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Int. J. Cancer: 70, 475–477 (1997)
r 1997 Wiley-Liss, Inc.
Publication of the International Union Against Cancer
Publication de l’Union Internationale Contre le Cancer
13-CIS RETINOIC ACID AND INTERFERON-a 6 IRRADIATION IN THE
TREATMENT OF SQUAMOUS-CELL CARCINOMAS
Wolfgang HOFFMANN1*, Martina SCHIEBE1, PETER HIRNLE2, Rainer SOUCHON3, Michael CLEMENS4, Iraenus ADAMIETZ5,
and Michael BAMBERG1
1Department of Radiotherapy, University of Tübingen, Germany
2Department of Gynecology, University of Tübingen, Germany
3Department of Radiotherapy, General Hospital, Hagen, Germany
4Department of Medical Oncology, University of Tübingen, Germany
5Department of Radiotherapy, University of Frankfrut, Germany
Pre-clinical data indicate that retinoid/interferon combinations
have significant activity in modulating malignant cell growth,
differentiation and programmed cell death in different hematologic
and solid tumor systems (Bollag et al., 1992; Hoffmann et al.,
1995). Clinically, the combination of 13-cis retinoic acid (13cRA)
and interferon-a (IFN-a) has been studied in a variety of tumor
types and was identified to have, among others, substantial activity
in advanced squamous-cell carcinomas (SCCs) of the skin and the
cervix (Lippmann et al., 1992a,b; Alberts et al., 1993; Dmitrovsky
and Bosl 1992; Roth et al., 1994). Since radiotherapy (XRT) is a
substantial part of the treatment of SCC, the question arises as to
whether the therapeutic results obtainable with radiation alone can
be further improved by using the additive effect of a systemic
treatment with 13cRA and IFN-a. The rationale for this approach is
based on experimental data since both IFN and retinoids have been
demonstrated to synergistically potentiate the radiation toxicity of
human SCC cells (Hoffmann et al., 1994). In addition, it has been
shown that vitamin A and its derivates potentiate the response of
experimental animal tumors to radiation (Tannock et al., 1972;
Seifter et al., 1983).
We evaluated prospectively the feasibility and toxicity of such a
combination, using 13cRA and IFN together with simultaneous radiation in SCCs of different origin, and compared our results with a group
of patients treated systemically with 13cRA and IFN-a alone.
PATIENTS AND METHODS
Patient selection and study design
Adult patients (18–75 years) with histologically confirmed
diganosis of SCC were eligible for this study. The eligibility criteria
included an adequate performance status (ECOG 0–2); a life
expectancy of at least 3 months; and unimpaired bone narrow, liver
and renal functions. Patients with brain metastases or severe
cardiovascular diseases were excluded. The study was approved by
the ethics committee of the Medical Faculty at the Eberhard-KarlsUniversity, Tübingen, Germany.
Pre-treatment evaluation included a complete medical history
and physical examination, chest X-ray, electrocardiogram, complete blood cell counts and biochemical profile. Conventional
radiology, ultrasound and CT scans were performed for tumor
measurements. Toxicity and response were determined by WHO
criteria. Doses of systemic treatment were reduced if necessary on
the basis of the level of toxicity (dose reduction in case of grade III
or grade IV toxicity). In patients who received concomitant
irradiation, the response was evaluated only if measurable disease
outside the irradiation field was present. Comparisons were made
between patients receiving 13cRA/IFN-a concomitantly to radiotherapy (group A) and patients receiving systemic treatment alone
(group B).
Treatment and drug administration
Group A. Twenty-seven patients underwent external beam
irradiation using linear accelerators. Radiotherapy was administered according to standard irradiation procedures of the distinct
tumor entities. Doses given ranged between 50 and 70 Gy in
1.8–2.0 daily fractions over 5–8 weeks (ICRU report 50) depending on tumor type, stage and treatment intention. Patients with
cervical cancer received additional brachytherapy using a remote
after-loading device equipped with 192Ir, 3 to 6 3 7.0 Gy point A.
Patients received 13cRA, 0.5 mg/kg body weight, orally once a
day and IFN-a, 3 3 106 UI s.c., 3 times a week. After irradiation
was terminated the RA dose was elevated to 1 mg/kg body weight
and the IFN dose to 3 3 106 IU s.c. daily.
Group B. Thirty patients receiving systemic treatment alone
were treated with 1.0 mg/kg body weight 13cRA orally and IFN-a,
3 3 106 UI s.c., once a day.
Treatment was maintained for 12 weeks in all patients without
progressive disease. For the responding patients, treatment was
maintained until disease progression was evident. Mean duration of
systemic treatment in both groups was 105 days, with a median of
97.5 days (range 22–239 days).
RESULTS
Patient population
A total of 57 patients were eligible for toxicity and feasibility of
the therapeutic regimens performed. Patients’ characteristics are
listed in Table I.
Hematological toxicity
In both treatment groups A and B, myelotoxicity was moderate
and did not exceed WHO grade II in most cases. In 3 patients out of
group B, who were irradiated for cervical (n 5 2) and head and
neck (n 5 1) cancer, WHO grade III leucopenia (1.0–1.9/µl) led to
interruption of trial medication for 7 days. In group A, only 2
patients developed grade III toxicity, with leucopenia in a head and
neck cancer patient and in one patient with esophageal cancer with
anemia combined with thrombocytopenia, causing treatment interruption for 7 and 10 days, respectively. None of the patients
required blood transfusion or antibiotic treatment. Table II summarizes the hematological side effects.
Non-hematological toxicity
Tables III and IV demonstrate the toxicity data and mean
severity of side effects for both treatment groups. Fatigue and
‘‘flu-like symptoms’’ occurred in 35% of all cases. Fever on the
days of IFN medication could easily be managed using paracetamol
3 3 500 mg p.o. and was always transient. Three out of 5 patients
with head and neck cancer in group A developed grade III
mucositis in the course of radiotherapy. One head and neck cancer
patient developed grade III cheilitis with dry skin desquamation.
Parenteral alimentation did not become necessary in any case. No
severe mucositis or skin toxicity was observed in the patient group
without concomitant irradiation. Combined treatment (RA/
IFN 1 RT) induced slightly pronounced toxicity scores of mucositis and skin toxicity compared with patients treated systemically
only. Diarrhea was rare (9 patients). Only 2 women with cervical
cancer in group A and 1 cervical cancer patient in group B
developed more pronounced diarrhea. In all other patients, gastro-
*Correspondence to: Department of Radiotherapy, University of Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany. Fax: 7071 29 58 94.
HOFFMANN ET AL.
476
TABLE I – PATIENTS’ CHARACTERISTICS
Group A
(13cRA/IFN-a/XRT)
Group B
(13cRA/IFN-a)
27
12
15
0–1
27–71
30
18
12
0–2
38–70
13
5
8
1
12
10
5
3
Elegible (total n 5 57)
Male
Female
Performance status (ECOG)
Age (range, years)
Tumor type
Cervix
Head and neck
NSLC
Esophagus
DISCUSSION
TABLE II – HEMATOLOGICAL TOXICITY
WHO grade 1-2-3-4
Tumor type
Leucopenia Thromboeytopenia
Group A (13cRA/IFN-a/XRT)
Cervix
Head and neck
NSCLC
Esophagus
Group B (13cRA/IFN-a)
Cervix
Head and neck
NSCLC
Esophagus
Anemia
2-2-2-0
0-2-1-0
2-1-0-0
0-0-0-0
2-0-0-0
0-0-0-0
0-0-0-0
0-0-0-0
2-2-0-0
3-0-0-0
1-1-0-0
0-1-0-0
3-3-0-0
1-3-1-0
0-0-0-0
1-0-0-0
0-0-0-0
0-0-0-0
0-0-0-0
0-0-1-0
3-4-0-0
1-2-0-0
0-1-0-0
1-0-1-0
TABLE III – NON-HEMATOLOGICAL TOXICITY
WHO grade 1-2-3-4
Tumor type
Lung
The overall response rate of all 16 cervical cancer patients
evaluable for response was 5 out of 16 (31%; 95% CI 11–59%).
Mean duration of response was 106 days in patients with cervical
cancer (median 92.5 days, range 0–239 days). Mean time to
progression was 135 days for patients with cervical cancer, with a
median of 217 days (range 22–239 days) (Table 5).
Nausea
Group A (13cRA/IFN-a/XRT)
Cervix
3-1-0-0 4-2-3-0
Head and neck 4-0-1-0 2-0-0-0
NSCLC
4-1-0-1 4-2-0-0
Esophagus
0-0-0-0 0-0-0-0
Group B (13cRA/IFN-a)
Cervix
1-0-0-0 1-2-1-0
Head and neck 3-1-1-0 2-1-1-0
NSCLC
6-2-1-0 4-0-0-0
Esophagus
0-0-0-0 2-1-0-0
Mucositis
Dry skin
Diarrhea
desquamation
5-3-0-0
0-0-3-0
3-1-0-0
1-0-0-0
2-8-0-0
1-2-1-0
0-5-0-0
0-0-0-0
3-1-1-0
1-0-0-0
1-0-0-0
0-0-0-0
2-1-0-0
8-0-0-0
1-0-0-0
1-0-0-0
0-3-1-0
2-5-0-0
2-2-0-0
0-3-0-0
0-0-1-0
0-0-0-0
0-0-0-0
0-1-0-0
intestinal side effects, such as nausea, were mild and transient,
occurring equally in both treatment groups.
Pulmonary symptoms were pre-existing due to obstructive lung
disease and were not exaggerated by systemic treatment. More
pronounced pulmonary side effects were documented in one patient
with non-small-cell lung cancer (NSCLC) suffering from grade IV
pulmonary toxicity. This patient was a 53-year-old woman presenting with an advanced NSCLC. Systemic treatment with RA/IFN
and radiotherapy of the primary tumor led initially to a good partial
response inside and outside the irradiation field. However, 2
months after completion of radiotherapy the patient developed
severe pneumonitis and finally died with progressive respiratory
failure, which was induced by pulmonary fibrosis and massive
tumor progression. Pathologic examination revealed a change of
histo-morphological appearance with a small cell component
which initially was not apparent.
Response
Group A. Four partial responses were observed outside the
irradiation field (2 3 cervical cancer, 1 3 head and neck cancer,
1 3 NSCLC). Median duration of response was 152 days and 50
days for the patients with cervical cancer.
Group B. Treatment with RA/IFN-a alone led to 3 partial
responses in patients with cervical cancer. All together, 7 patients
out of a total of 36 evaluable for response responded to the systemic
treatment with a partial remission (19.4%; 95% CI 8–35%).
In patients with solid tumors, toxicity of systemic treatment with
RA/IFN alone has been previously described to be mild and to
consist mainly of fatigue and skin changes (Lippmann et al.,
1992b; Tomna et al., 1994). We have integrated the regimen of
13cRa and IFN-a into standard comprehensive radiotherapy of
SCCs of different sites. In combination with radiotherapy, acute
toxicity is revealed to be moderate and generally does not exceed
the toxicity seen with radiation only. In the present study, dose
escalations for defining dose-limiting toxicity and maximum
tolerated dose have not been performed in order to not compromise
curatively intended treatment by unexpected toxicity. With the
regimen used, the comparison between toxicity of combination
treatment with a group of patients treated with systemic treatment
alone revealed a very mild increase of acute toxicity only.
Hematological toxicity was mild and transient in both treatment
groups, necessitating treatment interruption in a few cases only.
Among non-hematological manifestations of toxicity in patients
with cervical cancer, diarrhea was more pronounced with systemic
treatment plus radiation. One other preliminary report of such a
combination describes the toxicity in an ongoing phase II trial in
patients with cervical cancer using 13cRA (0.5–1.0 mg/kg/body
weight) and IFN 6 3 106 IU/daily in combination with CO60
radiation (Lippmann et al., 1993). The results reported so far
describe severe radiation-induced proctitis as being dose-limiting.
We used modern linear accelerators and a 4-field box technique and
administered uniform doses of 0.5 mg/kg 13cRA and 3 3 106 IU
IFN-a in our study. With this regimen, proctitis has not been
observed. In patients with head and neck cancer, mucositis was
more severe when the treatment was combined with radiotherapy.
Cheilitis as a known side effect of RA treatment was not found to be
exaggerated with radiation since the lips have not been included in
the target volume. The only case with WHO-IV toxicity was seen in
a female patient with NSCLC (group A) who initially responded
well to treatment with 13cRa/IFN and XRT. Both the primary
tumor and the lung metastases outside the irradiation field showed a
partial response after completion of radiotherapy. The patient
developed severe pneumonitis 8 weeks later and finally died as a
consequence of massive tumor progression and respiratory failure
from interstitial fibrosis. The change in histology from NSCLC to
SCLC upon autopsy confirms the activity of the systemic treatment
which eradicated the squamousa cell compound. Furthermore,
microscopic examination of the lung revealed diffuse pneumonitis
as occasionally induced by radiotherapy, which in this case might
have been potentiated by IFN-a (Dritschiko et al., 1982; Davis et
al., 1992). Systemic treatment in combination with irradiation led
to remissions in group A, with 4 partial responses outside the
irradiation field (2 3 cervical cancer, 1 3 NSCLC and 1 3 head
and neck cancer). Together with the 2 partial responses in cervical
cancer observed in group B, out of all 16 patients with cervical
cancer evaluable for responses, the partial response rate was about
30%. This confirms other observations describing only casuistic
responses in patients with head and neck tumors, NSCLC or
esophageal cancer, suggesting that biological differences among
different tumors, including different etiologies, account for the
responsiveness of skin and cervical cancers and the relative failure
of other SCCs (Roth et al., 1994; Toma et al., 1994) Another
possible explanation is under investigation—namely, whether the
coincidence of cervical cancers with HPV (human papilloma
viruses)-infection could explain the susceptibility of these tumors
to this kind of treatment since both IFN-a and retinoids are known
to exert anti-viral effects (Lippman et al., 1993; Hoffmann et al.,
1995). Since the combination of RA and IFN-a has been shown to
13cRA, INF-a 6 RADIOTHERAPY IN SCC
477
TABLE IV – MEAN SEVERITY OF SIDE EFFECTS
Tumor type
Cervix
Side effects
Anemia
Leucopenia
Thrombocytopenia
SGOT/SGPT
Mucositis
Nausea
Diarrhea
Pulmonary toxicity
Fever
Skin/cheilitis
Head and neck
Lung
Group A
Group B
Group A
Group B
Group A
Group B
0.46
0.92
0.15
0.15
0.85
1.311
0.62
0.38
0.38
1.381
0.92
0.75
0.00
0.50
0.33
0.66
0.25
0.08
0.70
0.75
0.60
1.401
0.00
0.00
1.801
0.40
0.20
1.401
1.201
1.601
0.50
1.001
0.00
0.20
0.80
0.70
0.00
1.201
0.40
1.201
0.38
0.50
0.00
0.00
0.63
1.001
0.13
1.251
1.001
1.251
0.40
0.00
0.00
0.20
0.20
0.80
0.00
1.401
0.40
1.201
Mean severity (MS) of side effects (WHO toxicity score). Values represent calculated mean of side
effects.
MS 5
n 1 ? 1 1 n 2 ? 2 1 n3 ? 3 1 n 4 ? 4
n0 1 n1 1 n2 1 n3 1 n4
n1, number of cases with Grade 1 toxicity;
n2, number of cases with Grade 2 toxicity;
n3, number of cases with Grade 3 toxicity;
n4, number of cases with Grade 4 toxicity.–1WHO values $1.
be effective in advanced SCC and since the addition of ionizing
radiation tests on both a pre-clinical and clinical rationale, we
conclude that this treatment is indeed feasible. We suggest that
further evaluation of the 13cRA/IFN combination in phase I/II
trials as an adjunct to radiotherapy might define the ultimate role of
the combination. However, patients should be carefully monitored
for the onset of pulmonary toxicity as well as for other side effects,
such as mucositis, skin reactions or diarrhea.
ACKNOWLEDGEMENTS
The assistance of Dr. I. Zuna, Heidelberg with the documentation of clinical data is gratefully acknowledged.
TABLE V – RESPONSES
Tumor type
Evaluable
Group A (13cRA/IFN-a/XRT)
Cervix
4
Head and neck
1
NSCLC
1
Esophagus
1
Group B (13cRA/IFN-a)
Cervix
12
Head and neck
9
NSCLC
5
Esophagus
3
CR
PR
SD
PD
0
0
0
0
2
1
1
0
1
0
0
1
1
0
0
0
0
0
0
0
3
0
0
0
6
8
3
3
3
1
2
0
CR, complete response; PR, partial response; PD, progressive
disease; SD, stable disease.
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