Prospective randomized study of thrice weekly six-month and nine-month chemotherapy for cervical tuberculous lymphadenopathy ANTHONY PO WING YUEN, FRCS,SIMON HON WAI WONG, FRCS,CHEUK MING TAM, MRCP,FCCP,SHIU LUN CHAN, FRCP, FCCP,WILLIAM IGNACE WEI, FRCS,FACS,and SAI KIT LAU, FRCS,Hong Kong The aim of this study is to compare the efficacy of a thrice weekly 6-month regimen, 4S3H3R3Z3/2H3R3 (which consists of an initial 4 months of streptomycin (S), isoniazid (H), rifampicin (R), and pyrazinamide (Z) followed by 2 months of isoniazid and rifampicin), with a thrice weekly 9-month regimen, 4S3H3R3Z3/5H3R3 (which consists of an initial 4 months of streptomycin, isoniazid, rifampicin, and pyrazinamide followed by 5 months of isoniazid and rifampicin), in the treatment of cervical tuberculous lymphadenopathy. A total of 113 patients were recruited between August 1987 and December 1993. Twenty-two patients were excluded from the analysis because of defaulting treatment or modification of regimen. Ninety-one patients were included in the analysis. Forty-three patients were given the 6-month regimen, and 48 patients were given the 9-month regimen. Two (5%) patients of the 6-month regimen and one (2*/.) patient of the 9-month regimen had primary failure after completion of treatment (relative risk, 2.23; 95% confidence interval, 0.21 to 23.76). Of the 88 patients who had initial clinical remission after completion of treatment, the 5-year actuarial remission rates were 89% for the 6-month regimen and 9 0 0 for the 9-month regimen (Wilcoxon, p = 0.44). There were no significant differences of both primary failure rate and 5-year actuarial remission rate of the two regimens. The 6-month regimen is recommended as the initial treatment of tuberculous lymphadenopathy. (Otolaryngol Head
Neck Surg 1997;116:189-92.)
C e r v i c a l tuberculous lymphadenopathy is a common extrapulmonary manifestation of mycobacterial tuberculous infection. The commonly used treatment regimen of cervical tuberculous lymphadenopathy in Hong Kong was a thrice weekly 9-month regimen consisting of 4S3H3R3Z3/5H3R 3. It was found that the treatment of pulmonary tuberculosis could be shortened to 6 months by omitting treatment during the last 3 months of the 9month regimen without increasing the risk of relapse. 1,2
From the Division of Otorhinolaryngology-Headand Neck Surgery, Department of Surgery (Drs. Yuen, Wong, Wei, and Lau), University of Hong Kong, Queen Mary Hospital; and the Wanchai Chest Clinic (Drs. Tam and Chan), Tuberculosisand Chest Service, Departmentof Health, Hong Kong Government. Supported in part by a research grant from the Universityof Hong Kong (337/048/0014). Reprint requests: Anthony Po Wing Yuen, FRCS, Department of Surgery, Universityof Hong Kong, Queen Mary Hospital, Hong Kong. Copyright © 1997 by the American Academy of OtolaryngologyHead and Neck SurgeryFoundation, Inc. 0194-5998/97/$5.00 + 0 23/1/71884
It was uncertain whether similar reduction of duration of treatment might also be applicable in the treatment of cervical tuberculous lymphadenopathy. There is no report of a prospective randomized study on the use of thrice weekly 6-month chemotherapy for cervical tuberculous lymphadenopathy in the literature. The aim of this study is to evaluate the efficacy of our thrice weekly 6-month regimen. PATIENTS AND METHODS From August 1987 to December 1993, patients with cervical tuberculous lymphadenopathy were recruited from the Wanchai Chest Clinic of the Tuberculosis and Chest Service, Department of Health, and also from the Otorhinolaryngology Clinic of the Department of Surgery, the University of Hong Kong, Hong Kong. All patients in this study had tuberculous lymphadenopathy affecting the cervical region only. Patients were not recruited if they were in relapse of previously treated cervical tuberculous lymphadenopathy or had prior antituberculous chemotherapy. A total of 113 patients were recruited in the study. Five patients defaulted treatment (2 patients in the 6-month group, 3 patients in 189
OtolaryngologyHead and NeckSurgery 190 YUEN et al.
Table 1. P a t i e n t d a t a Data Patient no. Female/male ratio Mean age (SD) Neck lymph node Left side Right side Bilateral Mean lymph node no. (SD) Largest node size (mm) Mean SD Abscess Discharging sinus
43 1.4 32 (14)
48 1.7 28 (10)
Chi-square, p = 0.67 t test, p = 0.08
14 20 9 3 (2.4)
7 29 12 3 (2.5)
Chi-square, p = 0.125
19 14 4 (9%) 2 (5%)
23 15 1 (2%) 1 (2%)
t test, p = 0.181
the 9-month group), and drug reactions (11 druginduced hepatitis, 3 gastrointestinal upset, 1 gastrointestinal upset with skin rash, 1 tinnitus, 1 thrombocytopenia) requiring modification of treatment developed in another 17 patients (4 patients in the 6-month group, 13 patients in the 9-month group), all of whom were excluded from the analysis. The remaining 91 patients had completed the treatment and were all included in this analysis. Patients were assessed clinically with documentation of size and site of all lymph nodes. All patients had fine-needle aspiration of the lymph nodes for cytology and culture for Mycobacterium tuberculosis as the initial investigation for cervical lymphadenopathy. Other investigations were carried out including the Mantoux test and chest x-ray. Excision biopsy of the most easily accessible lymph node compatible with tuberculous lymphadenopathy was performed when necessary to confirm the diagnosis and to obtain tissue for myobacterial culture and antibiotic sensitivity tests. No attempt was made to excise all of the involved lymph nodes. Abscesses were drained surgically before the commencement of treatment. All patients with tuberculous lymphadenopathy were randomly selected to receive either the 6-month regimen or the 9-month regimen of antituberculous chemotherapy. The 9-month regimen was 4S3H3R3Z3/ 5H3R3, and the 6-month regimen was 4S3H3R3Z3/2H3R 3. Both groups of patients received the same treatment for the initial 6 months. The 9-month regimen patients received additional treatment for 3 more months. All drugs were administered on alternate days 3 times per week and consisted of streptomycin, isoniazid, rifampicin, and pyrazinamide for the first 4 months (4S3H3R3Z3) for both groups of patients. After completion of the initial 4 months of treatment, additional
t test, p = 0.995
Fisher's exact, p = 0.185 Fisher's exact, p = 0.6
treatment was given with isoniazid and rifampicin on alternate days 3 times per week for 2 months (2H3R3) for the 6-month regimen and 5 months (5H3R3) for the 9-month regimen. Streptomycin was given as a 1-gm intramuscular injection. The doses of the oral drugs were isoniazid 15 mg/kg, rifampicin 600 mg, and pyrazinamide 2.5 gm and 2 gm for patients with body weight above and below 50 kg, respectively. All patients received thrice weekly fully supervised treatment in the chest outpatient clinic. In this study a residual lymph node after completion of treatment was not considered failure of treatment as long as its size was decreasing or smaller than 0.5 cm diameter, and it required no additional treatment. Suspicious residual nodes would be reassessed by needle aspiration for cytology or excision biopsy for histology. Primary failure was defined as a persistent residual lymph node at the end of treatment confirmed to be persistent tuberculous lymphadenopathy by fineneedle aspiration cytology or excision biopsy. Relapse was defined as recurrence of a residual lymph node or appearance of a new node confirmed to be tuberculous lymPhadenopathy after a period of initial clinical remission. The period from the date of completion of treatment to the date of first appearance of relapse was used in censoring relapse, and the period from the date of completion of treatment to the date of the last follow-up was used in censoring remission. The life table method and Wilcoxon (Gehan) statistics (SPSS for windows release 6; SPSS, Inc., Chicago, Ill.) were used in the analysis of actuarial remission rate. RESULTS
Of the 91 patients included in the analysis, 43 received the 6-month regimen, and another 48 received the 9-month regimen. The two groups of patients had
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comparable pretreatment clinical parameters as shown in Table 1. The median follow-up period after completion of treatment was 21 months, with the longest follow-up of 66 months. Bacterial cultures for the Mycobacterium tuberculosis were positive in 67 patients. Of the antibiotic susceptibility tests for the streptomycin, isoniazid, rifampicin, and pyrazinamide, 6 (9%) patients had strains resistant to the streptomycin. Other resistant strains and multidrug-resistant strains were not found in the 67 positive cultures. Treatment was not modified for the 6 patients who had strains resistant to streptomycin, and these 6 patients had no subsequent treatment failure. Of the 43 patients in the 6-month regimen, 2 (5%) had primary failure. Of the 48 patients in the 9-month regimen, 1 (2%) had primary failure. The 3% difference is statistically not significant (relative risk, 2.23; 95% confidence interval, 0.21 to 23.76; Fisher's exact test, p = 0.6). Of those 88 patients who had initial clinical remission after completion of treatment, the actuarial remission rates of the two groups are shown in Fig. 1. Of the 41 patients receiving the 6-month regimen, the 5-year actuarial remission rate was 89%; of the 47 patients receiving the 9-month regimen, the 5-year actuarial remission rate was 90%. The 1% difference is statistically not significant (Wilcoxon, p = 0.44). DISCUSSION
The sources of the causative organism of cervical tuberculous lymphadenopathy are multiple. The possible portals of entry for the tubercle bacilli to the cervical lymph node include the lung, 3,4 tonsils, 5 and nasopharynx. 6,7Most patients in this study had progressive enlargement of neck lymph nodes without other symptoms at presentation. We used a combination of needle aspiration for cytology and the Mantoux test as the initial investigation to establish the diagnosis of tuberculous lymphadenopathy.8,9 Before the era of chemotherapy, surgical excision of all the lymph nodes was the main form of treatment. 1° With the introduction of antituberculous chemotherapy in the 1950s, excision of all grossly involved lymph nodes followed by antituberculous chemotherapy from 12 to 24 months was found to be more effective treatment. H,I2 It was later found that lymph node excision was not necessary, and chemotherapy alone gradually became the standard treatment. The duration of chemotherapy has decreased during the years with the use of more effective bactericidal drugs, t3-16 In Hong
YUEN et al. 191
4020 0 0
Fig. 1. Actuarial remission rates of the 6-month a n d 9month regimens.
Kong the thrice weekly 9-month regimen with rifampicin and isoniazid supplemented by streptomycin and pyrazinamide for the first 4 months was commonly used as the treatment of tuberculous lymphadenopathy. The success of a daily 6-month regimen for tuberculous lymphadenopathy was first reported in a retrospective study 16 and later confirmed by a prospective randomized study by Campbell et al. 17 They reported a successful 6-month regimen in the treatment of tuberculous lymphadenopathy of the neck, axilla, and chest wall; the regimen was daily treatment with rifampicin and isoniazid for 6 months supplemented with pyrazinamide for the initial 2 months. A thrice weekly 6month regimen is more convenient than the daily regimen, particularly when supervised treatment is necessary. The use of a thrice weekly 6-month regimen for tuberculous lymphadenopathy was reported in a retrospective nonrandomized study by Jawahar et al.15 They used rifampicin, isoniazid, streptomycin, and pyrazinamide thrice weekly for the initial 2 months followed by twice weekly streptomycin and isoniazid for 4 months. Although their results showed that only 3% of patients had relapses requiring additional treatment, the regimen was criticized because it was not a prospective randomized study, the longest follow-up was only 36 months, and the use of streptomycin and isoniazid for the last 4 months was not optimal. There is no report on the prospective randomized study of the thrice weekly 6-month chemotherapy for cervical lymphadenopathy. The aim of our study is to evaluate the feasibility of our thrice weekly 6-month regimen. Multiple drugs administered for a prolonged period are always required in a standard treatment protocol for tuberculosis to avoid the development of drug-resistant
19:2 YUENet al.
strains. This combination of antituberculous drugs in a thrice weekly supervised regimen is generally well accepted by the patients, as is shown by the low default rate of 4%. Side effects are, however, not u n c o m m o n in our patients. The most common side effect was hepatitis, which occurred between 2 weeks and 5 months after treatment was begun. All of these patients had symptoms of hepatitis with raised liver enzyme levels, but there was no jaundice, and all patients recovered after modification of treatment. Gastrointestinal upset was also a common side effect requiring modification of treatment. Other side effects, including skin rash, tinnims and thrombocytopenia, were uncommon. Although development of drug-resistant strains is becoming a major threat in the treatment of tuberculosis, it is impossible to guide the initial treatment according to culture and antibiotic susceptibility tests becausethe results are not readily available. In this study, in vitro drug-resistant strains were found in 9% of positive cultures, and they were all resistant to streptomycin alone. The treatment regimen was not modified in the presence of streptomycin resistance alone. It has been shown that regimens containing four or five drugs, including rifampicin and pyrazinamide, are effective for the treatment of pulmonary tuberculosis even in the presence of strains resistant to isoniazid and streptomycin. 1,2,18 In the presence of resistance to rifampicin, second-line drugs have to be used with at least two and preferably more drugs to which the organisms are susceptible. This study showed that there was no significant clinical or statistical difference in the remission rate between the 6-month regimen and the 9-month regimen. There was only a 1% difference in the 5-year actuarial remission rate. Additional treatment of 3 more months for those patients who had clinical remission after the 6-month treatment did not further reduce the relapse rate. In view of the insignificant difference in the risk of relapse between the two regimens, it is therefore safe to discontinue the treatment at the end of the 6-month treatment if the patient has clinical remission. However, those patients who do not have clinical remission after completion of the 6-month regimen will still require further treatment. In conclusion, the thrice weekly 6-month regimen
OtolaryngologyHead and Neck Surgery February 1997
4S3H3R3Z3/2H3R 3 can be recommended as one of the alternative initial treatments of choice for cervical tuberculous lymphadenopathy.
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