types 6 and 11 has been reported in these lesions; the same viral subtypes are associated with genital condylomata.1 Standard management consists of microendoscopic excision of the lesions, usually with a carbon dioxide laser. Although surgery removes visible warty growths, the human papillomavirus genome remains in normal-appearing tissue.2
In 1976 a group of Scandinavian investigators found consistent responses in a small group of patients with recurrent respiratory papillomatosis who were treated with natural leukocyte interferon.3 This and other small, uncontrolled trials4 , 5 led us to mount a controlled crossover study of six months of treatment with lymphoblastoid interferon alfa-nl (Wellferon, Wellcome Laboratories, Beckenham, Kent, United Kingdom). In 19886 we reported the results of that trial. A scoring system was developed to quantify the amount of papilloma present at each operation, and a significant difference was found between the lesion scores in the group treated with interferon and those in the observation group in each six-month period. In addition, 8 of the 57 patients with assessable disease had achieved complete remission after six months of therapy. At about the same time, another report was published evaluating the efficacy of human leukocyte interferon in 123 patients randomly assigned to either interferon treatment or observation for one year.7 Those investigators found that during the first six months the growth rate of papillomas was significantly lower in the interferon group than in the control group (P = 0.0007). The difference diminished during the second six months, despite the continued administration of interferon, and by the end of the year it was no longer statistically significant (P = 0.68). In our study, patients continued or recommenced treatment with interferon at the investigators' discretion at the end of the one-year study period. We now report data on late follow-up for 60 patients. A durable response to interferon therapy (defined as a complete or partial remission lasting more than 500 days) was seen in 22 of the 60 patients. It thus appears that this group of patients treated with lymphoblastoid interferon alfa-n1 had longer-lasting responses than those who received leukocyte interferon.
Methods
Lymphoblastoid Interferon Alfa-n1
Lymphoblastoid interferon alfa-n1 is a purified preparation of alfa interferons produced by Sendai viral stimulation of the human lymphoblastoid cell line Namalwa. It contains at least 18 human interferon alfa subtypes.8 The biologic activity of lymphoblastoid interferon is expressed in megaunits (MU; 1×106 IU equals 1 MU) and was originally determined in an inhibition assay of viral cytopathic effect. Since 1985 it has been titrated against an international reference preparation of lymphoblastoid interferon that is standardized to the international standard human interferon alfa (lymphoblastoid) National Institutes of Health reference reagent GA 23901–532.
Patient Eligibility
The criteria for inclusion in the initial study were as follows: the diagnosis of histologically proved recurrent respiratory papillomatosis with no evidence of anaplasia; onset of disease before the age of 16 years; a history of documented disease of at least six months' duration; at least two operations during the six months before entry into the study; an age of more than 12 months and less than 35 years; and availability for follow-up at one of the participating centers. Informed consent was given by each patient or guardian on forms approved by the centers' institutional review boards. Otolaryngologists from 12 institutions throughout North America enrolled patients in the study. Once the patients had completed the study they were eligible for additional treatment with lymphoblastoid interferon on an addendum protocol if they and their physicians believed it to be in their best interests to continue. This report describes the responses we observed during both the initial and the addendum studies.
Treatment Plan
During the first year of the study, endoscopic examination and excision were repeated every two months. During the addendum period, surgery was performed as clinically indicated until a minimum of two operations had been performed with no papilloma seen. All detectable papillomas were resected at each operation. Patients were assigned by randomization in the initial study. One group received 5 MU of interferon alfa-nl per square meter of body-surface area daily for 28 days, then the same dose thrice weekly for 5 months, after which the patients crossed over to observation for 6 months. The patients in the other group were observed for six months and then crossed over to six months of interferon alfa-n1 therapy as an adjuvant to surgery. All injections were given intramuscularly by the patient or a family member.
After the one-year study period ended, the patients were eligible to continue or recommence treatment with lymphoblastoid interferon on an addendum protocol. The investigators at each institution selected one of two regimens, either 2 MU per square meter daily or 4 MU per square meter every other day. The dose selected for the addendum study was lower than that in the original study, since only 22 percent of the patients over the age of 15 had been able or willing to complete treatment with the recommended dose of 5 MU per square meter because of side effects that included malaise, headache, fatigue, and anorexia.6 There was no limit to the length of time that the drug could be given. Some patients entered the addendum study to maintain an achieved response, and others to achieve a second response as described below. All the patients were followed up by questionnaire in 1987–1988 and by on-site visit and a review of records in 1989. A formal assessment of toxicity, with laboratory studies at required intervals, was performed only during the one-year randomized study.
Assessment of the Extent of Disease and Definition of Response
A scale called a KL score was developed to describe the extent of disease.9 The scale took into account disease activity at nine designated anatomical sites within the tracheobronchial tree. One KL point was given for each site affected, and another if more than one third of the surface area was covered with lesions or if the lumen was occluded by one third or more, for a maximal possible KL score of 27. All definitions of response were based on endoscopic examination. A partial response was defined as a decrease in the KL score to 50 percent of the score before treatment, and the persistence of the low score for at least two months (i.e., during two surgical interventions). A complete response was defined as a KL score of 0 for at least two months. A partial response was considered to have ended if the KL score was 50 percent higher than the patient's best score during two consecutive operations, and a complete response was considered to have ended if the score rose above 0. Routine endoscopic evaluation could be discontinued after two successive negative evaluations if the patient remained asymptomatic, although some patients continued to have yearly examinations while in remission.
Papillomavirus Subtypes
The subtypes of human papillomavirus (subtypes 6 and 11 ) were identified by nucleic acid hybridization of snap-frozen tissues.10 Subtype 11 has been designated 6c in previous publications.
Antibody Measurements
Serum specimens were collected from the patients at entry into the study and during treatment with lymphoblastoid interferon. Neutralizing antibodies in the serum were assayed as described elsewhere.11 Briefly, serum from the patients or pooled normal human serum was preincubated at a dilution of 1 to 20 with up to 64 U of lymphoblastoid interferon alfa-nl per milliliter, and the mixture was then added to established monolayers of GLV3 cells. After 18 to 24 hours, the cells (except the control cells) were challenged with the Semliki Forest virus. Cell viability was assessed visually after the monolayers had been stained with crystal violet or after absorbance of neutral red dye at 540 nm, and antiviral activity in the negative control and the other samples was compared.
Results
Clinical Response
Sixty-six patients were enrolled in the original study. Thirty-three were randomly assigned to receive lymphoblastoid interferon initially. Data on response and late follow-up are reported for 29 patients in that group. Thirty-three patients were assigned to initial observation. Data on late follow-up are reported for 31 of those patients. The reasons for exclusion have been reported.6 In our original report 57 patients were considered. Three additional patients who received interferon initially despite their assignment to the observation group have been added for this analysis. None of the three responded to treatment. The median follow-up period was four years from the completion of the original study. During that period the number of surgical interventions per patient ranged from 0 (for the patients already in surgically defined complete remission) to 39, with a median of 11.
Thirty-one patients received a single course of interferon. Twenty-eight patients had an interrupted course; in 18 of them therapy recommenced after the required six months of observation, and in the other 10 it was resumed electively after the one-year trial had ended, in an attempt to reinduce or improve response. The median period of interferon treatment after the first year was 200 days (range, 0 to 1850). When the best response achieved with any course of lymphoblastoid interferon treatment is considered, there were 22 complete remissions, 25 partial remissions, and 13 failures to respond (Table 1Table 1
Best Responses to Treatment with Lymphoblastoid Interferon Alfa-n1 in 60 Patients in the Late-Follow-up Papillomatosis Study.). The complete remissions were achieved a median of 315 days (range, 90 to 1400) after the start of treatment. In addition to the eight patients who had a complete response with the initial six months of therapy, there were nine who entered complete remission more than six months after starting treatment and five who entered complete remission during their second course of treatment. Partial responses were achieved more quickly (median, 140 days; range, 65 to 1000). The percentage of patients achieving a response is shown in Figure 1Figure 1Percentage of Patients Responding to Interferon Therapy.. Of the 22 who eventually entered complete remission, 18 (81 percent) had achieved a partial response by day 180.The duration of response is shown in Figure 2Figure 2
Duration of Response in Patients with Respiratory Papillomatosis Receiving Interferon Therapy.. Complete responses lasted up to 2400 days, and 15 patients were still in complete remission at the time of the last follow-up. Two patients relapsed while receiving interferon, and five relapsed after interferon treatment had been discontinued. Partial responses lasted up to 1400 days. Eight patients relapsed while receiving interferon, and 10 after therapy had ended. The percentage of patients who responded was the same in the two groups in the initial study — those who had an interrupted course of lymphoblastoid interferon (22 of 29 responded) and those whose treatment was not interrupted (25 of 31 responded). Eighteen of the patients whose course of interferon was interrupted started treatment again after the observation period. Seven of the patients in the group that received interferon during the second six-month study period continued to receive interferon for six months without interruption, and two of these patients had an additional course after a break; eight recommenced treatment electively after a break.Table 2Table 2
Best Responses to Treatment with Lymphoblastoid Interferon Alfa-n1, According to the Patients' Clinical Characteristics. shows the patients' responses to treatment according to their clinical characteristics. Patients in all age groups were equally likely to have a response to treatment, but the older children were particularly responsive. There were responses in patients with every papillomavirus subtype. Data on subtypes were not available for all the patients, but are shown for 44. Patients with human papillomavirus 11 had a 75 percent rate of response, and those with human papillomavirus 6 had a 78 percent rate. Patients had responses regardless of whether they had undergone tracheostomy. Of the 28 patients who enrolled with a tracheostomy, 14 were decannulated during the study period.Table 3Table 3
Response to a Second Course of Treatment with Lymphoblastoid Interferon Alfa-n1, According to Treatment Regimen and Response to First Course of Treatment. shows the results of a second course of therapy in the patients who resumed treatment after an interruption of at least one month. Thirteen of the 28 patients achieved a response with a second course of treatment. The proportion of patients achieving a response was similar whether they were given 2 MU per square meter daily (7 of 17 responded) or 4 MU per square meter every other day (6 of 11 responded). Table 3 also shows the likelihood of achieving a second response given the nature of the first response. Both of the patients who had an initial complete response responded a second time, as did 7 of the 15 who had an initial partial response and 4 of the 11 who did not respond to the first course of treatment. Thus, some patients in each category responded. The patients whose treatment stopped because the protocol required it were more likely to respond to a second course of treatment (11 of 18 responded) than those who elected to stop treatment (2 of 10 responded).Antibodies
Fifty-three patients could be tested for serum antibodies to interferon. In 11 (21 percent), neutralizing antibody developed during treatment. Of the 11, 9 had a partial or complete response, 1 had no response, and 1 had pulmonary parenchymal disease only, so that the response could not be assessed. The overall rate of response (complete and partial) among the patients with neutralizing antibody was thus 90 percent, and for those tested and found to be negative it was 83 percent. There was no abrogation of response with the development of antibody.
Toxicity
Acute toxicity was assessed in a systematic fashion only during the first year of the crossover study and has already been reported.6 There was an expected tachyphylaxis to the inflammatory symptoms that occurred with initial administration. Over the long term, the patients reported intermittent fatigue, occasional headache, and anorexia, and four patients had depression, although they did not require formal psychiatric intervention.
During the period of late follow-up 4 of the 60 patients died. All four had tracheostomies, and all died of airway complications due to papillomatosis while not receiving interferon. Three of the four patients had not responded to lymphoblastoid interferon, and one had had a partial response lasting 170 days, with a relapse when medication was withdrawn.
We reviewed the rate of somatic growth in children who were less than 15 years old at the time of enrollment. Base-line percentiles of height were available for 46 children. Of these, 13 (28 percent) were at or below the 5th percentile for age when they entered the study. Girls 4 to 16 years old were particularly affected. Six of seven girls in this age group were at or below the 5th percentile at base line, suggesting that the persistence of this relatively severe disease can be associated with growth impairment before therapy begins. Considering the patients for whom paired values at the beginning and end of observation were available, we found that 51 percent (19 of 37) were at or above the 50th percentile for height when the study began and 35 percent (13 of 37) finished therapy at or above the 50th percentile. There was no correlation between the duration of lymphoblastoid interferon treatment and the pattern of growth, but some deleterious effect of interferon on growth cannot be ruled out.
Discussion
The majority of the patients in this study (47 of 60 [78 percent]) responded to treatment, and in 22 the response was ongoing at the time of the last follow-up. In our initial study,6 8 of 57 patients entered complete remission. This increased to 22 of 60 with prolonged therapy. The median length of treatment required for a complete response was 180 days, but at least half the patients continued to receive therapy for a year. Thirteen of 28 patients had second responses after they recommenced therapy. The patients in this study had relatively severe disease that required frequent surgical intervention; none of them entered complete remission with six months of surgery alone. This finding suggests that the responses were in fact due to the lymphoblastoid interferon treatment and were not just part of the natural history of the disease. The degree and persistence of response in these patients were not related to age, initial extent of disease, or duration of disease. The patients with tracheostomies, for example, had a good record of response and 14 of 28 were decannulated. Sustained and repeated responses of recurrent respiratory papillomatosis to lymphoblastoid interferon alfa-nl were seen in every category of patients.
The level and duration of response in this study are in marked contrast to those seen in the study by Healy et al.,7 who found that only in the first six months was the growth rate of papillomas in the group treated with interferon slower than the rate in the surgery-only group. This difference between the studies does not seem to be explained by the character of the patients. The median duration of disease before enrollment was comparable in both studies (17 months in ours and 28 months in that of Healy et al.). Our patients were somewhat younger at entry (mean age, 52 vs. 65 months), but the older children in our study seemed to respond particularly well.
It is unlikely that the duration of treatment accounted for the difference, because six months of treatment was sufficient to produce at least partial remission in the majority of our. Patients who did respond. A more plausible explanation may be that the preparation, dose, or schedule of interferon we used was more effective. Healy and colleagues administered 2 MU of human leukocyte interferon per square meter intramuscularly every day for 7 days and then thrice weekly for 12 months. In our study 5 MU of lympho-blastoid interferon per square meter was administered intramuscularly every day for 28 days and then every other day for 6 months. Thereafter, therapy involved either 4 MU per square meter every other day or 2 MU per square meter daily. Thus, the patients in our study who underwent continuous treatment received approximately three times the dose of interferon that the patients of Healy et al. received. A high rate of response (11 complete and 7 partial remissions in 20 patients) was also reported by Zenner et al.12 with interferon alfa-2c given in a dose of 1.5×105 IU per kilogram of body weight daily for six weeks and then thrice weekly. Assuming the usual conversion factor of 30, this dose is close to 4.5 MU per square meter. Lymphoblastoid interferon may also be more effective than other types of interferon in the control of papillomavirus-induced disease, although a study by Reichman et al.13 found no difference in efficacy between lymphoblastoid interferon alfa-nl and interferon alfa-2b given as intralesional injections to treat condyloma acuminatum.
Neutralizing antibodies can develop in patients who receive recombinant or natural preparations of interferon alfa. In patients with hairy-cell leukemia and chronic myelogenous leukemia there is some suggestion that the formation of antibody to recombinant interferon alfa is associated with an abrogation of response.14 , 15 In the extensively studied population with juvenile-onset respiratory papillomatosis described herein, 21 percent of the patients had neutralizing antibodies to interferon.11 There was no correlation, however, between the development of neutralizing antibodies and diminished clinical responses.
We recommend that patients who require surgery every two to three months for recurrent respiratory papillomatosis be given a six-month trial of interferon alfa-n1 in a dose of 2 MU per square meter per day or 4 MU per square meter every other day. If there is no response after six months, treatment should be discontinued, since 81 percent of our patients who entered complete remission had at least a partial response within six months. If a partial response is achieved and toxicity is tolerable, then continued treatment is justified. If complete remission is achieved, treatment should end; we have no data that support the use of maintenance therapy, and it is possible to reinduce a response.
*The surgeons at the 12 collaborative institutions of the Papilloma Study Group were as follows: K. Clark, M.D. (Oklahoma City), S. Cohen, M.D. (Los Angeles), H. Dedo, M.D. (San Francisco), D. Donovan. M.D. (Houston), B. Fearon, M.D. (Toronto), L. Gardiner, M.D. (New Haven, Conn.), H. Goepfert, M.D. (Houston), H.K. Kashima, M.D. (Baltimore), R. Lusk, M.D. (St. Louis), B.F. McCabe, M.D. (Iowa City, Iowa), H. Muntz, M.D. (St. Louis), M. Richardson, M.D. (Seattle), G. Singleton, M.D. (Gainesville, Fla.), and A. Yonkers, M.D. (Omaha, Nebr.).
Source Information
From the Departments of Oncology and Pediatrics (B.G.L.) and Otolaryngology (H.K.K.) and the School of Hygiene and Public Health (P.M.), Johns Hopkins University, Baltimore; and the Departments of Experimental Therapy (L.T.), Clinical Immunology (S.C., S.B.), and Clinical Statistics (D.W.), Burroughs Wellcome Co., Research Triangle Park, N.C. Address reprint requests to Dr. Leventhal at the Johns Hopkins Oncology Center, 550 N. Broadway, Suite 1121, Baltimore, MD 21205.
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