Japanese Journal of Clinical Oncology Advance Access originally published online on August 22, 2006
Japanese Journal of Clinical Oncology 2006 36(9):570-577; doi:10.1093/jjco/hyl082
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© 2006 Foundation for Promotion of Cancer Research
Randomized Phase II Study of Immunomodulator Z-100 in Patients with Stage IIIB Cervical Cancer with Radiation Therapy
1 Kinki University, 2 Department of Biostatistics/Epidemiology and Preventive Health Sciences, University of Tokyo, Tokyo, 3 Saiseikai Suita Hospital, Suita, Osaka, 4 Department of Obstetrics and Gynecology, Osaka City University, Osaka, 5 Bell-land General Hospital, Sakai, Osaka, 6 Department of Quantum Medical Technology, Kanazawa University, Kanazawa, 7 Department of Radiologic Technology, Tokushima University School of Health Science, Tokushima, 8 Department of Radiology and Radiation Oncology, Gunma University Hospital, Maebashi, 9 Department of Gynecology and Obstetrics, Kyoto University, Kyoto, 10 Department of Radiology, Hakujikai Memorial Hospital, Tokyo, 11 Toki Municipal Hospital, Toki, Gifu, 12 Medical Scanning Shibuya, Tokyo and 13 Department of Obstetrics and Gynecology, Kawasaki Medical School, Kurashiki, Okayama, Japan
For reprints and all correspondence: Keiichi Fujiwara, Gynecologic Oncology, Department of Obstetrics and Gynecology, Saitama Medical University, 38 Morohongo, Moroyama, Iruma, Saitama 350-0495, Japan. E-mail: fujiwara{at}med.kawasaki-m.ac.jp
Received March 9, 2006; accepted June 8, 2006
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Abstract |
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Objective: To find the optimal dose of immunomodulator Z-100 in patients with stage IIIB squamous cell carcinoma of the cervix in combination with radiation therapy.
Methods: The patients were randomly assigned to the dosage levels of 2, 20 or 40 µg of Z-100. Z-100 was subcutaneously injected twice a week during radiotherapy and once in two weeks during the maintenance period. The response rate after radiotherapy was evaluated, and the optimal clinical dosage was then determined. Safety of Z-100 was evaluated during the radiation therapy and maintenance therapy. Survival was also evaluated.
Results: A total of 116 patients were entered. The adverse reactions were not dose-dependent and no serious toxicities were observed. The response rates were 72.2% (26/36) in the 2 µg group, 84.6% (33/39) in the 20 µg group and 94.3% (33/35) in the 40 µg group (P = 0.006). However, the survival was not significantly different.
Conclusions: The optimal dose of Z-100 was determined to be 40 µg in combination with radiation therapy for stage IIIB cervical cancer. However, impact of Z-100 on survival must be determined by the placebo controlled randomized trial, because survival benefit was not observed in this small population study.
Key Words: immunomodulator • cervical cancer • radiotherapy • Z-100 • SSM
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INTRODUCTION |
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Z-100 (ZERIA Pharmaceutical Corporation, Ltd.) is a product extracted from the human-type mycobacterium tuberculosis strain Aoyama B (1,2). It has been on the market as a treatment for leukopenia in cancer patients undergoing radiotherapy in Japan (brand name: Ancer20® injection) (3). Mycobacterium tuberculosis (4) and its extracts (5,6) have shown to have anti-neoplastic effects by enhancing the human immune system. A number of reports describing the anti-neoplastic effects of Z-100 have been published (7–11). It has been considered to be a biological response modifier (BRM).
It is well known that cervical cancer is radiosensitive. However, the prognosis of locally advanced cancer has not always been favorable. A useful strategy would be to combine drugs that have radiosensitivity enhancing effects. A combination of anti-neoplastic BRM such as Z-100 with radiotherapy would therefore be of great interest.
In this study, Z-100 was combined with radiotherapy. To determine the optimal dose of Z-100, the clinical effect on the tumor was evaluated in patients with cervical cancer by assessing the tumor response, which was measurable in a short period, as the primary end point (12,13).
Phase I clinical studies on healthy adult males (14–16), an early phase II study (17), a late phase II study (18) and a phase III study (19) of Z-100 for leukopenia due to radiotherapy have been performed with Z-100. The approved dosage and administration schedule were twice a week at 20 µg subcutaneously during irradiation, up to a dose of 40 µg. In the present study, the optimal dosage for the tumor reduction effect was estimated by comparing three dosages (2, 20, 40 µg) of Z-100. Also, as a reference, we performed a follow-up study and collected the survival data after recording the tumor reduction effects.
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PATIENTS AND METHODS |
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PATIENTS
This study was carried out as a multi-institutional project by 49 nationwide facilities in Japan. The patient registration period was between May, 1992 and April, 1994. Patients with primary cervical cancer who could be treated by radiation alone and who met the following criteria were eligible: (i) histopathologically confirmed squamous cell carcinoma; (ii) FIGO stage IIIB; (iii) Cases with initial treatment; (iv) Size and extension of the primary lesion can be measured or assessed; (v) Age ranging from 16 to 75 years; (vi) Performance status (PS) was 0–3; (vii) No active concurrent cancer; (viii) No serious complications, especially severe dysfunction of the liver, kidney or bone marrow; (ix) Written or oral consent obtained by freewill after the content of the study was explained fully to the patient before the study. Patients with recurrence, pregnant women, nursing mothers, patients with allergies and patients suspected of having para-aortic lymph node metastasis, as assessed by CT scan, were excluded.
This study was carried out according to the ‘Guidelines for clinical study of drugs (Good Clinical Practice )’ (Yakuhatsu no. 874) (20), which took effect on 2 October 1989. Before the study, approval was obtained from the protocol review committee of each institution.
TREATMENT SCHEDULE
The patients were randomly allocated for Z-100 at 2 µg/ml/ampoule, 20 µg/ml/ampoule or at 40 µg/ml (Z-100 20 µg injection in 2 ampoules). Stratification was made by size of the tumor, small and medium (SM) or large (L). The size SM was defined as the size of tumor that is smaller than goose egg, parametrial infiltration to the pelvic wall is unilateral and the severity is mild to moderate. When it is difficult to judge whether the severity is moderate or severe, it should be classified to SM. The size L was defined as the parametrial infiltration to the pelvic wall is unilateral but the size of tumor is bigger than goose egg and the severity is severe, or bilateral parametrial infiltration to the pelvic wall.
Radiotherapy was performed according to the Japanese standard of radiotherapy for cervical cancer (21). Radiation treatment was a combination of external whole pelvic irradiation and intracavitary brachytherapy (ICBT). However, ICBT was not performed until the total dosage of external irradiation reached 30 Gy.
During radiotherapy, Z-100, at 2 µg/ml/ampoule, 20 µg/ml/ampoule or at 40 µg/ml, was injected in the upper arm subcutaneously twice a week separated by a 3–4 day interval. After the completion of radiotherapy, the same dose was applied once every 2 weeks as maintenance for as long as possible (more than 1 year). During the study, no other immunotherapy was performed. During radiotherapy, chemotherapy was also prohibited.
EVALUATION OF TREATMENT
The tumor lesion was measured at the following intervals: before radiotherapy was started; when total dosage of external irradiation was at 15 Gy; at 30 Gy; immediately after radiotherapy was completed; and 4 weeks after radiotherapy was completed. The size and extension of the tumor were assessed by palpation (pelvic and rectal examination) or from the image findings. The response was defined as follows. Complete Response (CR), disappearance of tumor by palpation of the size, or imaging diagnosis; Partial Response (PR), tumor size reduction of 50% or more; Minor Response (MR), tumor size reduction of 25–50%; and No Change (NC), met none of above mentioned criteria. Cases in whom the tumor response was judged as ‘CR’ or ‘PR’ were regarded as responded cases. The response rate was defined as (Number of patients with PR or CR)/Number of total cases.
Response rate was assessed at the time of total dosage of external irradiation of 15 and 30 Gy and 4 weeks after the completion of radiotherapy. Toxicity during the treatment and survival of each group and adverse events during the follow-up period were also examined.
The survival of the patients was investigated for 5 years from the time of registration of the last registered patient.
STATISTICAL ANALYSIS
The response of the tumor was analyzed by the Cochran–Armitage test. The survival was calculated by the Kaplan–Meier method. The survival curve was extended until 5 years after the starting date of radiotherapy of the last patient, and a Log-rank test was performed.
The patients' backgrounds were tested statistically by the chi-squared test or the Kruskal–Wallis H test. For the quantitative values, ANOVA was used. The significance standard was 
= 0.05 (two sided) and P < 0.05 was considered significant. The significance standard for patients' background was = 0.15 (two sided) and the deviation and its effect were evaluated.
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RESULTS |
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TREATMENT OF THE PATIENTS
The treatment flow chart of the patients when the tumor reduction effect was evaluated is shown in Fig. 1. Thirty eight patients in the 2 µg group, 40 patients in the 20 µg group and 38 patients in the 40 µg group, totaling 116 patients, were registered in the study. Among those in the 40 µg group, one patient was mistakenly administered the Ancer20® injection instead of the trial drug. This patient was completely excluded from all analyses (complete exclusion case). Two patients (one in the 20 µg group and one in the 40 µg group) discontinued after two administrations of Z-100 due to adverse reactions.
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These two patients, therefore, lacked the proper number of administrations. Three patients (two in the 2 µg group and one in the 40 µg group) had undergone chemotherapy before radiotherapy was started. As a result, these five patients were considered as protocol deviation cases and only safety was evaluated.
Finally, 110 patients (36 in the 2 µg group, 39 in the 20 µg group and 35 in the 40 µg group) were evaluated for the tumor response. Among these 110 patients Z-100 was discontinued in 6 patients by 4 weeks after the completion of radiotherapy because of the following reasons: progression of the primary disease (1), aggravation of complication or incidental disease (2), patients' request (2) and for surgery (1).
Among the 110 patients who were evaluated for the tumor reduction effect, one patient (in the 2 µg group) was discovered to have been mistakenly administered Ancer20® injection after transition to the maintenance administration and was excluded. Thus, 109 patients (35 in the 2 µg group, 39 in the 20 µg group and 35 in the 40 µg group) were evaluated for survival.
Among the 115 patients evaluated for safety when the tumor reduction effect was evaluated, there were 10 excluded patients. The excluded patients were as follows: one patient who was discovered to have been mistakenly administered an Ancer20® injection after the transition to the maintenance administration; two patients (one in the 20 µg group and one in the 40 µg group) who lacked the number of administrations; six patients (two in the 2 µg group, three in the 20 µg group and one in the 40 µg group) who discontinued administration by 4 weeks after the completion of radiotherapy; and one patient (in the 20 µg group) who could not be on the maintenance administration due to death by aggravation of the primary disease after the completion of radiotherapy. Therefore, 105 patients were evaluated.
PATIENTS' BACKGROUND
The background of the 110 patients who were evaluated for the tumor reduction effect is shown in Table 1. The age distribution showed that there were significantly more patients younger than 59 years in the 40 µg group compared with the other two groups (H test, P < 0.15). The tumor volume (SM, L) distribution showed that there were more patients with tumor size L in the 40 µg group compared with the other two groups and it was a significant deviation (P < 0.1, Chi-squared test). Other factors were equally distributed among each group with no significant differences among groups.
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TUMOR RESPONSE
The summary of the tumor response according to the treatment schedule is summarized in Table 2. The response effective rate at the completion of radiotherapy (external + internal irradiation), which was the chief assessment item in the study, was 72.2% (26/36) in the 2 µg group, 82.1% (32/39) in the 20 µg group and 91.4% (32/35) in the 40 µg group. The effective rates of tumor reduction increased as the dosage increased and these were significant differences (Cochran–Armitage test, P = 0.018). The effective rates at 4 weeks after the completion of radiotherapy was 72.2% (26/36) in the 2 µg group, 84.6% (33/39) in the 20 µg group and 94.3% (33/35) in the 40 µg group and the difference among the dosages became more noticeable (Cochran–Armitage test, P = 0.006). There was significant difference in the effective rate when the total dosage of external irradiation before internal irradiation was 15 Gy. There was no difference at the completion of radiotherapy at 30 Gy.
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There was no difference in the patients classified as size SM (51 patients). However, there was a significant increase of effective rate as the dosage increased in the size L patients (59 patients). The effective rates at the completion of radiotherapy (external + internal irradiation) were 64.7% (11/17) in the 2 µg group, 77.8% (14/18) in the 20 µg group and 95.8% (23/24) in the 40 µg group. The increases in the effective rates as the dosages increased were more noticeable than the tumor reduction effect in all patients (Cochran–Armitage test, P = 0.005).
ADVERSE REACTIONS
The adverse reactions seen at evaluation of the tumor reduction effect at 4 weeks after the completion of radiotherapy are shown in Table 3. The rates of occurrence of adverse reactions were 7.9% (3/38) in the 2 µg group, 10.0% (4/40) in the 20 µg group and 16.2% (6/37) in the 40 µg group. In effect, the rate of adverse reactions increased as the dosage increased. The symptoms were fever, abnormality at the site of injection (redness, fever, swelling, nodule, pain), liver dysfunction (elevation of GPT, GOT), headache and skin rash. All of these have been reported as adverse reactions of Z-100. All reported adverse reactions were not serious and the patients recovered uneventfully without clinical problems.
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LABORATORY DATA ABNORMALITIES
The changes in the averages of each laboratory test data before radiotherapy and 4 weeks after the completion of radiotherapy are shown in Table 4. The tumor markers, both CEA and SCC, showed statistically significant decreases at 4 weeks after the completion of radiotherapy. This appeared to be due to the effect of radiotherapy. Other significant differences, with a significance standard of <5%, were seen in the red blood cell count in the 20 µg group; the white blood cell count in all groups; neutrophils in the 20 µg group; lymphocytes in all groups; eosinophils in the 2 µg group; monocytes in the 2 µg group and the 20 µg group; platelet count in all groups; total protein in the 20 µg group; GOT in the 40 µg group; total bilirubin in the 2 µg group and the 40 µg group; creatinine in the 2 µg group; and Na in the 40 µg group. These were all judged as the changes within normal limits or due to the effect of radiotherapy.
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SURVIVAL
The survival curves extended to 5 years after the last registered patient started radiotherapy are shown in Fig. 2 (Kaplan–Meier method). The 5 year survival was 59.2% (95% CI: 42.7–75.7%) in the 2 µg group, 59.6% (95% CI: 43.8–75.4%) in the 20 µg group and 47.4% (95% CI: 30.6–64.2%) in the 40 µg group, but the Log-rank test did not deem them as significant differences (P = 0.598).
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The summary of adverse events observed in the 105 patients who were transferred to maintenance administration is shown in Table 5. The rate of occurrence of adverse reactions was 5.7% (2/35) in the 2 µg group, 8.6% (3/35) in the 20 µg group and 2.9% (1/35) in the 40 µg group. No relationships were evident among the dosages. Skin rash was seen in one patient in the 20 µg group. As for new symptoms, shingles was seen in one patient in each group, back pain in one patient in the 20 µg group, bilateral knee joint pain in one patient in the 20 µg group and right leg pain in one patient in the 40 µg group. None of them was serious.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Radiotherapy for cancer patients is often accompanied with BRM because it is able to improve hematopoiesis and enhance the antitumor activity of irradiation. Various BRMs, such as streptococcal preparation OK-432 (22), 1
3-ß-D-glucan (23,24), heat-killed Lactobacillus casei preparation (25), alpha-galactosylceramide (26) and CpG oligodeoxynucleotide (27), have been reported to enhance the antitumor activities of radiotherapy in clinical or pre-clinical trials. These reports indicated that the combination of radiotherapy and immunotherapy could be useful in treating patients with cancer through augmentation of host defense mechanisms by immunotherapy. The present study evaluated whether Z-100 could enhance the effect of irradiation and also tried to determine the optimal dosage of Z-100 from the point of view of effectiveness and safety using the tumor response as an end point in patients with cervical cancer (28,29). The results demonstrated the dose response of Z-100 by assessment of reduction of tumor size. The strongest effect was seen in the 40 µg group, which was the maximum dosage. The tumor size reduction effect was more significant when the tumor size was larger. This is an important observation. Because, as larger tumor size is a predictive factor for poorer prognosis, it will be beneficial if Z-100 can improve the response and hopefully the survival of the patients with poor prognosis. It appeared that the effect of radiotherapy is emerging at the time of completion of radiotherapy and becomes clearly manifested 4 weeks later.
The safety of Z-100 for cancer patients has been proven as a commercially available Z-100 for the treatment of radiation therapy-induced leukopenia. No relationship to dosage was evident. All the adverse events that developed with the maximum dosage in the 40 µg group was minor. Therefore, 40 µg was confirmed as the safe and maximum dosage of Z-100. The safety of prolonged use of Z-100 at 40 µg was also confirmed in the study. Therefore, it will be feasible to perform a randomized phase III trial to investigate the true value of Z-100 taking survival as the primary endpoint, as suggested by the Japanese guideline for the clinical evaluation of anti-neoplastic BRM, published in 1993.
We admit the limitation of the current study, that is, the fact that the trial drug was not blinded. The fact that assessment of tumor reduction included a palpation by the physician is also another weakness. Another concern is the fact that survival was not different between 2, 20 and 40 µg group. The sample size of the study was not sufficient to test the survival because it was not the primary endpoint. We have conducted a phase III double-blind randomized trail to investigate the clinical usefulness of Z-100 to compare the efficacy of 0.2 and 40 µg of Z-100, focusing on tumor response, overall survival and progression-free survival as the clinical endpoints. The results are in press for publication in Gynecologic Oncology.
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Acknowledgments |
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The authors acknowledge Isamu Saida and Kazuhiro Matsumoto, ZERIA Pharmaceutical Co., Ltd for their collaboration. The authors also thank their colleagues who participated in this trial. This work was supported by ZERIA Pharmaceutical Co., Ltd, Tokyo, Japan.
Participating Institutions (Japan): Sapporo Medical University Hospital, Hokkaido University Medical Hospital, National Sapporo Hospital, Asahikawa Medical College Hospital, Hirosaki University School of Medicine Hospital, Tohoku University Hospital, Sendai National Hospital, Miyagi Prefectural Cancer Center, Akita University Hospital, Gunma University Hospital, Kitasato Instiute Medical Center Hospital, Tokyo Womens' Medical University Hospital, Tokyo Medical University Hospital, Keio University Hospital, Komagome Hospital, Nippon Medical School Hospital, National Tokyo Medical Center, Nippon Medical School Second Hospital, Yokohama City University Hospital, Kitasato University Hospital, Niigata University Medical Hospital, Niigata Cancer Center Hospital, Kanazawa University Hospital, Shinshu University Hospital, Aichi Cancer Center, Nagoya National Hospital, Nagoya University Hospital, Shiga University of Medical Science Hospital, Kyoto Prefectural University of Medicine, Kyoto University Hospital, Osaka National Hospital, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka City University Hospital, Kansai Medical University Hospital, Kinki University Hospital, Kobe City General Hospital, Hyogo Medical Center for Adults, The Hospital of Hyogo College of Medicine, Okayama University Hospital, Kawasaki Medical School Hospital, Hiroshima University Hospital, Hiroshima General Hospital, National Kure Medical Center, Yamaguchi University School of Medicine, University of Tokushima, National Kyushu Cancer Center, Kyushu University Hospital, Nagasaki University Hospital, Beppu National Hospital.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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