1949
Effect of LC9018 Combined with
Radiation Therapy on Carcinoma
of the Uterine Cervix
A Phase 111, Multicenter, Randomized, Controlled Study
Tomohiko Okawa, M.D.," Hideo Niibe, M.D.,t Tafsuo Arai, M.D.J.
Kaoru Sekiba, M.D.,Ej Kiichiro Noda, M.D., I( Shoshichi Takeuchi, M.D.,ll
Shozo Hashimoto, M.D.,# and Nobuya Ogawa, M.D.**
Background. The failure rate with radiation therapy
alone for Stage 111cervical cancer is quite high, and there-
fore other modalities are being pursued as adjuvants to
radiation therapy in hopes of improving the results.
Methods. A randomized, controlled, comparative
study on the efficacy and safety of radiation therapy com-
bined with LC9018 (a biologic response modifier pre-
pared from heat-killed Lactobacillus casei YIT9018) was
conducted using 228 patients with Stage IIIB cervical
cancer.
Results. LC9018 enhanced tumor regression (P < 0.1)
by radiation after both 30 Gy of external radiation and at
the completion of radiation therapy. The combination
therapy also prolonged survival and the relapse-free in-
terval (P< 0.05) compared to radiation alone. Analysis of
survival using the Cox proportional hazard model indi-
cated that use of LC9018 was a significant factor related
to survival duration. Major side effects of combined
LC9018 included fever and skin lesions at the injection
site, but no severe symptoms were noted. Radiation-in-
duced leukopenia was significantly less severe (P < 0.05)
in the LC9018-combined group than in the radiation-
alone group, suggesting that this agent might help to pre-
vent leukopenia during radiation therapy.
From the Departments of Radiology, *Tokyo Women's Medical
College, Tokyo, and tGunma University School of Medicine, Gunma;
the $Division of Hospital, National Institute of RadiologicalSciences,
Chiba; the Departments of Obstetrics and Gynecology, GOkayama
University School of Medicine, Okayama, and IIKinki University
School of Medicine, Osaka; the TClinical Division, BiotechnologyRe-
search Center, Teikyo University, Kanagawa; the #Department of
Radiology, Keio University School of Medicine, Tokyo; and the **De-
partment of Pharmacology, Ehime University School of Medicine,
Ehime, Japan.
Address for reprints: Tomohiko Okawa, M.D., Department of
Radiology, Tokyo Women's Medical College, 8-1, Kawada-cho, Shin-
juku-ku, Tokyo 162, Japan.
Accepted for publication April 28, 1993.
Conclusions. LC9018 was shown to be an effective
agent for adjuvant immunotherapy when combined with
radiation therapy. Cancer 1993; 72:1949-54.
Key words: biologic response modifier, adjuvant therapy,
cervical cancer, radiation therapy, Lactobacillus casei.
Radiation therapy has played an important role in
treating carcinoma of the uterine cervix, and has con-
tributed to an improvement in the cure rate.'-' Radia-
tion, however, also has its limitations in the treatment
of progressive cancer, as does surgery. For more effec-
tive radiation therapy, it is necessary to improve the
local control rate (a major prognostic factor) as well as
prevent recurrence and metastasis, which unfortu-
nately still are too common even after curative irradia-
tion. Accordingly, extensive studies on radiation sensi-
tizers and adjuvant therapy have been performed,
including radiation therapy combined with chemother-
apy or immunotherapy.
Nonspecific immunotherapy, primarily with bio-
logic response modifiers (BRM), can be used to activate
the immune system after its suppression by radiati~n.~,'
LC9018 (Yakult Honsha Co., Ltd., Tokyo, Japan) is a
kind of BRM prepared from heat-killed Lactobacillus ca-
sei YIT9018, a nonpathogenic bacterium of human on-
gin that has long been used to manufacture drinking
yogurt in Japan. Animal studies showed that LC9018
could inhibit the growth and metastasis of implanted
tumors, and extend survival.*-" It also inhibited the
proliferation of pathogens such as Pseudomonas aeru-
ginosa and Listeria rnonocytogene~."-'~ The antitumor
and antiinfectiveactivitieswere found to be due to mac-
rophage activated by LC9O18,8,l4 and subsequent en-
hancement of myelop~iesis'~~'~ in the treated animals. It
1950 CANCER September 15, 1993, Volume 72, No. 6
also has been reported that LC9018 induced the produc-
tion of cytokines such as interferons,16colony-stimulat-
ing factors,I3and interleukins-1 and -TI7
Our previous randomized, controlled trial using 61
patients with FIGO Stage IIB or I11 cervical cancer
showed that radiation therapy combined with LC9018
produced significant tumor reduction enhancement
after cumulative doses of 15 and 30 Gy of external irra-
diation.” LC9018 also was shown to augment the histo-
logic effect of radiation therapy.
Other investigators’’ have performed a compara-
tive randomized study of LC9018 with doxorubicin and
doxorubicin alone for the treatment of malignant
pleural effusion secondary to lung cancer, and reported
intrapleural LC9018 therapy was useful for the treat-
ment of malignant pleural effusions.
The current report shows the results of a multi-
center, randomized, controlled, comparative study that
was carried out to evaluate whether LC9018 could en-
hance tumor regression and prolong survival in irra-
diated patients with Stage IIIB uterine cervical cancer.
Patients and Methods
The study was carried out by a cooperative study group
of 50 institutions. Patients were registered with a cen-
tral telephone order system during the period from Feb-
ruary, 1987 to January, 1989, and were followed up
until February, 1991.
Patients with FIGO Stage IIIB squamous cell carci-
noma of the uterine cervix who were newly treated
with radiation therapy were studied. The following
women were excluded: aged 76 years or older, a perfor-
mance status (World Health Organization classifica-
tion) of 4, those with active double cancer, those with
paraaortic nodal metastasis on computed tomography
or lymphangiography, and those with serious compli-
cations. Informed consent was obtained before enroll-
ment.
Patients were stratified according to tumor volume
into a group with small- to medium-sized lesions (mild
to moderate unilateral pelvic wall involvement) and a
group with large tumors (severe unilateral pelvic wall
invasion or bilateral involvement), and were then ran-
domly allocated to receive either radiation therapy with
LC9018 (RT-LC group) or radiation therapy alone (RT
group).
Radiation therapy was performed according to the
rationale of each institution; however, external irradia-
tion generally consisted of 25-30 Gy of whole-pelvis
irradiation and 20-30 Gy of centrally shielded irradia-
tion, for a total dose 2 45 Gy. Fractions of 1.8-2.0 Gy
were administered 5 days per week. Intracavitary ther-
apy generally was delivered as 40-45 Gy of low-dose
rate irradiation (in 3-4 fractions) or 24-30 Gy of high-
dose rate irradiation (in 4-7 fractions) on the basis of
the dose at point A. Intracavitary therapy generally was
preceded by 30 Gy of external radiation.
Based on the results of a previous Phase I1 trial,I8
LC9018 was administered intradermally at a dose of 0.1
mg twice a week or 0.2 mg once a week during radiation
therapy, and afterward at 0.1 mg/2 weeks or 0.2 mg/
month for 2 years or until tumor recurrence. Both
groups also received adjuvant chemotherapy orally
with 5-fluorouracil (200 mg/day) for 6 months after
radiation therapy.
Periodic assessment was made of tumor regression,
histology, immunologic parameters, tumor markers,
side effects, and routine laboratory tests. The tumor re-
sponse to treatment was graded as follows: complete
response (CR), partial response (PR, a 2 50% decrease
in tumor size), minor response (MR, a 2 25% decrease
in tumor size), or no change (NC), measuring the size
and extent of the tumor and the uterine mobility by
pelvic examination or imaging diagnosis. The histologic
effect of therapy was evaluated according to Shimosato
et al.’s criteria.*’
The patients’ eligibility for analysis as well as
the efficacy of treatment were judged by the study com-
mittee.
Statistical Analysis
Data were analyzed by group comparison using the fol-
lowing statistical methods: the chi-square test or the
Fisher exact probability test for patient characteristics
and abnormal laboratory data, the Mann-Whitney U-
test for tumor response and histologic effect, and the
chi-square test, the Fisher exact probability test, or the
U-test for the relative incidences of side effects. Sur-
vival and recurrence rates were calculated by the Ka-
plan-Meier method, and the log-rank test was used to
determine the significance of differences in survival
and recurrence. Factors related to survival were deter-
mined by multivariate analysis using the Cox propor-
tional hazard model.’l
Results
Pa tien t Profile
Two hundred twenty-eight patients (112 in the RT-LC
group and 116 in the RT group) were registered. Fifteen
of them subsequently were excluded because of prior
radiation therapy (4), erroneous registration of tumor
volume (2), failure to receive radiation therapy (2),
Stage IV disease (5), failure to receive LC9018 (l),and
incorrect administration of LC9018 in the RT group (I).
Of the 213 subjects eligible for the assessment of safety
LC9018 and Radiation for Cervical CancerlOkawa et al. 1951

Table 1. Patient Characteristics Table 1 shows the characteristics of the 2 13 eligible

~~ ~~

RT-LC Statistical patients who fulfilled the entry criteria. No significant

Factor group RT group analysis biases were present between the RT-LC and RT groups
Tumor volume in relation to the following background factors: tumor
Small-medium 56 55 NS* volume, age, performance status, histologic grade,
Large 46 56 menopausal status, and intravenous pyelography find-
Age (yr) ings. There also were no differences between the
30-39 2 1 NS* groups with regard to the cumulative doses of external
40-49 11 11 and intracavitary irradiation.
50-59 30 24
60-69 33 43
Tumor Response and Histology
70-75 26 32
Performance
status Table 2 shows the tumor response observed after 30 Gy
0 59 77 NS' of irradiation (before intracavitary irradiation) and at
1 35 24 the completion of radiation therapy. CR or PR was
2 4 6 achieved in 54.7% (52/95) of the patients after 30 Gy of
3 4 4 radiation in the RT-LC group, andin 41.1% (44/107) of
Histologic the RT group (P < 0.1, U-test). At the completion of
cell type
radiation therapy, CR was achieved in 53.7% (51/95)
LNK 69 77 NS*
of the RT-LC group and in 42.1% (45/107) of the RT
SNK
K
8
21
7
19
-=
group (P 0.1, U-test).
Unknown 4 8 A histologic effect (percent of patients with 2
Menopausal Grade 3 changes according to Shimosato et al.'s criteria)
status was noted in 33.8% (27/80) of the RT-LC group and
Pre 16 11 NS" 31.9% (30/94) of the RT group after 30 Gy of radiation,
Post 86 100 and in 86.0% (80/93) and 86.5% (90/104), respec-
IP findings tively, at the completion of radiation therapy. No dif-
Bilateral
normal kidneys 79 83 NS" ference was detected between the two groups.
Unilateral
normal kidney 20 22 Survival and Recurrence
Bilateral
hydronephrosis 3 6
Figure 1 shows the survival curves for the 211 eligible
Cumulative external
radiation dose 40.0-75.0 29.0-66.0 NSt
subjects analyzed (94 in the RT-LC group and 107 in
(Gy) (mean k SD) (51.7 ? 6.3) (51.1 ? 5.4) the RT group). The 4-year survival rate was 69.2% for
Cumulative intracavitary the RT-LC group and 46.2% for the RT group, with a
radiation dose, point A 9.6-70.0 0.0-58.3 NSt significant difference (P < 0.05, log-rank test). In addi-
*
(Gv) (mean S.D.) (29.3 k 10.8) (28.4 k 10.51 tion, when the 201 patients who completed the therapy
R T radiation therapy; LC: LC9018;NS: not significant; LNK nonkeratinizing were assessed, the duration of survival still was signifi-
large cell type; SNK nonkeratinizing small cell type; K keratinizing type; IP:
intravenous pyelography. cantly longer in the RT-LC group.
* By chi-square test. Figure 2 shows combined recurrence and recrudes-
t By Student t test. cence curves for 183 patients (87 RT-LC and 96 RT)
whose tumors had been eliminated (CR) or reduced in
size (PR) at the completion of radiation therapy. The
(102 in the RT-LC group and 111 in the RT group), 11 4-year recurrence rates were, respectively, 33.5% and
failed to complete treatment owing to the lack of intra- 51.5% for the RT-LC and RT groups (P < 0.05, log-rank
cavitary irradiation (7), discontinuationof LC9018 dur- test). There was no difference between the two groups
ing radiation therapy (3), and death during radiation with regard to the type of recurrence (local versus dis-
therapy (1).Thus, 202 subjects (95 RT-LC and 107 RT) tant).
managed to complete the specified treatment. The pa- Table 3 shows the analysis of survival using the
tient who died during radiation therapy and one other Cox proportional hazard model in 201 patients who
patient who died immediately after the completion of completed therapy. The analysis was performed in re-
radiation therapy were excluded from the analysis of lation to eight factors, including the use of LC9018, tu-
survival and recurrence. Ten patients who died of unre- mor volume, age, histologic diagnosis, tumor response,
lated causes during the follow-up period were analyzed histologic effect after 30 Gy of radiation, and the nadir
as censored cases. of the hemoglobin and leukocyte counts. Each factor
 1952 CANCER September 25, 2993, Volume 72, No. 6

Table 2. Tumor Response

After 30 Gy At t h e completion
of radiation of radiation therapy

RT-LC RT-LC
Tumor response group RT group group RT group
CR 2 1 51 45
PR 50 43 37 51
MR 31 48 6 7
NC 12 15 1 4
CR rate (YO) 2/95 (2.1) 1/107 (0.9) 51/95 (53.7) 45/107 (42.1)
CR + PR rate
(%) 52/95 (54.7) 44/107 (41.1) 88/95 (92.6) 96/107 (89.7)
U test P = 0.085 P = 0.094

R T radiation therapy;LC: LC9018; CR complete response; PR partial response;M R minor response; NC: no change.

was divided into two categories so that there was no
excessive bias regarding the number of patients in any
category. Age was divided so as to be well balanced
with respect to the actual measured values. In the case
of missing or unclassifiable data, the mean values ob-
tained after excluding these data were used. Tumor re-
gression, tumor volume, age, leukocyte count, the use
of LC9018, and the extent of histologic damage after 30
Gy of radiation all were shown to be factors with a
significant effect on survival.
Side Effects
Table 4 lists the side effects induced by the two regi-
mens. LC9018 caused fever in 9 (8.8%) of the 102 eligi-
ble patients fulfilling the entry criteria, and there was a
significant difference between the RT-LC and RT
groups (P < 0.05, Fisher exact probability test). The
fever, however, was mild (I 39"C), transient, and re-
solved after several days in all cases. Radiation caused a
high incidence of diarrhea, anorexia, and other side ef-
fects, but no significant differences were noted between
the two groups. These symptoms also disappeared
spontaneously with the completion of radiation
therapy.
Local reactions noted at the site of LC9018 injection
included pain (20.6%), tenderness (19.6%), erythema
(42.2YO), induration (32.4YO), swelling (24.5Yo), abscess
formation (15.7%), and necrosis (2.0%). Induration and
swelling resolved after 1-2 weeks of treatment with
cold, moist dressings. Abscesses and localized necrosis
resolved or improved within 2 weeks after cleansing
and the application of antibiotic ointment.
Laboratory Abnormalities
Table 5 shows the major abnormal laboratory findings.
The incidence of leukopenia was 26.7% (27/101) in the
RT-LC group and 48.2% (53/110) in the RT group (P <
0.05, chi-square test). The incidence of neutropenia also

100-
\:ool
80 Logrank test
lLL, 80- P =O. 045
h RT-LC group h

5 7x,. 69.2% (100 cases) $

60-
--.---
%--%

al
4-
LL_____, 3 60-
-F L--RT group L

0
__-_____
---__--RT group
9
._ 40- 46.2% ( 1 1 1 cases) 2 ,#>-*-LL---LY
I L L
51.5% (96 cases)
>
L $ 40-
RT-LC group
In 20- P=0.039
Logrank test 22 20- / - ! I 33.5% (87 cases)

07 . . . . . . . . . . . . . . . . . . . . . . . .
0 100 200 week 03 . . . . . . . . . . . . . . . . . . . . . . .
Lc9018 and Radiation for Cervical Cancer/Okawa et al. 1953

Table 3. Analysis of Survival Using Table 5. Major Abnormal Laboratory Findings

Cox Proportional Hazard Model Statistical
Hazard Item Grouo Incidence analysis*
Factor Coefficient P value ratio Hemoglobin/ RT-LC 13/101 (12.9) NS
LC9018 (presence/absence) 0.641 0.020 1.90 RT 24/111 (21.6)
Tumor volume (small- Leukocytes/ RT-LC 27/101 (26.7) P=0.002
medium/large) 0.807 0.004 2.24 RT 53/110 (48.2)
Age (559/2 60) (yr) -0.708 0.008 2.03 Neutrophils4 RT-LC 4/101 (4.0) P= 0.004
Histologic cell type RT 19/110 (17.3)
(keratinizing/nonkeratinizing) -0.448 0.174 1.57 GOT? RT-LC 3/101 (3.0) NS
Tumor regression (CR/< PR) 0.938 0.001 2.56 RT 2/111 (1.8)
Histologic damage after 30 Gy of GPTt RT-LC 3/101 (3.0) NS
radiation (Grades 0-II/III-IV) -0.660 0.036 1.94
RT 5/111 (4.5)
Nadir hemoglobin count
(grades O / r 1) 0.432 0.201 1.54 R T radiation therapy; LC: LC9018; NS: not significant; GOT: AST (aspartate
aminotransferase); GPT:ALT (alanine aminotransferase).
Nadir leukocyte count
(grades O / h 1) -0.766 0.009 2.15 * By either chi-square test or Fisher exact probability test.

CR: comulete resoonse: P R Dartial resuonse.

Discussion
was significantly lower in the RT-LC group than in the There is a paucity of literature on the use of radiation
RT group. There were no significant differences be- therapy combined with BRMs for progressive uterine
tween the two groups with regard to the other labora- cervical cancer. Okamura et a1.6 conducted a compara-
tory abnormalities. The leukocyte and neutrophil tive trial in 220 patients with Stages I1 and 111 cervical
counts returned to normal after radiation therapy was cancer using the polysaccharide sizofiran prepared
completed. from Schizophyllum commune Fries. They reported that
radiation with this BRM was more effective than radia-
Immunologic Parameters and Tumor Markers tion alone, because it enhanced tumor response and
extended the interval until recurrence and also ex-
Serial tests of phytohemagglutinin blastogenesis and tended the survival period in patients with Stage I1 dis-
the intradermal reaction to purified protein derivative ease. Noda et al.' compared the therapeutic effect of
(tuberculin) (PPD) showed no significant changes and surgery with postoperativeirradiation or radiation ther-
no marked differences between the two groups. Squa- apy alone to those with or without adjuvant OK-432 (a
mous cell carcinoma-related antigen and carcinoem- Streptococcus pyogenes type A preparation) in 382 pa-
bryonic antigen levels also were monitored. The squa- tients with Stages IB-IV cervical carcinoma, and re-
mous cell carcinoma-related antigen level decreased ported a significant prolongation of the recurrence-free
rapidly after the initiation of treatment in both groups, interval by the addition of OK-432 therapy.
whereas no clear changes were noted for carcinoem- With respect to the combination of radiation and
bryonic antigen. chemotherapy, numerous neoadjuvant and adjuvant
therapies have been tried, and cisplatin has shown
Table 4. Side Effects some p r ~ m i s e , but
~ ~ ,no
~ ~ prospective, randomized,
controlled study of cisplatin has been published.
Statistical There are noteworthy studies on radiosensitizers.
Symptom Group Incidence analvsis'
Hreshchyshyn et al.24used hydroxyurea or placebo
Fever RT-LC 9/102 (8.8) P=0.013 combined with radiation to treat 90 evaluable patients
RT 1/111 (0.9) with advanced squamous carcinoma of the cervix, and
Anorexia RT-LC 27/102 (26.5) NS reported hydroxyurea enhanced tumor regression and
RT 36/111 (32.4)
prolonged the progression-free interval and survivalpe-
Diarrhea RT-LC 39/102 (38.2) NS
riod. Stehman et aL2' performed a randomized, con-
RT 42/111 (37.8)
7/102 (6.9) NS
trolled study on radiation therapy combined with hy-
Abdominal pain RT-LC
RT 6/111 (5.4)
droxyurea or misonidazole for 296 evaluable patients
Otherst RT-LC 5/102 (4.9) NS with Stage IIB-IVA cervical cancer, showing that hy-
RT 11/111 (9.91 droxyurea extended the progression-free interval and
RT: radiation therapy; LC: LC9018; NS: not significant.
controlled intrapelvic recurrence. Because the study
* By either chi-square test or Fisher exact probability test. was performed according to a well designed protocol,
t RT-LC: rash (3). fatigeu (l), and nausea/vomiting (1).R T nausea/vomiting hydroxyurea appears to be a promising radiosensitizer;
(7), fatigue (I), abdominal discomfort (I), dizziness (I), and hemorrhage (1). however, side effects such as bone marrow suppression
1954 CANCER September 15, 1993, Volume 72, No. 6
and gastrointestinal toxicity frequently were observed
in the treated patients.
The current randomized, controlled, comparative
study on intradermal LC9018 therapy combined with
radiation to treat cervical cancer revealed augmented
tumor regression and a significant extension of the sur-
vival and recurrence-free intervals in the RT-LC group
in comparison with the RT group. LC9018 therapy also
was confirmed to be a significant factor affecting sur-
vival by multivariate analysis using the Cox propor-
tional hazard model. The major side effects of LC9018
included skin lesions at the site of injection and fever,
but these were mild and did not prevent the continua-
tion of treatment.
Nomoto et a1.26 gave LC9018 subcutaneously to
mice after whole-body irradiation, and reported an in-
crease in serum colony-stimulating activity and subse-
quent enhanced recovery of the number of colony-
forming units for granulocytes and macrophages in the
bone marrow and spleen. There also was an improve-
ment of survival, suggesting the possibility of this agent
for treating myelosuppression during or after radiation
therapy. The less severe leukopenia and neutropenia in
the RT-LC group in our study also indicated that
LC9018 could be beneficial for preventing radiation-in-
duced leukopenia.
Thus, LC9018 is thought to be a useful agent for
adjuvant immunotherapy combined with radiation
therapy, and further studies are required to determine
its possible benefits in other types of progressive cancer.
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