[CANCER RESEARCH 48, 1663-1670, March 15, 1988]
Randomized Trial of Combined Modality Therapy with and without Thymosin
Fraction V in the Treatment of Small Cell Lung Cancer1
Howard I. Scher,2 Brenda Shank, Robert Chapman,3 Nancy Geller, Carl Pinsky, Richard Cralla, David Kelsen,
George Bosl, Robert Golbey, Gina Petroni, Donna Niedzwiecki, Nael Martini, Robert Heelan, Phyllis Hollander,
Basil Hilaris, Herbert Oettgen, and Robert E. Wittes4
Solid Tumor [H. I. S., R. C., D. K., G. B., R. G., P. H., R. E. W.], Immunology fC. P., H. O.J, and Developmental Chemotherapy [R. G.J Services, Department of
Medicine. Department of Radiation Oncology [B. S., B. H.], Department of Biostatistics fN. G., G. P., D. N.], Division of Thoracic Surgery [N. M.J, Department of
Surgery, Department of Diagnostic Radiology [R. H.J, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021; Department of
Medicine [H. I. S., R. C., R. G., D. K., G. B., R. G., R. E. W., C. P., H. O.J, Cornell University Medical College, New York, New York 10021
ABSTRACT
A randomized trial of thymosin fraction V (60 mg/m2 s.c. twice weekly)
given during induction chemotherapy and radiation therapy was per
formed in 91 patients with small cell carcinoma of the lung. Induction
chemotherapy consisted of four cycles of an alternating combination of
drugs(cyclophosphamide/Adriamycin/vincristineandcisplatin/etoposide).
Radiation to the primary complex was given to patients with limited
disease. All patients received prophylactic cranial irradiation. There were
35 patients with limited disease (18 randomized to thymosin and 17 to
no thymosin) and 56 with extensive disease (28 thymosin and 28 no
thymosin). I'retreat ment immunological parameters were comparable
between the two groups. For limited disease patients the overall response
rate was 100%, including 66% (21 of 32) complete responders. The
median duration of response was 19 mo (range, 5-57 mo) and survival
21 mo (range, 4 days to 57 mo). The 3-yr survival was 32%. For ED
patients the overall response rate was 95% with 29% (13 of 48) complete.
The median duration of response was 10 mo and the median duration of
survival 12 mo with 13% alive at 2 yr. A comparison of the thymosinversus no thymosin-treated patients revealed no difference in response
rate, response duration, or survival whether analyzed as a whole or by
extent of disease. An analysis based on pretreatment immune function
and total white blood cell and absolute lymphocyte count revealed no
difference in the survival distributions. No differences in the pattern of
toxicity were observed between the thymosin- versus no thymosin-treated
patients. The addition of thymosin fraction V during induction chemo
therapy and consolidation radiotherapy did not alter outcome.
INTRODUCTION
Despite sensitivity to a variety of chemotherapeutic agents,
therapeutic gains in the treatment of SCCL5 have been modest
over the past several years (1-3). The median survival for all
patients remains 12-14 mo and long-term survival is restricted
to those with LD at presentation.
Reports of immune deficits in patients with SCCL have led
to clinical trials using nonspecific immune potentiators.
Defects
include a diminished response to DNCB challenge (4, 5), deReceived6/27/86; revised7/15/87, 12/15/87; accepted 12/17/87.
The costs of publication of this article were defrayed in part by the payment
of page charges. This article must therefore be hereby marked advertisementin
accordancewith 18 U.S.C. Section 1734solelyto indicatethis fact.
1Supported in part by American Cancer Society Junior Faculty Clinical
Fellowship No. 632 (B. S.) and NIH Contract No. l-CM-97274 and Grant CA05826.
2 Recipient of an American Cancer Society Clinical Oncology Career Devel
opment Award. To whom requests for reprints should be addressed, at Solid
Tumor Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue,
New York, NY 10021.
3 Present address: Henry Ford Hospital, Detroit, Ml.
4 Present address: Division of Cancer Treatment, National Cancer Institute,
Bethesda, MD.
5The abbreviations used are: SCCL, small cell carcinoma of the lung; LD,
limited disease; BCG, Bacillus Calmette Guérin;CR, complete response; PR,
partial response; ED, extensive disease; CAV, cyclophosphamide/Adriamycin/
vincristine; DDP/Vp, cisplatin/etoposide; PCI, prophylactic cranial irradiation;
NMD, no bidimensionally measurable disease; MDR, median duration of re
sponse; MDS, median duration of survival; TI. thoracic irradiation; DNCB,
dinitrochlorobenzene; SK/SD, streptokinase/streptodornase.
pressed lymphocyte blastogenic response in vitro (5), decreased
total lymphocyte counts, and decreased T-cell levels (6). The
trials have met with limited success (7). Three randomized
studies comparing patients treated with chemotherapy with or
without the methanol extraction residue of BCG showed no
benefit for the combined approach (8-10). A fourth study
showed no difference in CR rate with BCG, although a survival
advantage was shown for responding patients with LD treated
with BCG who lived longer than 1 yr (11). However, the same
investigators reported a possible deleterious effect on response
duration for patients with ED (12).
Thymosin fraction V is a soluble product of calf thymus
consisting of a group of polypeptides with a molecular weight
of 1,000 to 15,000 (13). Studies suggest that it reconstitutes
immune function, rather than augments normal immune pa
rameters (14-18). Direct antitumor effect has been seen in
patients with renal cancer (19) but not in patients with nonsmall cell lung cancer or malignant melanoma (20).6
A randomized study using thymosin fraction V during the
initial 6 wk of induction chemotherapy for patients with SCCL
has been reported (21). Patients were randomized to receive
thymosin 20 or 60 mg/m2 s.c. twice weekly or no thymosin. All
received the same chemotherapy. The results showed an im
proved survival, median 14 mo, for patients treated with the
higher dose of thymosin versus low-dose thymosin and controls
(median 9 mo). The results were confirmed in a subsequent
analysis that included an additional seven patients treated with
a different chemotherapy regimen (22).
A previous study at this institution used CAV alternating
with DDP/Vp for four cycles as induction therapy for patients
with SCCL (23, 24). PCI was given to all patients and LD
patients received radiation therapy to the mediastinum and
primary complex. The CR rate was 83% for LD and 65% for
ED with a median response duration of 11 and 5 mo, and
median survival of 18 and 12 mo, respectively. Four of 23 LD
patients remain disease free.
Based on these results, we conducted a prospective random
ized trial of thymosin fraction V, given during induction chemo
therapy and radiation therapy in patients with SCCL. The aim
was to evaluate whether the addition of thymosin would in
crease the proportion of responders, response duration, and
survival. The results have been reported in preliminary form
(25, 26).
MATERIALS AND METHODS
From May 1979 to May 1982, 91 patients with SCCL were entered.
Eligibility requirements included pathological confirmation, no prior
systemic therapy, and a serum creatinine less than 1.4 mg/dl. Initial
evaluation included a complete history and physical examination, com
plete blood count with differential, screening profile, 5'-nucleotidase,
'A. Fefer, personal communication.
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THYMOSIN
V IN SMALL CELL LUNG CANCER
and serum creatinine. Staging included a chest X-ray, bone marrow
aspiration and biopsy, and bone scan with subsequent radiographs of
abnormal areas. Liver scans were performed if either the clinical ex
amination or laboratory values suggested liver involvement. For staging,
patients were categorized as having limited disease (confined to one
hemithorax or ipsilateral supraclavicular nodes) or extensive disease
(other than limited). Patients with pleural effusions were classified as
ED.
Immunological evaluation included DNCB sensitization and chal
lenge, intradermal skin tests with recall antigens (purified protein
derivative, Candida, SK/SD, and mumps), response of isolated lym
phocytes to mitogens and Candida antigens, and studies of 1-7 and t-¿t
markers on lymphocytes. Immunological assays were performed at the
start of therapy, completion of induction chemotherapy, and after
consolidation radiotherapy.
The treatment regimen is outlined in Table 1. Patients were random
ized to receive thymosin or no thymosin. For induction therapy, two
cycles each of an alternating combination of drugs were used. Regimen
A consisted of CAV and regimen B, DDP/Vp. Cycles were repeated
every 21 or 28 days depending on blood counts. Patients randomized
to thymosin were treated with 60 mg/m2 s.c. twice weekly from the
start of induction through the completion of radiation therapy. Thy
mosin was obtained from Hoffmann LaRoche where in vitro activity
was confirmed.
Blood counts were performed weekly during induction and measur
able disease was reassessed at the start of each cycle. Restaging was
performed after completion of induction chemotherapy and again after
radiation therapy. PCI with "Co was given via parallel opposed fields
as 300 cGy daily in 10 fractions over 14 elapsed days. This is equivalent
to 4000 cGy by the NSD concept (27). LD patients received radiation
to the primary site and anterior mediastinum via a multifield treatment
plan using three or four fields with an energy of at least 10 Mev. A
computed tomography scan following simulation was obtained prior to
the start of radiation therapy to facilitate treatment planning, protect
as much normal lung as possible, and ensure that spinal tolerance was
not exceeded. Treatments were given at a dose of 250 cGy/fraction, 4
fractions per wk for 18 fractions for a total dose of 4500 cGy [5100
cGy at conventional fractional ¡onby the NSD formulation (27)]. Cyclophosphamide (500 mg/m2) and vincristine (1.4 mg/m2) were given
on Days 1 and 14 along with radiation therapy.
Patients in CR after completion of radiation therapy (TI and PCI
for LD, PCI alone for ED) were given a 10-wk rest period followed by
3 cycles of maintenance chemotherapy (Table 1). Patients with incom
plete responses were started on maintenance chemotherapy with no 10wk rest period and treated until relapse. For restaging, all initially
abnormal tests were repeated; however, bronchoscopies were not per
formed routinely to evaluate CRs.
There was no dose attenuation during induction chemotherapy.
During radiation therapy if the white blood cell count was <2,000 cells/
mm3 or platelets <75,000 cells/mm3 treatment was interrupted until
blood counts increased. During maintenance, if counts remained below
the above levels, therapy was delayed until counts recovered, or 2 wk
at most. If counts were still low, the dose was reduced by 50%. Standard
response criteria were used as previously described (28).
Statistical Methods. This trial was designed to enter 80 patients in
order to be able to detect a 25% increase in CR rate at 2 yr, from 5%
(which was the 2-yr CR rate at the time of first entry) to 30%, with
90% power, when significance testing was undertaken at the 5% level.
Actual enrollment was 91 patients. Randomization was by the method
of random permuted blocks, stratified for Karnofsky performance status
(Karnofsky performance status >70 versus <70) and extent of disease
(LD versus ED) (29).
Differences in patient characteristics between the thymosin and no
thymosin groups were tested using the x2 test to evaluate difference in
sex, the Wilcoxon rank sum test for difference in Karnofsky perform
ance status (29), and the f-test for age differences. Base-line values for
individual immune parameters were compared between thymosin and
no thymosin groups using /-tests. Due to the large number of i-tests
performed, single variables were considered significantly different if the
P value was <0.001. Transformations, such as logarithm or square
root, were used as necessary to satisfy the normality and equal variance
assumptions of the i-test, but means and SEMs are reported in original
units.
To compare values of individual postinduction chemotherapy and
Table 1 Combined modality treatment program
Cycle 2 B°
Cycle 1 A
Induction
Cyclophosphamide*
Adriamycin
Vincristine
Cisplatin
Etoposide
Thymosinc
Consolidation
Cyclophosphamide
Vincristine
Radiation therapy
Primary complex
Whole brain
Thymosin'
1200 day I
50 day 1
1.2 days 1,8
Cycle 3 A
Cycle 4 B
1200 day 1
50 day 1
1.2 days 1,8
60 day 1
120 days 4, 6, 8
60 day 1
120 days 4, 6, 8
60 mg s.c. twice weekly (cycles
1-4)
500 days 1, 14
1.4 days 1, 14
250 cGy x 18 fractions (4 wk)
300 cGy x 10 fractions (14
days)
60 mg s.c. twice weekly
Maintenance1'
CCNU
Methotrexate
Procarbazine
Cyclophosphamide
Adrimycin
Vincristine
Cisplatin
Etoposide
60 p.o. day 1
30 Q W x 4 wk
100 p.o. x 14 days
1000 day 42
30 day 42
1.2 day 63
50 day 63
120 days 67,
69,71
' The second cycle of chemotherapy was initiated after 21 or 28 days depending on blood counts (see text).
* All doses are expressed as mg/m.2
c For patients randomized to receive immunotherapy, thymosin was given at a dose of 60 mg/m1 s.c. twice weekly beginning with the first cycle of chemotherapy
through the completion of radiation therapy.
''Maintenance chemotherapy was begun after a 10-wk rest period for patients in CR after induction. All other patients started maintenance therapy as soon as
counts recovered. CCNU, l-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea.
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THYMOSIN V IN SMALL CELL LUNG CANCER
Table 2 Patient characteristics
postconsolidation immune parameters for thymosin and no thymosin
groups, the variables Zi (the postinduction chemotherapy value Xi
adjusted for the base-line X0) and /... (the postconsolidation value \..,
adjusted for the base-line X0) were calculated as follows
Z, =
A|
Limited disease
Extensive disease
thymosin1853
EnteredAge
(yr)KPS
(%)°M:FPrior
— XQ
thymosin2853
(39-69)80(50-100)9:9112(80)663021\9P
(35-73)80(20-100)20:849(33)1502V1012481373N
(32-72)80
(40-90)19:915(21)172221
X,
lloiclling's
RTResponseCR
I statistic was used to test the equality of the group means
of Z, and Z2 simultaneously for each of the individual immune param
eters. Hotelling's T2 was also used at each time point [base-line,
postinduction chemotherapy, and postconsolidation (30)] to test the
equality of group means for all immune parameters simultaneously.
Analyses were conducted on all patients as well as separately for LD
and ED subgroups.
Survival time distributions and remission duration distributions were
estimated using the product limit method of Kaplan and Meier (31)
and comparisons were made using the logrank test (32). Survival
(remission duration) was measured from date of protocol entry to date
of death (relapse) or last follow-up for those patients still alive (not yet
relapsed). For patients with NMD, the time to treatment failure was
measured to the first documentation of progression. No patients were
excluded from the survival analysis irrespective of the cause of death.
With hypothesis testing at the O.OSlevel and actual enrollment of 45
and 46 patients on the thymosin and no thymosin arms, a doubling in
median survival times could be detected with power 0.90 if all patients
were followed to death (33).
To evaluate the association of the immunological parameters with
survival patterns, patients were classified as normal or abnormal (based
on the values obtained in the reference laboratory) for each parameter
and survival distributions for these classifications were compared. For
survival, a result was regarded as significant if/' - - 0.05. All significance
(%)PRE-RTPOST-RTPRNC/STABNMDNEVMDR(M)MDS
(53)45*800015168043302No
0.3221=
P 0.385Thymosin2859
=
(MO)Survival:1
0.8812/>
1P =
0.491
=
(%)2
YR
(%)3
YR
(%)Alive
YR
NEDThymosin1759(41-72)90(60-100)11:609
' KPS, Karnofsky performance status; RT, radiation therapy; NC/STAB,
no change/stable; NEV, not évaluable.NED = no evidence of disease.
* Includes 1 patient converted to complete remission with surgical resection.
' Includes 1 patient randomized to the thymosin treatment arm who never
received therapy.
0 LIMITEDDISEASE (32 PTS . 9 CENSORED)
1 EXTENSIVE
DISEASE(47 PTS . 6 CENSORED)
TICKMARK(i) INDICATESLAST FOLLOW-UP
tests were two sided.
At the time of analysis of the trial, the importance of the LD and
ED subgroups was well recognized (1-3) and so separate analyses were
undertaken to be certain a combined analysis was sensible. Because the
thymosin arm had a higher response rate in the ED subgroup and the
no thymosin arm had a higher response rate in the LD subgroup, a test
for qualitative interaction between response and LD or ED was per
formed (34). Since a significant interaction was found, results for LD
and ED are reported separately.
12
24
36
48
60
MONTHSFROMSTARTOFTHERAPY
RESULTS
B
100r
Patient characteristics for LD and ED and for thymosin
versus no thymosin are shown in Table 2.
Limited Disease. Thirty-five patients were entered; 18 were
randomized to thymosin and 17 to no thymosin. Three were
inevaluable for response; one died after 5 days of a gastrointes
tinal hemorrhage and 2 were considered to have NMD at the
start of therapy. Both had undergone thoracotomies for pre
sumed non-small cell lung cancer; one was completely resected
and the second underwent 125Iimplantation. Both were random
ized to the no thymosin group.
The overall response rate was 100%, with 66% (21 of 32)
CR. Ten achieved CR after induction chemotherapy alone and
an additional 10 became CR after radiation therapy to the
primary complex. One patient was rendered disease free after
surgical resection of a residual malignant pulmonary nodule
that persisted after induction chemotherapy and radiation ther
apy consolidation. She remains free of disease 4.7 yr after the
start of therapy. The MDR was 19 mo (range, 5-57 mo), with
a median survival of 21 mo (range, 4 days to 57 mo) (Fig. 1, A
and B). The survival at 1 yr was 80%, at 2 yr 43%, and at 3 yr
32%. Seven patients are currently alive and disease free 30 to
57 mo from start of therapy.
The pretreatment characteristics of the thymosin group
showed a higher median age and performance status and a male
I
O LIMITEDDISEASE (35 PTS. 9 CENSORED)
ûEXTENSIVE
DISEASE (56 PTS.. 4 CENSORED)
TICKMARK(i) INDICATESLAST FOLLOW-UP
60-
24
36
48
SURVIVALIN MONTHS
Fig. 1. Remission duration (.1) and survival distributions (II) for limited and
extensive disease patients. Distributions were determined using the method of
Kaplan and Meier (30). PTS., patients.
predominance versus the no thymosin group. The overall CR
rate was 53% (9 of 17) versus 80% (12 of 15) [x2 (corr) = 1.53,
l d.f., P = 0.22], and CR rate to induction alone 24% (4 of 17)
versus 40% (6 of 15) for thymosin versus no thymosin [x2 (corr)
= 0.386, l d.f., P = 0.54]. MDR was 15 versus 19 mo (logrank
X2= 0.981, P = 0.32) (Fig. 2A) and median survival times were
also similar, 16 versus 21 mo (logrank x2 = 0.981, P = 0.38)
(Fig. 3/1). With a median follow-up of 42 mo, 5 of 18 patients
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THYMOSIN
V IN SMALL CELL LUNG CANCER
1.00
1.00
O THYMOSIN
(17 PTS . 3 CENSORED)
a NO THYMOSIN
(18 PTS.. 6 CENSORED)
TICK MARK (i) INDICATES LAST FOLLOW-UP
O THYMOSIN
(17 PTS.. 3 CENSORED)
NO THYMOSIN
(15 PTS , 6 CENSORED)
TICK MARK (i) INDICATES LAST FOLLOW-UP
.80
.60
.40
20-
.00
12
12
24
36
48
24
36
48
60
72
60
SURVIVAL
IN MONTHS
MONTHS FROM START OF THERAPY
1.00
1.00
0 THYMOSIN
(23 PTS., 4 CENSORED)
1 NO THYMOSIN
(24 PTS.. 2 CENSORED)
TICK MARK (i) INDICATES LAST FOLLOW-UP
O THYMOSIN
(28 PTS , 3 CENSORED)
A NO THYMOSIN
(28 PTS.. 1 CENSORED)
TICK MARK (l) INDICATES LAST FOLLOW-UP
£ .60
1.40
.00
00
12
24
36
48
60
12
24
SURVIVAL
MONTHS FROM START OF THERAPY
Fig. 2. Remission duration for patients treated with thymosin versus no
thymosin. A, limited disease patients (x2 = .981, P = 0.32). B, extensive disease
patients (x2 = .485, P = 0.49). No difference in remission duration was found
between the two groups. PTS., patients.
who did not receive thymosin are disease free (including 1 with
NMD) compared to 2 of 17 patients treated with thymosin.
Extensive Disease. Fifty-six patients were entered, 28 in each
arm. The median age was 57 (range, 32-73 yr) and median
Karnofsky performance status 80% (range, 10-100). The eight
patients inevaluable for response, four with NMD at the start
of therapy and four early deaths, were equally distributed be
tween thymosin and no thymosin. Of the early deaths, one
developed a gastrointestinal hemorrhage after 5 days of therapy
despite a normal platelet count and was lost to follow-up; a
second developed intractable hemoptysis and died 3 days after
starting therapy; a third died of sepsis on day 10 and a fourth
was randomized but never received treatment. All are included
in the survival analysis. Of the 4 patients with NMD one had
positive cranial CT scan although the pulmonary disease was
resected, a second had hepatic disease évaluableby liver spleen
scan and I25I implantation in the chest, a third had a resected
axillary node as the sole site of disease, and the fourth had
évaluabledisease by brain scan.
Of the 48 patients évaluablefor response (24 thymosin and
24 no thymosin), the CR rate was 29% (13 of 48) and overall
response rate (CR + PR) 95%. The MDR was 10 mo (range,
1-55 mo) and MDS 12 mo (range, 2 days-55 mo) (Fig. 1, A
and B). Forty-eight % were alive at 1 yr and 13% at 2 yr. Four
patients are currently alive and disease free, 38 to 55 mo from
start of therapy.
The pretreatment characteristics and sites of initial disease
for ED patients treated with thymosin versus no thymosin were
similar. The CR rate was 33% (8 of 24) for thymosin versus 5
of 24 (21%) for the no thymosin arm [x2 (corr)= 0.422, 1 d.f.,
P = 0.52] with overall response rates of 96 and 92%, respec-
36
60
IN MONTHS
Fig. 3. Survival distributions for thymosin versus no thymosin-treated patients.
A, limited disease patients (x! = .981, P = 0.38). B, extensive disease patients (x:
= .485, P = 0.49). No differences in survival were found between the two groups.
PTS., patients.
lively. The MDR was 10 versus 11 mo, respectively (logrank x2
= 0.485, P = 0.49), and MDS 12 mo for both groups (Figs. IB
and 3B). The survival at 1 yr was 54 versus 49% and 2 yr 11
versus 18%. Three patients are alive and disease free in the
thymosin and one in the no thymosin group.
Although no significant differences in response rates in either
the LD or ED subgroups were detected, it was noted that in the
LD subgroup, the no thymosin arm had a 27% higher response
rate than the thymosin arm, whereas in the ED subgroup, the
thymosin arm had a 12% higher response rate than the no
thymosin arm. Due to the small size of the LD subgroup, the
lack of a significant difference in the LD response rates was
not surprising. However, a hypothesis test of qualitative inter
action (34) between treatment effects and the LD and ED
subsets was significant at the 0.001 level, raising the possibility
that thymosin was either minimally beneficial or had no effect
in ED and was detrimental to LD patients.
Relapse from CR. The analysis is restricted to patients who
relapsed from CR, as incomplete responders generally relapsed
at a site of initial involvement. For LD, 13 of 21 (62%) CR
patients relapsed with a median time to relapse of 16 mo (range,
6-57 mo) from the start of therapy. One patient with NMD
relapsed at 16 mo. Four patients relapsed within the radiation
field. In 2 patients this was the sole site of relapse (13 and 39
mo), while in two others, simultaneous relapses were docu
mented in the chest and s.c. tissues and chest and liver. Intra
parenchyma! brain relapse occurred in only 1 patient. A second
developed an intramedullary spinal cord relapse outside the
radiation portal.
The sites of initial disease in comparison to sites of relapse
for the 13 CR with ED were as follows. For thymosin-treated
patients, 4 of 5 relapsed, including 2 at sites of initial disease,
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THYMOSIN V IN SMALL CELL LUNG CANCER
infectious complications during drug-induced myelosuppres
sion.
Although nausea and vomiting were seen in most patients,
the majority of treatment cycles were administered on an out
patient basis. One patient required discontinuation of cisplatin
due to a diminution in renal function. Allergic reactions to VP16 requiring discontinuation of the drug occurred in 2 patients.
Overall, 87 of 91 patients (86%) received full doses of the
planned induction chemotherapy.
Radiation-induced pneumonitis occurred in 3 cases. Two
were successfully treated with corticosteroids, but the third died
in PR of pulmonary decompensation. One additional patient
died at 40 mo of progressive pulmonary disease, but this was
attributed primarily to repeated pulmonary infections from his
underlying chronic obstructive pulmonary disease. Significant
mucositis developed in 6 cases, 2 of which required hospitalization, while esophagitis from combined chemotherapy and
means of the adjusted differences between postinduction and radiation therapy developed in 4 cases. None of these four was
postconsolidation values is presented in Table 4. Comparisons
hospitalized. Skin reactions, including a rash and pruritis, de
of the thymosin versus no thymosin groups at each time point
veloped in 4 cases. Three patients developed herpetic reactions,
showed no variation between the groups.
including an endophthalmitis in 2 and a disseminated infection
An analysis of survival based on base-line immune function
in one.
and total white blood cell and absolute lymphocyte count was
A mild to moderate peripheral neuropathy which required a
performed in two ways. First, patients were divided into two reduction in the dose of vincristine occurred in 8 cases. Two
groups on the basis of the calculated group mean for an indi
patients developed decreased gastrointestinal motility, two an
vidual parameter and the survival distributions between those
autonomie neuropathy manifested by orthostatic hypotension,
and two complained of impotence from the combined modality
groups were compared. The second analysis classified patients
as normal or abnormal based on the mean normal values for therapy.
Late central nervous system toxicity was observed in five
the reference laboratory. No differences in survival distribution
cases. Two developed decreased intellectual acuity; the third
would be demonstrated by either method for the parameters
developed increased intracranial pressure with hydrocephalus
tested.
Toxicity. The primary toxicity was myelosuppression which requiring placement of a ventriculoperitoneal shunt. The fourth
was comparable by cycle for each treatment group (Table 5). developed headaches and diploplia which progressed to incon
The median nadirs following treatment with DDP/Vp were tinence, ataxia, and a progressive dementia 31 mo after com
pletion of whole brain radiation therapy. The fifth patient
higher than those following CAV. The degree of myelosuppres
developed diminished visual acuity in the left eye at 32 mo. On
sion was slightly higher for the ED versus LD patients but there
examination the optic nerve head was edematous and the periwas no difference between thymosin versus no thymosin pa
pupillary area infiltrated. Ultrasound examination revealed op
tients. A total of 55 admissions for neutropenia and sepsis (43
tic nerve swelling but no masses. No specific therapy was
patients) occurred during induction chemotherapy. This in
advised.
cluded 16 LD (5 thymosin and 11 no thymosin), and 27 with
Two patients developed pancytopenia 30 and 33 mo after
ED (12 thymosin and 15 no thymosin). Four patients died of initiation of therapy. Bone marrow examination revealed less
than 10% myeloblasts in both cases. One patient has undergone
Table 3 Base-line immune parameters
a trial of c/s-retinoic acid with no response, the second remains
Base-line values for lymphocyte blastogenesis for thymosin- versus no thymopancytopenic.
sin-treated patients. Each value represents a mean of duplicate samples expressed
in counts per minute x Id1. Values for antigen and Staphylococcus aureus were
No differences in the pattern of toxicity was observed between
calculated using logarithmic transformation (see text). Absolute lymphocyte
thymosin and no thymosin-treated patients. Thymosin was
counts were calculated using values for total granulocytes x the percentage of
lymphocytes on differential counts. Percentages of T-cells were calculated using
generally well tolerated. The most common reaction was pain
an assay for resetting with sheep red blood cells.
and inflammation at the site of injection. Nine of 45 (20%)
thymosinMitogenPHANo
required modifications in thymosin dosage due to local reac
tions. Six were subsequently escalated back to full dosage, only
value0.930.210.740.610.310.470.710.500.470.830.060.410.12
±SEM1.89
tic-0.09-1.270.330.51-1.02-0.73-0.37-0.680.71-0.211.940.831.59P
±SEM1.89
3 (7%) had permanent dose adjustments. Chills and fever within
±0.0415597
±0.0317108
24 h of injection occurred in 5 patients but generally resolved
(OIL)"Cona
±8416107
8336846
±
without
specific therapy.
50468.5
±
1 with meningea! disease and 1 with intraparenchymal brain
métastases,despite PCI. For no thymosin patients, 6 of 8
relapsed, including 4 at sites of initial involvement and 2 in the
intramedullary space. Of the three continued responders, 1
presented with a superior vena cava syndrome and abnormal
liver function tests, the second with extensive hepatic disease
and the third extensive nodal disease.
Immune Parameters. A comparison of the base-line immune
parameters for thymosin versus no thymosin patients is pre
sented in Table 3. No significant differences between the groups
were observed whether analyzed as a whole or by extent of
disease. For skin testing, no differences in base-line and posttreatment values was observed. For evaluation of lymphocyte
blastogenesis to mitogen, Staphylococcus aureus, and antigen,
logarithmic transformations were used in parametric statistical
analysis. A comparison by Hotelling's T-square statistic of the
52070.6
±
2.92.0
±
2.82.1
±
0.6474
±
±0.0579
(LOG)CanEcoliSA
±554
552±
3.93.32
±
53.4±
0.0839
±
0.0544
±
(LOG)PPDLymphocytesT-CellT-xT-7No.44444443444344444440194646Mean
±5576
5562±
4764.9
±
4474.3
±
4.84.35
±
±2.18.41
3.63.9
±
3.33.3
±
±1.3T-statis±1.9No.41414141414041414144154545ThymosinMean
" PHA, phytohemagglutinin A; DIL, diluted; Con A, concanavalin A; PWM,
pokeweed mitogen; Ant, antigen; LOG, logarithm; Can, Candida antigen; Ecoli,
Escherichia coli; SA, Staphylococcus aureus; PPD, purified protein derivative.
(OIL)PWMAnt
DISCUSSION
The results of the present study using an intensive combined
modality treatment program produced an overall CR rate of
60% for LD and 25% for ED patients. The median survival for
LD was 21 mo, with 30% alive, free of disease at 3 yr from the
start of treatment. While these results are encouraging, the
median survival for ED was only 12 mo, and only 4 long
survivors were seen. The median survival postrelapse was only
1667
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THYMOSIN V IN SMALL CELL LUNG CANCER
Table 4 Hotel/ing's T-square statistic for changes in lymphocyte blastogenesis
Changes in lymphocyte blastogenesis measured at start of therapy, end of induction chemotherapy, and end of consolidation radiation therapy for thymosin- versus
no thymosin-treated patients. Values for /., and Z2 were calculated as described in the text. Differences expressed represent the group mean for all patients studied.
No differences were detected for any of the parameters studied.
patientsNo
thymosin
of no
(Mean
SEM)0.09
±
of thymosin302432262723261828202922252226201519All
(Mean
SEM)0.01
±
thymosin301532IS3115281325132217271923171613No.
Mitogenz,ZiPHA-Z,Z,Con
AZ,Z,PWMZ,Z,AntZ,Z2CanZ,Z,EcoliZ,Z2SAZ,Z,PPDZ,Z2No.
0.080.04
±
±0.10-0.26
0.100.06
+
±0.10-0.34
0.06-0.47
±
±0.11-0.14
0.06-0.56
±
0.06-0.18
±
0.09-0.39
+
±0.10-0.05
0.10-0.50
±
±0.10-0.04
0.07-0.34
±
4-0.06 ±0.1
±0.11-0.38
2-0.11 ±0.1
0.15-0.16
+
±0.140.04
±0.13-0.38
0.09-0.18
±
±0.18-0.29
0.15-0.31
+
±0.10-0.67
±0.14-0.18
±0.11-0.61
±0.19-0.15
±0.10-0.89
4-0.21 ±0.1
0.10-0.60
+
7-0.17 ±0.1
±0.14-0.88
3-0.02 ±0.1
±0.18-0.20
0.21-0.65
±
±0.19Thymosin
±0.13T-square0.341.190.590.112.464.021.421.913.24P0.840.560.750.95
* PHA, phytohemagglutin A; Con A, concanavalin A; PWM, pokeweed mitogen; Ant, antigen; Can, Candida antigen; Ecoli, Escherichia coli; SA, Staphylococcus
aureus; PPD. purified protein derivative.
Table 5 Hematological toxicity
Median nadirs for granulocyte and platelet counts during each cycle of induction chemotherapy for thymosin- and no thymosin-treated patients separated by extent
of disease at presentation.
Granulocytes
CycleLimited
diseaseNo.
évaluableGrade
(%)Grade
2
(%)Grade
3
(%)Extensive
4
diaeaseNo.
évaluableGrade
(%)Grade
2
(%)Grade
3
(%)1Thymosin152734727112244Nothymosin17411824261523352Thymosin1414702015105Nothymosin1388016131963Thymosin1619501921143333Nothymosin16253818233039224Thymo
4
diseaseNo.
évaluableGrade
(%)Grade
2
(%)Grade
3
(%)Extensive
4
diseaseNo.
évaluableGrade
(%)Grade
2
(%)Grade
3
4 (%)1Thymosin157702711118Nothymosin17800268442Thymosin1414002010100Nothymosin13800166IS43Thymosin161260211490Nothymosin16131902317944Thymosin13301
1668
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THYMOSIN
V IN SMALL CELL LUNG CANCER
6 wk, highlighting the importance of initial therapy.
The addition of thymosin fraction V during induction chemo
therapy and consolidation radiotherapy to the primary complex
did not alter the treatment outcome. Although the CR rate for
LD patients was 80% for no thymosin- versus 53% for thymosin-treated patients, and 5 of 7 long-term survivors were in the
no thymosin group, these differences were not statistically
significant. This is not surprising, since with our sample size of
LD patients, a difference in CR rates of 45% could be detected
with a power of approximately 0.80 if the true CR rate in one
arm was 50% and (two-sided) hypothesis testing was under
taken at the 0.05 significance level. The CR rate for ED patients
was 21% for no thymosin- versus 33% for thymosin-treated
group. With our sample size of ED patients, a difference in CR
rates of 40% could be detected with power 0.80, if the true CR
rate for ED in one arm was 30% and (two-sided) hypothesis
testing was undertaken at the 0.05 significance level. It was not
surprising that the response duration and survival distributions
were similar between the two treatment groups. The toxicity
pattern was also similar with respect to the degree of myelosuppression, number of infectious complications, and number
of hospitalizations for treatment-related toxicity.
The qualitative interaction found between treatment and
stage raises the possibility that thymosin is detrimental to LD
patients and either minimally beneficial to or having no effect
in ED patients. The reversal in effects was unanticipated and
necessitated separate analyses for the LD and ED subgroups.
Others have reported a beneficial effect for LD (11) and a
deleterious effect for ED patients (12). These hypotheses could
only be tested using larger sample sizes than were available for
the present study. In future studies, separate power calculations
for LD and ED subgroups are recommended.
Pretreatment immunological data were analyzed for an effect
on response rate, response duration, and survival. The study
confirms the report by Cohen et al., showing no increase in
response rate for thymosin-treated patients (21, 22). However,
no difference in response duration or survival could be dem
onstrated when groups were contrasted by pretreatment white
blood cell count, absolute lymphocyte count (35, 36), values for
skin tests, or in vitro assays of lymphocyte blastogenesis. Cohen
et al. suggested that survival benefit was restricted to CRs (21 ).
However, no increase was detected in the present trial. One
difference between the two studies was the use of radiation
therapy in the present study to a port that includes the thymus
for LD patients. It is possible that radiation negated an en
hancing effect of the thymosin. A recent study by Schulof et al.
using thymosin a, in patients with non-small cell lung cancer
after radiation therapy showed an improvement in T-cell num
ber and function using either a loading dose or twice-weekly
schedule. Thymosin treatment improved both the relapse-free
and overall survival (37). The timing of an immune potentiator
relative to radiation therapy must also be considered in future
studies.
Analysis of sequential changes in lymphocyte blastogenesis
using Hotelling's T2 statistic, allowing each patient to serve as
The effects of thymosin are not completely understood (39)
and the optimal dose is unknown. However, doses as high as
1800 mg/m2/day for 5 days have been given (40). In human
studies, an enhanced response to mitogen was noted in 18%
(10 of 54) of patients suggesting that thymosin acts to increase
depressed immunity without an effect on patients with normal
function (16). Fefer reported an increase in E-rosettes, la anti
gen, and blastogenic response to phytohemagglutinin A (20),
but in serial testing, equal numbers of patients showed positive
and negative variations from baseline in different assays. Faberga et al. likewise noted no consistent effect using a variety
of immune tests (40). Dillmann et al. found that while no single
test was of value in predicting biological response, an increased
percentage of T-cells was noted in 37% (7 of 19), increased
lymphocyte count in 32% (6 of 19), and increased PHA re
sponse in 35% (8 of 23) of patients treated (38). Smalley et al.,
in a review of clinical trials with thymosin fraction V, reported
no consistent effect on T-cell quantitation, lymphocyte blasto
genesis, or reactions to allogeneic antigens in mixed lymphocyte
reactivity assays in 193 patients treated with 0.6-960 mg/m2
(39). Our observations are similar to those of Fefer et al. (20).
and Faberga et al. (40) in that no consistent effect on the
immune parameters measured was observed between the thy
mosin- and no thymosin-treated patients.
The overall response rate, response duration, and survival
confirm the reports of our previous protocols using an alter
nating combination of agents (23, 24). The MDR and MDS for
LD patients may simply reflect the increased response from TI
as 10 patients were judged to be CR after completion of TI.
The continued response following 4 cycles of chemotherapy
with 5 different agents is also of interest, as radiation appeared
to be non-cross-resistant with the induction therapy. As CRs
are the only patients who can achieve long survival (41), and
the difficulty controlling disease in the primary site has been
well described (42), TI should be included in the treatment
program for LD patients. These results are consistent with
other studies using a minimum of 4500 rads (43, 44) and the
beneficial results seen for TI in randomized trials (45-47). The
delay in radiation until a response has been achieved reduces
the amount of normal lung that must be irradiated and probably
contributes to the low incidence of radiation-induced pulmo
nary complications.
The results of the present study showed that the use of the
nonspecific immune potentiator thymosin did not improve the
outcome for patients with SCCL. Advances in the understand
ing of the biology of this disease (47), coupled with the identi
fication of distinct cell types with different biological character
istics (48), specific growth factor requirements, and antibodies
to the growth factor receptors (49), may allow more specific
immunotherapy for this disease.
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have been observed, since the effects of thymosin on blastogen
esis can be detected only up to 48 h after a single dose (38).
The timing of blood analysis relative to thymosin treatment
was not uniformly controlled in the present study.
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Randomized Trial of Combined Modality Therapy with and
without Thymosin Fraction V in the Treatment of Small Cell
Lung Cancer
Howard I. Scher, Brenda Shank, Robert Chapman, et al.
Cancer Res 1988;48:1663-1670.
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