ARTICLE
Auteur(s) :, Mark E
Borowsky, Kevin S Elliott, John C Pezzullo, Paul Santoso,
Walter Choi, Kwang Choi, Ovadia Abulafia
State University of New York Health Science Center at Brooklyn?
Department of Obstetrics and Gynecology? Box #24? 450 Clarkson
Avenue? Brooklyn, NY 11203
Radiation therapy has become the standard of care treatment for
locally advanced cervical cancer in the United States. Techniques
first described in the early 1900s utilized intracavitary radium
(226Ra) for the treatment of carcinoma of the uterine
cervix and corpus [1–3]. In the 1930s the use of orthovoltage
teletherapy X-ray machines (operating at less than 1000 kV) was
pioneered in the treatment of malignant tumors [4]. From the
beginning it was recognized that tumor control was correlated with
the dose of radiation delivered, but that irradiation of normal
adjacent tissues was dose limiting. Modifications of teletherapy
technique were sought to maximize tumor cell kill while limiting
toxicity. One of the first advances was refinement of dose
fractionation that occurred in the 1930s [4]. This allowed a higher
total dose of radiation to be delivered to the tumor while limiting
the effects to normal tissues. In 1938 the Manchester brachytherapy
technique utilizing 226Ra was first described [5]. A
modified Manchester technique utilizing Cesium (137Cs)
in place of 226Ra, remains the most common delivery
technique today. Today, the combination of teletherapy and
brachytherapy, allows high doses of radiation to be delivered
directly to the tumor while limiting the dose to normal adjacent
tissue. This combination therapy has changed little today from
early descriptions in the literature in the mid-1960s [6,7].More
recent efforts to maximize tumor kill while maintaining or reducing
toxicity have focused on concomitant systemic delivery of various
substances to increase the sensitivity of the tumor to ionizing
radiation. Such therapy may work by increasing local tissue oxygen
concentration via hyperbaric oxygen [8,9], blood transfusion [10],
erythropoietin [11] or by targeting hypoxic tumor cells that are
relatively radio resistant [12]. None of these strategies has
provided a dramatic improvement in the treatment response or
survival of patients with locally advanced cervical cancer. By
contrast, early reports of the use systemic cytotoxic chemotherapy
with radiotherapy [13,14] seemed much more promising, and led to
the design and implementation of large, randomized phase III
trials.In 1999 and 2000, five randomized trials examining
concurrent chemoradiation (CRT) vs. radiation alone (RT) or with
hydroxyurea (HU) in the treatment of cervical cancer were published
in the New England Journal of Medicine and the Journal of Clinical
Oncology [15–19]. In each of the studies, chemoradiation (CRT) was
given with cisplatin (CDDP) with or without 5-fluorouracil (5-FU)
and compared to radiation (RT) alone or with hydroxyurea (HU). Four
of theses studies focused on patients with locally advanced disease
(FIGO stage IB2-IVA) [15–18] while one study examined
post-operative adjuvant radiation in patients with high risk, early
stage disease [19]. The results of these studies were remarkably
consistent and the benefit of CRT was large. Each study
demonstrated a relative risk of death of 0.54 to 0.74 for the CRT
groups compared to RT alone or with HU. This prompted the National
Cancer Institute to issue a rare clinical alert in February of
1999, urging a new standard of care for locally advanced cervical
cancer [20]. According to this new standard of care, strong
consideration should be given to adding concurrent chemotherapy
with a regimen containing CDDP when giving curative intent
radiation therapy for the treatment of invasive cervical cancer
[20].A more recent randomized phase III trial conducted by the
National Cancer Institute of Canada (NCIC) compared CRT to RT in
patients with cervical squamous cell carcinoma that was locally
advanced (IB2-IVA) or early stage (IA-IB1) with pelvic lymph node
metastases [21]. In this trial no statistically significant
difference was found in survival or progression free survival
between the RT and CRT arm. This recent study, as well as the
excellent editorial by Rose and Bundy in the same issue of the
Journal of Clinical Oncology [22] prompted us to examine our own
experience with RT vs. CRT.
Materials and methods
We performed a retrospective analysis of all of the patients with
locally advanced (stage IB-IVA) cervical cancer who were treated at
the State University of New York Downstate Medical Center or the
Kings County Medical Center between the years 1985 and 2000. Data
was collected from the individual hospital tumor registries and the
individual patient charts and by contacting patients and next of
kin. Data was collected regarding the date of diagnosis, tumor
histology, tumor stage, presence or absence of pelvic or
para-aortic lymph node metastases, dates of treatment, radiation
dose delivered to points A and B, use of concomitant chemotherapy
including type of chemotherapy and chemotherapy dose and schedule.
Information was also recorded regarding tumor recurrence, site of
recurrence and patient survival. Comparison of age between
treatment groups was by the Mann-Whitney U test; comparisons of
race, stage, grade and histology were by the Fisher Exact test.
Comparison of hemoglobin levels, radiation dose to point A and
duration of radiation therapy between treatment groups was by the
Student’s t-test. The analysis of the combined effects of age,
stage, grade, and treatment on survival was by Cox
proportional-hazards regression. Statistical analysis was performed
using Statistical Package for the Social Sciences (SPSS Inc.,
Chicago, IL) and R (http://www.R-project.org).
Results
We identified 291 patients treated with primary ‘intent-to-cure’
radiation therapy for stage IB to IVA squamous-cell carcinoma or
adenocarcinoma of the cervix. Table 1( Table
1 ) shows the characteristics of the 291 patients treated,
grouped according to whether they received concurrent chemotherapy
(with CDDP or 5-FU or both) and compared to those who did not
receive concurrent chemotherapy with either CDDP or 5-FU. There
were no differences between the two groups in any of the
descriptive characteristics that we examined (Table 1). However
there was a trend for the patients in the CRT group to be of a
higher stage (p=0.070) and younger at diagnosis (p=0.057).
All patients included in the analysis were treated with
‘intent-to-cure’ therapy which included the delivery of 75 Gy to
point A for those patients who were stage IB-IIA and 85 Gy to point
A for those patients with stage IIB or greater. The total dose was
intended to be delivered within 8 weeks of the treatment start
date. Teletherapy was delivered using 180 cGy daily fractions given
5 days per week for 25 to 28 fractions. Brachytherapy was delivered
using standard low dose rate 137Cs implants applied
using Fletcher-Suit or Henschke applicators utilizing the
Manchester technique [5]. Many of these patients received treatment
prescribed by Gynecologic Oncology Group or Radiation Therapy
Oncology Group protocols. The mean dose of radiation delivered to
point A did not differ significantly between the two treatment
groups (Table 2( Table 2 )). The time to
completion of treatment also was not statistically different
between the RT and CRT groups (Table 2). There was a trend toward
lower mean hemoglobin levels at presentation among patients in the
CRT group (10.62 vs.11.92 g/dL, p=0.055). Nadir hemoglobin levels
were lower among the CRT group than in the RT group (9.49 vs. 10.83
g/dL) and this difference was statistically significant
(p=0.015).
We analyzed patients using a stepwise Cox regression, including
as possible predictors: clinical stage, age at diagnosis, use of
concurrent chemotherapy with radiation and teletherapy delivered
with Cobalt (60Co) vs. linear accelerator (Linac). In
each analysis, the Univariate Tests of Significance tables show
which variables are individually associated with survival or
disease-free survival. For both disease free survival and
overall survival, clinical stage was highly significant as
expected. Age at diagnosis was a significant predictor of disease
free survival (p=0.043) but did not reach significance as a
predictor of overall survival (Table 3( Table
3 )). The teletherapy delivery device utilized
(60Co vs. Linac) was not a significant predictor of
outcome. The use of concurrent CDDP or 5-FU chemotherapy with
radiation (CRT) was also not associated with an increase in disease
free survival (p=0.734) or overall survival (p=0.989)
(Table 3).
We also examined survival as a function of CRT with a CDDP or
5-FU containing regimen using the Kaplan-Meier estimates of overall
survival (figure 1-3). For each stage of disease or stage grouping,
there appeared to be a trend favoring CRT over RT. However in all
cases the differences in survival curves were not statistically
significant. A multivariate analysis of the combined effects of
age, stage, grade, and treatment on survival (Table 4( Table 4 )) indicated that greater age and lower
tumor stage were highly significantly associated with survival
(p=0.003 and p<0.001, respectively), but grade of tumor and type
of treatment (CRT vs. RT) were not significantly associated with
survival (p=0.808 and p=0.265, respectively).
Table 1 Patient characteristics
|
- RT Without
- CDDP or 5-FU
- (n = 136)
|
RT with CDDP and/or 5-FU (n = 155)
|
Total (n = 291)
|
P value
|
|
Age
|
|
|
mean ± SD
|
56.4 ± 14.0
|
52.6 ± 14.1
|
54.4 ± 14.1
|
0.057
|
|
median (min – max)
|
55.5 (28 – 88)
|
51 (16 – 82)
|
54 (16 – 88)
|
|
Race
|
|
Black
|
108 (79.4%)
|
118 (76.1%)
|
226 (77.7%)
|
0.636
|
|
White
|
12 (8.8%)
|
19 (12.3%)
|
31 (10.7%)
|
|
Hispanic
|
12 (8.8%)
|
15 (9.7%)
|
27 (9.3%)
|
|
Asian
|
4 (2.9%)
|
2 (1.3%)
|
6 (2.1%)
|
|
Other or unknown
|
0
|
1 (0.6%)
|
1 (0.3%)
|
|
Stage
|
|
I-B
|
17 (12.5%)
|
7 (4.5%)
|
24 (8.2%)
|
0.0702
|
|
II-A
|
2 (1.5%)
|
1 (0.6%)
|
3 (3.0%)
|
|
II-B
|
55 (40.4%)
|
56 (36.1%)
|
111 (38.1%)
|
|
III-A
|
1 (0.7%)
|
4 (2.6%)
|
5 (1.7%)
|
|
III-B
|
51 (37.5%)
|
74 (47.7%)
|
125 (43.0%)
|
|
IV-A
|
10 (7.4%)
|
13 (8.4%)
|
23 (7.9%)
|
|
Grade
|
|
1
|
13 (9.6%)
|
8 (5.2%)
|
21 (7.2%)
|
0.148
|
|
2
|
36 (26.5%)
|
58 (37.4%)
|
94 (32.3%)
|
|
3
|
35 (25.7%)
|
39 (25.2%)
|
74 (25.4%)
|
|
Unknown
|
52 (38.2%)
|
50 (32.3%)
|
102 (35.1%)
|
|
Tumor histology
|
|
Squamous cell carcinoma
|
123 (90.4%)
|
143 (92.3%)
|
266 (91.4%)
|
0.795
|
|
Adenocarcinoma, adenosquamous, and other
|
13 (9.6%)
|
12 (7.7%)
|
25 (8.6%)
|
Table 2 Patient treatment characteristics
|
RT Without CDDP or 5-FU
|
RT With CDDP and/or 5-FU
|
P value
|
|
Hemoglobin (g/dL)
|
|
- Pretreatment mean ± SD
- Nadir mean ± SD
|
- 11.92 ± 2.16
- 10.83 ± 1.52
|
|
|
|
Radiation dose to point A (cGy)
|
|
|
mean ± SD
|
7842 ± 742
|
7934 ± 701
|
0.498
|
|
Radiation treatment duration (days)
|
|
|
mean ± SD
|
63.5 ± 9.8
|
68.3 ± 17.1
|
0.368
|
Table 3 Univariate tests of significance in
disease-free and overall survival
|
Variable
|
p-value for effect of variable on
|
|
Disease-free survival
|
Overall survival
|
|
Age at diagnosis
|
0.043
|
0.069
|
|
Stage
|
< 0.001
|
< 0.001
|
|
CRT use
|
0.734
|
0.989
|
|
Co60 vs. linear accelerator
|
0.816
|
0.372
|
Table 4 Multivariate analysis of predictors of overall
survival
|
Predictor
|
Regr coeff ± SE
|
Relative risk (95% CI)
|
P-value
|
|
|
|
|
|
Age at diagnosis (years)
|
–0.018 ± 0.006
|
0.982 (0.971 – 0.994)
|
0.003
|
|
Stage of tumor
|
+0.355 ± 0.067
|
1.426 (1.251 – 1.625)
|
<0.001
|
|
Grade of tumor
|
+0.038 ± 0.157
|
1.039 (0.764 – 1.414)
|
0.808
|
|
CRT vs. RT alone
|
–0.184 ± 0.165
|
0.832 (0.601 – 1.150)
|
0.265
|
Discussion
There have been few major advances in the treatment of cervical
cancer over the past three decades. In 1999 the addition of
concomitant chemotherapy to radical radiotherapy became the new
standard of care according to the National Cancer Institute [20].
This paradigm shift was based on the near simultaneous reporting of
five randomized, controlled clinical trials which all showed an
improvement in survival of between 26% and 46% [15–19]. Not all
studies since that time have found the same magnitude of a
difference between RT and CRT. In particular, the large prospective
NCIC trial reported an improvement in survival in the CRT group of
13%, but that difference was not statistically significant and had
a 95% confidence interval of –23% to 67% [21]. In our own
retrospective data analysis there appeared also to be a trend in
favor of CRT over RT, but this difference was not statistically
significant. The relative risk of death for patients treated with
CRT was 0.832 (95% CI, 0.601, 1.150) with a p value of 0.265.
Although our study was a retrospective data analysis, our RT and
CRT patients appear to be well matched. There was no statistical
difference on characteristics such as age, race, tumor histology,
and tumor stage and tumor grade. With respect to pelvic and
para-aortic node status, tumor size at diagnosis, pre-treatment
hemoglobin levels, total radiation dose delivered and the total
time to radiation completion, our groups appeared to have been
equivalent at diagnosis. All of these factors have previously been
shown to be significant predictors of survival in patients with
locally advanced cervical carcinoma treated with radiation therapy
[23].
Although there were no statistically significant differences in
any of the above factors, there were some trends suggesting a
difference between our groups. Specifically the CRT group had a
trend toward higher stage of disease (p=0.070), longer time for
completion of therapy (68.3 vs. 63.5 days) and lower hemoglobin at
presentation (p=0.055) and yet there was a trend favoring increased
survival in the CRT group as compared to the RT group (RR of
death=0.832). We hypothesize that if our RT and CRT groups been
even more similar, the 17% improvement in survival favoring CRT
would have been even greater.
Another finding of interest was the association of increased age
with an improvement in disease free survival (p=0.043) (Table 3).
While this difference was not quite large enough to extend to
overall survival (p=0.069) (Table 3), it stands in contrast to
several large studies that have found no difference in survival
based on age [24,25] or an improvement in disease free and/or
overall survival with younger age when other known risk factors are
controlled for [26–28].
Our data also confirmed that 60Co and Linac units
offer comparable rates of disease free and overall survival in
patients with locally advanced cervix carcinoma, a finding which
our institution had previously reported on a subset of these same
patients [29].
We agree that the preponderance of the evidence suggests a
benefit of CRT over RT. This survival benefit which has been
estimated by others to be 35 % [22] was not apparent in our
data. In our study the improvement in survival for CRT vs. RT was
about a 17 %. This was not statistically significant owing to
a lack of power of our study to detect a difference in survival of
this magnitude. The rather wide confidence interval around our risk
estimate indicates that the benefit of CRT over RT could be as
large as 40 %, which would be consistent with the other
reported estimates [15–19]. We offer the following possibilities as
to why we were unable to show a difference in survival between RT
and CRT. The first possibility is that the two groups we examined
were substantially different from each other in a way that we
failed to detect. This is a possibility in a study where the
treatment assignments are non-random. For example, we have already
addressed that there were trends suggesting that the CRT group was
of somewhat more advanced disease at diagnosis (higher stage, lower
hemoglobin). Additionally it is possible that the CRT patients had
more medical co-morbidities than the group which was offered RT
alone. Another plausible possibility is that the true magnitude of
the treatment effect is considerably less than the 35 %
previously reported. Our study was adequately sized to provide
80 % power to detect this 35 % effect size, but as is
always the case, smaller effects require larger samples to
demonstrate significance. For example, if CRT actually provides
only a 20 % survival benefit over RT, then a retrospective
study such as ours would need about 1,100 subjects for 80 %
power to obtain a significant result. Our results agree with the
recent randomized prospective phase III trial conducted by the
National Cancer Institute of Canada in which no statistically
significant difference was found in survival or progression free
survival between RT and CRT in patients with locally advanced
(IB2-IVA) or early stage (IA-IB1) cervical cancer with pelvic lymph
node metastases [21]. In that study as in ours, there was a trend
in favor of CRT, but the magnitude of the difference was smaller
than that which had been previously reported.
At our institution we continue to offer and deliver concurrent
cisplatin based chemotherapy to our patients with locally advanced
cervical cancer. We continue to pursue techniques and adjuncts to
the treatment of this disease in the desire to make greater headway
towards decreasing recurrence and improving survival. The addition
of therapeutic vaccines [30] or anti-angiogenesis agents such as
angiostatin [31] or cox-2 [32–34] inhibitors may eventually add
additional survival benefit to CRT when these agents are added in
the initial treatment of patients with locally advanced cervical
cancer. The Radiation Therapy Oncology Group is currently studying
in a phase II trial the combination of celecoxib and
cisplatin-based chemotherapy with radical radiation therapy in
patients with locally advanced cervical carcinoma. Preliminary
evidence suggests that inhibition of COX-2 can down-regulate
angiogenesis and may work cooperatively to increase the efficacy of
radiation therapy without enhancing toxicity [32–34].
Alternatively, agents that are selectively cytotoxic to hypoxic
cells may work to complement radiation therapy which is primarily
effective in well oxygenated tissue. One such agent, tirapazamine
(TPZ), has been studied and found to be well tolerated when given
in combination with CDDP and radical radiotherapy [35]. The use of
combination chemotherapy, or the addition of agents that
specifically inhibit angiogenesis, increase tumor apoptosis or
target hypoxic cells will, when added to radiation, likely
represent the next significant gain in the treatment of locally
advanced cervical carcinoma.
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