YUICHI YAMAMUKA,
MD,* MITSUNOKISAKATANI,MD,
TAKESHI
OGURA,MD, A N D ICHIROAZUMA,PHD

Four hundred fifty-five patients with lung cancer were treated with oil-attachedcell-wall skeleton of bacillus Calmette-Guerin (BCG-CWS) as adjuvant immunotherapy following initial conventional therapy. The overall survival
period of the patients was prolonged significantly as compared with that of 380
patients in a historical control group receiving initial conventional therapy
alone (p < 0.0001). The prolongation of the survival period of the patients was
also statistically significant when classified according to clinical stages andhistological cell types. The therapeutic effect was remarkable in patients combined with malignant pleurisy. Intrapleural injection of BCG-CWS resulted
in not only prevention of accumulation of pleural effusion and abrogation oftumor cells but also in prolongation of survival period (p = 0.016). No serious
side effects due to BCG-CWS were experienced. From the previous experimental studies and clinical experiences with human tumors, it can be concluded
that adjuvant immunotherapy with BCG-CWS is a useful therapeutic modality
for lung cancer, especially in cases combined with malignant pleurisy.
Cancer 43:1314-1319, 1979.

T

10970142, 1979, 4, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/1097-0142(197904)43:4<1314::AID-CNCR2820430420>3.0.CO;2-6 by Cochrane Japan, Wiley Online Library on [25/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

ADJUVANT IMMUNOTHERAPY OF LUNG CANCER W I T H
BCG CELL WALL SKELETON (BCG-CWS)

PATIENTSA N D METHODSBENEFITS of immunotherapy with bacillus Calmette-Gukrin
Patients(BCG) €or human cancer have been confirmed
in prolonging the survival period of the paA total of 455 patients with primary lungtients as well as duration of remission of the cancer- treated in our collaborative group condisease.3,5.8.9~13,14.’5.1Y
However, many investi- sisting of 11 hospitals were entered in thisgators have also noticed various kinds of seri- study between April 1974 and December
ous side effects during the therapy.3,11.1z,20,21.2”
1976. All patients were classified to either
In previous studies, we have shown that cell- squamous cell carcinoma, adenocarcinoma,
wall skeleton (CWS), having a principal struc- small cell carcinoma or large cell carcinoma by
ture of mycolic acid-arabinogalactan-muco- histological examination of the sputum,
peptide complex, is a biologically active pleural fluid and/or biopsy material.
component in irnrnunopotentiati~n.~~~~~~~~
ReClinical staging was done according to thecent studies have demonstrated that the classification by M 0 ~ n t a i n . lAll
~ patients rematerial has a potent immunotherapeutic ceived initially conventional therapy such as
effect on human tumors as well as ani- surgery, irradiation and/or chemotherapy.
mal tumors when given in oil-attachedOil-attached BCG-CWS was prepared byform.2.16,28,29,30.31,32
the same method as used p r e v i o u ~ l y . ~ ~ , ~ ~ ~ ~ ~This report expands our initial cooperative
clinical study with the use of BCG-CWS for Procedure of Immunotherapy withimmunotherapy of lung cancer patients in 11 BCG-CWS
collaborative hospitals.
In principle, treatment with BCG-CWS was
introduced following the initial conventional
From the Third Department of Internal Medicine, therapy, and in some cases during the therMedical School, Osaka University, Osaka, Japan.
apy. After skin test with 10 pg of BCG-CWS,* Professor and chairman.
Address for reprints: Yuichi Yamamura, MD, in most cases 200 to 400 p g of oil-attachedBCG-CWS was administered weekly or biFukushima-ku, Osaka, 553 Japan.
Accepted for publication May 22, 1978.
weekly into the skin of bilateral upper arms as
H E CLINICAL

0008-543)(/79/0400/ 1314 $0.80 0 American Cancer Society1314

BCG-CWS LUNGCA THERAPY*
Yninamuru et al.

induction of the immunotherapy. In somecases, the same dose of BCG-CWS was injected
directly into the intrathoracic unressectable
tumor at surgery, intrabronchial tumor withbronchofiberscope, or cutaneous metastatic
tumor. In 55 patients combined with malignant pleurisy histologically certified, BCGC WS was injected repeatedly into the affected
pleural cavity at one or two weeks intervals.
Following several injections of BCG-CWS as
mentioned above, patients were referred tomaintenance therapy, in which 100 or 200
p g of BCG-CWS was injected monthly into theskin of bilateral upper arms. The termination of the therapy was not fixed.
When patients showed hyperreaction at initial skin test with BCG-CWS or during thetreatment with BCG-CWS, the dose given was
adequately reduced.

Evaluation of Immunotherapy
Three hundred eighty lung cancer patientsin the same hospital, who had conventional
therapy alone between April 197 1 and March
1974 were used as historical control^.^ Not included in the control group are patients whosecell types were out of the four cell types mentioned above. T h e distribution of the majorclinical features which have been known to a€fect a prognosis of the disease is shown in
Table 1." T h e sex of the patients and themodality of the initial conventional treatment
including irradiation and operation were alittle different in distribution between theboth groups.
T h e effect of the immunotherapy wasevaluated in terms of survival period from adm i ~ s i o nSurvival.~
rate was calculated with life
table method and the difference between bothgroups was evaluated statistically by thegeneralized Wilcoxon test according toGeha n.

1315

TABLE
1. Major Clinical Features of Patients

Clinical features
Cell types
Squamous cell
carcinoma
Adenocarcinoma
Snrall cell
carcinoma
Large cell
carcinoma
Clinical stages
I
11
111

BUX\VS
treated(455 cases)

Contt-ol(380 cases)

38.2% (174)44.7% ( 1 70)

42.6

(194)

38.4

(146)

14.5

(65)

10.8

(41)

4.1)

(22)

6.1

(23)

NS

11.9% (.54)
12.5 (57)
7.5.6 (344)

10.5% (40)13.2 (50)76.3 (290)NS

73.8%, (366)26.2 (119)60 2 1 0

80.5% (306)19.5 (74)
ti2 2 10p < 0.05
NS

34.7% (158)56.3 (256)69.9 (318)
2.6 (12)
1974-1976

23.910 (91)66.1 (251)65.8 (250)
3.9 (15)197 I - 1974

Chi2 teat

Sex

Male
FemaleAge (years)'l'reatments
Ope[-ation
I rraciiation
Chemolherap)
Conservative
Patients entry

p < 0.0.5
p < 0.05
NS

NS

Numher of patients is indicated i n parentheses
NS: not significant.

periods of the patients according to histological cell type and clinical stage. T h e patientswith small cell carcinoma at various clinicalstages were evaluated inclusively in one
group, because they were too small in number
to be classified according to clinical stages.
T h e prolongation of survival period in immunotherapy group was also significant (p= 0.0008).
1

REsuLT s
Survival Period
One hundred sixty-three patients in the
immunotherapy group and 39 patients in the-1
control group are still alive as of April 1977.
p <O.OOol
T h e survival rates of all patients in the both
(Wikoxm-Gehen test)
0groups are shown in Fig. 1. T h e 50% survival
6
12
18
24
rates of all patients were 13.5 and 8.5 months
M~fithsfrom admission
in the immunotherapy and control group.
The difference was statistically significant (pFIG. 1. T h e survival of all patients. T h e survival rates< 0.0001). Table 2 shows 50% survival are depicted in SE.

10970142, 1979, 4, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/1097-0142(197904)43:4<1314::AID-CNCR2820430420>3.0.CO;2-6 by Cochrane Japan, Wiley Online Library on [25/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

No. 4

VOl. 43

TABLE
2. Fifty percent Survival According to Histological Cell Type and Clinical Staging
50% survival months
Statisticalsignificance( Wilcoxon-Gehan)

ClinicalstagesBCG-CWS
group

Control
group

Small cell carcinoma

I , 11, 111

11.0
(65)

5.5
(41)

p = 0.0008

Large cell cdrcinomd

I, 11, 111

11.0

7.5
(23)

NS

(22)

Histological cell types

Squanious cell carcinoma and adenocarcinoma

I , I1>23.0*
(90)

23.0
(74)

NS

Squamous cell carcinoma

111

12.0
(123)

8.0
(141)

p = 0.0005

Adenocarcinorna

111

12.0
(155)

6.5
(101)

p < 0.0001* The patients are still alive at 70%.

NS: not significant

Number of patients is Indicated in parentheses

I n large cell carcinoma, the 50% survival and 155 patients with adenocarcinoma inperiods of the patients were 11 months in the stage I11 were 12 months in the immunotherimmunotherapy group and 7.5 months in the apy groups, whereas those of 141 a n d 101
control group. However, the number of the respective control patients were 8 a n d 6.5
patients was considerably limited and the dif- months. T h e both differences were staference in survival period hardly deserved a tistically significant ( p = 0.0005 in squamous
statistical evaluation.
cell carcinoma, p < 0.0001 in adenocarT h e 50% survival period of the patients cinoma).
Fifty-five patients with malignant pleurisy
with squamous cell carcinoma and adenocarcinoma in stage I and I1 was 23 months in receiving BCG-C WS immunotherapy surthe control group, while 70% of the patients in vived much longer than controls (Fig. 2). I n
the immunotherapy group were still alive at this group, all major clinical features of the pathe same time. T h e 50% survival periods of tients statistically corresponded to those of
123 patients with squamous cell carcinoma controls as indicated in Fig. 2.
Clinical features

FIG.2. T h e survival of patientswith malignant pleural fluid receiving the intrapleural BCGCWS immunotherapy and conventional therapy alone.

Months from Admission

10970142, 1979, 4, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/1097-0142(197904)43:4<1314::AID-CNCR2820430420>3.0.CO;2-6 by Cochrane Japan, Wiley Online Library on [25/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

CANCER
April 1979

1316

BCG-CWS LUNGCA THERAPY. Ynrnarnura et nl.

Finally, in order to make clear the variation in patients’ survival period from institution to institution, four representative hospitals were compared in which the number ofpatients were enough to be examined statistically. As shown in Table 3, BCG-CWS
treated patients survived much longer thanthe control groups in every institution.

DISCUSSION
The present study revealed that additional
immunotherapy with BCG-CWS to initialconventional treatment such as surgery irradiation and/or chemotherapy resulted in
improvement of prognosis of the patients withlung cancer. Namely, the overall survival
period of the patients in immunotherapy
group was significantly longer than that of thecontrol group. Between both groups, there
was no significant difference in distribution ofhistological cell type, as well as clinical staging which has an important effect on prognosis. Accordingly, it can be concluded thatthe prolonged survival period in the immunotherapy group is not due to a difference inthese clinical features between both groups.
This was further confirmed with analysis
according to histological cell types of patientsin stage 111. In the immunotherapy groups,
50% survival periods of patients with squamous cell carcinoma and adenocarcinoma
were prolonged, respectively, to 12 months
with statistical significance as compared with 8
and 6.5 months in control groups. Particularly, the effect in patients with squamous cell
carcinoma in stage I11 seems to be evaluable
because other clinical features-sex
andmodality of initial conventional treatmentwere also comparable.
In the present study, modality of initialconventional treatment was not quite comparable between the immunotherapy and control groups as indicated in Table 1. Although
it has not been clear whether an annualchange in percent of a mode of initial conventional therapy influences survival, in order
to assess the influence on survival period
further analysis of the survival period of all
patients was carried out according to modalityof initial therapy, irradiation and surgery. In
each immunotherapy group, prolongation ofsurvival period was significant as comparedwith controls (p < 0.001 in irradiation group,p < 0.03 in operation group). This indicates

1317

TABLE
3. Fifty Percent Survival Months of Treated
and Control Patients by Institutions
Institution
Kinki Central Hospital for
Chest Disease (Osaka)
Kyushu Cancer Center(Fukuoka)
Osaka Medical Center for
Adult Disease (Osaka)
Tokyo Medical College

BCG-CWS
treatedControls

9.0 (86)

5.5 (27)19.0 (107)

9.5 (157)

24.0 (44)10.0 (128)

9.0 (12)8.5 (120)

Four representative institutions, in which number ofpatients were enough to be compared statistically, weresummarized in this table.
Number of patients is indicated In parentheses.

10970142, 1979, 4, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/1097-0142(197904)43:4<1314::AID-CNCR2820430420>3.0.CO;2-6 by Cochrane Japan, Wiley Online Library on [25/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

No. 4that the prolongation of the patients’ survival
period in BCG-CWS treated group was not
originated from the increase in percent of thepatients receiving operation.
The two year survival rate of patients withsquamous cell carcinoma and adenocarcinoma in stage I and I1 were 50 and 70% in
control and immunotherapy group, respectively. T h e difference is statistically insignificant, but it seems too early to be evaluated because many patients, most of whom had received operations, were still alive.
As previously reported, intrapleural injection of BCG-CWS into the affected pleuralcavity of patients with malignant pleurisy
resulted in prolongation of survival period.
All clinical features such as indicated in Table
1 are not different in distribution in Chi2 test
between both groups. Although precise
mechanism has remained undetermined, systemic immune potentiation and local effect on
pleural effusion are possibly responsible forthe clinical results.18*2s~30~31
Previously, we have shown that BCG-CWS
has an anti-tumor effect through the immunopotentiation at various levels when injected
into the tumor-bearing hosts.25~26~,27~2*~2Y~31
Some participants in this study have individually reported a close correlation between therapeutic effect and improvement ofpatient’s cellular immune response during thetherapy.10-24j31
These results led us to supposethat immunotherapy with BCG-CWS canmake the patient’s immune mechanism able
to react effectively against the tumor resulting
in prolongation of the survival period.
The uneven effect of immunotherapy on
50% of the survival periods from institution
to institution is probably related to the variedCANCER
April 1979

distribution of cell types and clinical stages ofpatients in institutions.
In view of side effects, BCG-CWS was muchless harmful as compared to living BCG,
even when administered intrapleurally or
intrale~ionally.~~-~~~~~
Ulcerations at the injected site of the skin were smaller and healed
within 4 to 8 weeks. N o case presented an en-Vol. 4 3

hancement of tumor growth due to thetherapy.
In conclusion, the present study leads us tobelieve that adjuvant inimunotherapy withBCG-CWS is a useful therapeutic modality inimproving the prognosis of patients with lungcancer, even though considering that evaluation with historical control has a moot result.

APPENDIX
Participants in the trial were as follows:f mtztution
Hiroshima University
Kinki Central Hospital for Chest Disease (Osaka)
Kyoto University
Kyushu Cancer Center (Fukuoka)
Niigata University
Okayama University
Osaka Medical Center for Adult Disease
Osaka University
Tokushima University
Tokyo Medical College'rmeyatna National Hospital (Osaka)

Rcspotuihle doctor
Yukio Nishirrioto
Kenji Sawamura
Chiaki Nagase
Kosei Yasumoto
Yoshio Ito
Shozo Yamaria
Shqji Hattori
Yuichi Yarnarnura
Eiro Tsubura
Yoshihiro Hayata
Yoshihiro Yamatnura

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