ARTICLE
Basal cell carcinoma (BCC) is the most common form of skin cancer. It
usually develops in areas of the skin most exposed to the sun, and incidence
is increased in old age. Despite effective therapies being available,
such as surgery, cryotherapy or radiotherapy, the treatment of BCC remains
problematical in some areas of the body, especially around the eyes and
mouth, and over the cartilage of the nose and ears. Although conventional
therapies are effective in these problem areas, they are often associated
with undesirable side effects, including scarring, and in some cases permanent
damage and functional defects. The consequences of these conventional
therapies are distressing to patients and can affect quality of life.
A different approach to the treatment of BCC, involving the injection
of recombinant interferon beta-1a (rIFN-beta-1a) directly into the tumour,
has been shown not only to be effective, but also to avoid the side effects
associated with conventional therapies. In a dose-finding study involving
69 evaluable patients with BCC, intratumoural application of rIFN-beta-1a
(0.5-3.0 x 106 IU, 1-3 times a week) resulted in complete remissions
(CR) in up to 86% of the patients [1]. In another placebo-controlled study,
which recruited 30 evaluable patients with BCC and used the same treatment
regime, 47% of intratumoural rIFN-beta-1a-treated patients had CR, compared
to 0% in the placebo group [2].
The objective of this study was to confirm the positive effect of intratumoural
rIFN-beta-1a demonstrated in previous trials, by evaluating the response
rate in a larger population of BCC patients. Secondary objectives of the
study were to determine the possible impact of tumour type/size on treatment
response as well as residues, cosmetic effects and the relapse rate after
CR, as well as to establish the safety profile of intratumoural rIFN-beta-1a
in BCC patients.
Patients and methods
Study design
This was an open-label, non-randomised, Phase III study evaluating the
efficacy of intratumoural rIFN-beta-1a in patients with BCC. The study
was conducted in accordance with the ethical principles stated in the
Declaration of Helsinki. The study protocol was approved by nine ethics
committees. All subjects gave written informed consent prior to participation
in the study.
Patients
Patients eligible for this study had a clinical and histological diagnosis
(by means of a 2 mm punch biopsy) of BCC with a mean diameter between
5-20 mm. For ethical considerations only patients were included in the
study who had been classified by the investigator as being a problematic
case i.e. owing to the tumor location or the patient's refusal
to undergo conventional therapy (excision or radiotherapy). Patients were
specifically excluded from the study if they had a scleroderma form of
BCC, severe concomitant diseases, significant abnormal laboratory values,
immune deficiencies, were taking immunosuppressive therapies or there
was a restricted legal capacity. A total of 139 Caucasian patients were
enrolled in the study, of which 133 patients were included in the efficacy
analysis. Four patients were excluded owing to withdrawal of consent,
death or lack of eligibility before the start of therapy. Two other patients
with major inclusion/exclusion criteria violations (BCC diameter too large
and/or scleroderma type of BCC) were also excluded from the efficacy analysis.
The patient baseline characteristics are summarised in Table
I.
Treatment
Patients received intratumoural injections of human rIFN-beta-1a derived
from Chinese hamster ovary (CHO) cells (Bioferon®, Rentschler
Biotechnology, Laupheim, Germany) three times a week for three consecutive
weeks. A single dose of rIFN-beta-1a contained 1.0 x 106 IU
(i.e. total dose 9.0 x 106 IU). According to the protocol,
at least eight of nine scheduled injections had to be given. The intratumoural
injections had to be administered in a way that ensured the entire tumour
was reached. 131 patients (including the two with major inclusion or exclusion
criteria violations) received nine injections of rIFN-beta-1a. One patient
received eight injections. Three patients received one, two or three injections,
respectively. Nevertheless, these three patients were included in the
efficacy analysis.
Asessement of treatment efficacy, side effects
and follow-up
During the 3-week treatment period and the subsequent 13-week observation
period, the clinical response to therapy and local and systemic adverse
events (AEs) were monitored. Laboratory parameters e.g. haematology
and blood chemistry, were investigated at baseline and after week 1, 2,
3 and 6 of the study. Blood serum was tested for neutralising anti-IFN-beta
antibodies at baseline and after Week 16. Therapeutic outcome was investigated
after week 16 both clinical and by histological examination (2 mm punch
biopsy or larger excision). Local AEs were generally considered to be
adverse drug reactions (ADRs). Systemic AEs were regarded as ADRs if they
were assessed to have a possible, probable or definite relationship to
the study medication. A follow-up examination was obligatory for all responders
after 6 months and 1 year following the 16-week assessment, and optional
after 2, 3, 4 and 5 years.
Statistical
analysis
All data were analysed descriptively. Discrete variables were evaluated
by absolute and relative frequencies. Quantitative variables were evaluated
by number of patients; minimum, median, maximum, mean and standard deviation.
For evaluation of the results of the rIFN-beta-1a therapy, success rates
were computed and their 95% confidence intervals were given. Furthermore,
chi-square test and Wilcoxon two-sample test were used for explorative
analysis.
Results
Efficacy evaluation
After 16 weeks, 66.9% (range 58.2-74.8%, 95% CI) of patients had responded
(i.e. clinical and histological CR) to treatment with rIFN-beta-1a.
The clinical and histological results of the responder and non-responders
are summarised in Table II.
Altogether, 89 patients were regarded as responders (87 with clinically
CR and negative biopsy) two patients achieved CR without confirmation
by biopsy. For one of these patients, both the clinical and the histological
results were missing after 16 weeks; however, one year later and on all
further scheduled follow-up examinations the patient presented with CR.
In the other patient with CR a final biopsy was not performed because
the patient died during the observation period 4 weeks after the last
application of rIFN-beta-1a (unrelated to the study medication). This
patient, however, was included according to the last-observation-carried-forward
method.
No difference could be shown in response rate between solid BCCs and
other types of BCC (chi-square test: two sided p = 0.94). Furthermore
no significant difference could be shown in BCC diameter (Wilcoxon two-sample
test: two-sided p = 0.47). Hence, within the 5.0-20 mm diameter
tumour size range, there were no significant differences in the response
rate, although there was a trend towards higher efficacy in smaller BCCs
(Fig. 1).
Residues of BCC and/or biopsy wounds were found in 96 patients (72%)
in the form of scars, milia, cysts, pigmentation, erythema and others;
31 patients (23%) had no residues. The proportion of patients without
residues was 22.5% (20/89) for responders (95%-CI: 14.3-32.6%) and 25%
(11/44) for non-responders (95%-CI: 13.2-40.3%). Investigators determined
that 88 patients (66%) had a very good or good cosmetic result and 36
patients (27%) had a moderate or bad cosmetic result. Among the responders,
a very good or good cosmetic result was observed in 74 patients (83%).
The patients considered the cosmetic result to be very good or good in
90 (68%) and to be moderate or bad in 33 (25%) cases. Of the responders,
74 (83%) rated the cosmetic result as very good or good.
One-year follow-up investigations were carried out in 82 (92%) responders,
and a 5-year follow-up in eight patients (9%). The median (mean) duration
of follow-up was 105.1 (120.1) weeks. At the follow-up assessments, local
relapses and the development of BCCs in other locations were examined.
Of the 89 responders, four patients showed a histologically confirmed
relapse (one patient after 6 months, two patients after 1 year and one
patient after 2 years). Thus, the relapse rate within the 105.1-week follow-up
period was 4.5% (95%-CI: 1.2-11.1%). In 19 of the 89 responders a larger
excision or several biopsies were performed at the final examination.
None of these 19 patients showed a relapse. Not including these patients,
the relapse rate for the remaining 70 patients was 5.7% (95%-CI: 1.6-14.0%)
after a median (mean) follow-up period of 106.0 (125.3) weeks. Seventeen
of the 89 responders developed an additional BCC at another site of the
body during the follow-up period.
Safety evaluation
Local adverse drug reactions (ADRs) were monitored and recorded after
Weeks 1, 2, 3, 6, 9 and 12, of the study. Erythema was the most commonly
recorded symptom. Other symptoms included swelling, infiltrate, crust,
inflammation, pruritus, and burning. All patients treated with at least
two injections experienced local inflammatory symptoms. These were graded
mild in 11%, moderate in 48%, intense in 35% and very intense in 6% of
the patients.
In total, 81 systemic ADRs occurred in 32 patients. Mild systemic ADRs
occurred in 17%, moderate in 8% and severe in 2% of the included patients.
There were no statistically significant changes in mean laboratory values
during the study. In six patients, drug-related changes in laboratory
values (toxicity grade 2) occurred. Altogether, systemic clinical ADRs
and drug-related laboratory changes occurred in 37/139 patients (26.6%,
95% CI: 19.5-34.8%). Serum samples of 107 patients were analysed for the
presence of neutralising anti-IFN-beta anti-bodies at baseline and after
16 weeks of therapy. No antibodies were detected.
Discussion
These results support the findings of two previous studies using the
same dosage and therapy regimen [1, 2]. The 66.9% response rate in this
study falls between the 86% and 47% response rates found in these studies.
The patient baseline characteristics were similar in all three studies
so the differences in response rate was probably due to the relatively
small number (14 or 15, respectively) of patients enrolled in the previous
studies. The present study reflects the findings of a much larger and
more representative patient population. The proportion of tumor tissue
removed by the obligatory diagnostic 2 mm punch biopsy before treatment
amounts for approx. 3 to 16% of BCCs measuring between 20 and 5 mm in
diameter respectively. As have been demonstrated, biopsies of comparable
size are insufficient to induce a tumor relapse without further treatment
[2].
The response rate (66.9%) found in this study is very similar to the
rate (67.1%) found in the largest trial using rIFN-alpha-2b (140 patients
with BCC), with similar inclusion and exclusion criteria [3]. This suggests
that both these interferons are equally effective in treating BCC.
In this study the relapse rate after CR was 4.5% (4/89) after a median
follow-up of 2 years. This is lower than found in the previous dose-finding
study (9%: 3/32), with median follow-up 1.5 years). The higher rate in
the former study is again likely to be the result of the small number
of patients that were enrolled. The results from this current study, however,
show that the relapse rate after successful treatment of BCC with rIFN-beta-1a
is no higher than after conventional methods (except Moh´s surgery)
[4-6].
All patients in the study experienced local ADRs in the form of
inflammatory reactions.
This inflammation was probably the result of the intratumoural (intracutaneous)
route of administration. The hypothesis that there is a correlation between
the level of inflammation and response was not confirmed. This, however,
does not exclude the possibility that an inflammatory reaction may be
a necessary part of therapeutic success when using intratumoural rIFN-beta-1a
in the treatment of BCC. As would be expected when using interferons,
systemic ADRs consisted mostly of flu-like symptoms. Systemic ADRs occurred
in 27% of the patients. This corresponded with data obtained in previous
studies using rIFN-beta-1a, and was considerably lower than that observed
when using IFN-alpha-2b [7-12]. The relatively low number of systemic
ADRs with rIFN-beta-1a, compared to IFN-alpha-2b, is probably due to its
higher tissue affinity and to the lower doses that are needed to induce
CR [13].
CONCLUSION
In summary, these results show that intratumoural injections of rIFN-beta-1a
are effective in the treatment of BCC in the majority of patients. In
addition, rIFN-beta-1a is safe and generally well tolerated. rIFN-beta-1a,
therefore, represents an effective alternative treatment for BCC.
Article accepted on 20/8/02
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