Review
Current approaches of
CONTENTS
Neoadjuvant chemotherapy
combined with radiation
Neoadjuvant chemotherapy
combined with
radical surgery
Concurrent chemoradiation
Neoadjuvant chemotherapy
for adenocarcinoma of
the uterine cervix
Cellular mechanisms
regulating the
responsiveness of
neoadjuvant chemotherapy
Expert opinion
Five-year view
Key issues
References
Affiliations
Division of Gynecologic Oncology,
Department of Obstetrics and
Gynecology, Niigata University
Graduate School of Medical and
Dental Sciences, 1-757 Asahimachi
dori Niigata 951–8510, Japan
Tel.: +81 25 227 2321
Fax: +81 25 227 0789
yoichi@med.niigata-u.ac.jp
KEYWORDS:
5-fluorouracil, cervical cancer,
cisplatin, concurrent
chemoradiation, hydroxyurea,
neoadjuvant chemotherapy,
paclitaxel, radical hysterectomy
www.future-drugs.com
neoadjuvant chemotherapy
in cervical cancer
Yoichi Aoki† and Kenichi Tanaka
Despite remarkable improvement in clinical management, the survival of cervical cancer
patients has shown only minor progress in the last decade, particularly in patients with
advanced and high-risk disease. Multimodal treatment option has been investigated,
such as the concurrent use of chemotherapy and radiation, neoadjuvant chemotherapy
and radical hysterectomy, or neoadjuvant chemotherapy followed by radiotherapy.
Recently, a flow of randomized clinical trials have demonstrated a benefit from the
concurrent chemoradiation for the treatment of the cancer of the cervix. This review will
summarize the role and benefit of neoadjuvant chemotherapy in combination with
sequential or concurrent radiotherapy and radical surgery for treatment of cervical
cancer.
Expert Rev. Anticancer Ther. 2(1), 73–82 (2002)
Cancer of the cervix is the second most com- Neoadjuvant chemotherapy
mon malignancy in women worldwide [1]. combined with radiation
Patients with locally advanced cervical cancer Although a variety of chemotherapeutic agents
comprise a significant proportion of the total provide overall response rates of 10–25% for
population with cervical cancer. The inability recurrent or metastatic cervical cancer,
to control pelvic tumors is still a significant response durations are usually short. The high-
concern. Surgery, radiation and chemother- est response rates are observed with cisplatin
apy have been used in a variety of settings in (20–25%). In randomized clinical trials, cispl-
hope of improving disease control and sur- atin-containing chemotherapy has often been
vival rates of patients with cervical cancer. carried out but has failed to demonstrate
Most investigators agree that patients at the improvement in survival in recurrent or meta-
early stages of cervical cancer can be treated static disease. However, in previously
with surgery or radiation therapy. Surgery, untreated patients in a neoadjuvant setting
however, is the preferred treatment in young much more encouraging response rates of 50–
women because it allows ovarian and sexual 60% have been reported by using multiple-
function to be preserved. Multiple modalities agent cisplatin-containing regimens [2–15].
may be applied only if required. However, Therefore, improvement in survival for
multimodal treatment can also be part of an patients with locally advanced disease was
initial treatment plan. Recently, a number of expected since these response rates could
clinical trials have demonstrated a benefit reduce tumor volume. A number of prospec-
from the preoperative neoadjuvant chemo- tive randomized trials were conducted to com-
therapy or the concurrent use of chemother- pare radiation alone with neoadjuvant chemo-
apy and radiation for the treatment of cancer therapy followed by radiation [2,4,8,9,11–15]. Of
of the cervix. This article will summarize the eight published trials, however, six showed
these studies, which provide the most signifi- no survival benefit from neoadjuvant chemo-
cant improvement in the treatment of locally therapy and two demonstrated a significantly
advanced or high-risk disease in more than better survival rate in patients treated with
30 years. radiation alone. Souhami et al. reported that
© Future Drugs Ltd. All rights reserved. ISSN 1473-7140 73
Aoki & Tanaka

patients treated with neoadjuvant chemotherapy consisting of
bleomycin, vincristine, mitomycin-C and cisplatin followed by
radiation had a significantly lower survival rate than those
treated with radiation alone [8]. In this study, four patients died
due to pulmonary bleomycin toxicity, which may have
explained the poor survival rate in patients treated with neoad-
juvant chemotherapy. A study by Tatersall et al. in 1995 uti-
lized cisplatin and epirubicin as the neoadjuvant regimen [9].
Despite the elimination of bleomycin, this study was discontin-
ued early when an interim analysis revealed a detrimental effect
of neoadjuvant chemotherapy on survival (p = 0.02).
Whether the initial response to chemotherapy predicts subse-
quent response to radiation and survival has been controversial.
Chauvergne et al. reported that patients who achieved a complete
or partial response by neoadjuvant chemotherapy had signifi-
cantly better survival rates than those treated with radiation alone,
although they demonstrated a lack of overall improvement with
neoadjuvant chemotherapy [2]. On the other hand, Leborgne
et al. showed that the response to neoadjuvant chemotherapy was
not a predictor of local control or survival [4].
Recently, Tiernery et al. performed meta-analysis concerning
the effect of neoadjuvant chemotherapy on survival of patients
with locally advanced cervical cancer [16]. They reported that
the estimated odds ratios varied across the individual trials, the
95% confidence intervals were wide and in general the trials
appeared were null or negative. Overall, the results of rand-
omized clinical trails of neoadjuvant chemotherapy combined
sequentially with radiation in the cancer of the cervix have been
disappointing (TABLE 1).
Neoadjuvant chemotherapy combined with radical surgery
Many investigators have begun to explore combinations of
neoadjuvant chemotherapy with radical surgery. Recently, neo-
adjuvant chemotherapy for bulky or locally advanced cervical
cancer has received increasing attention and some authors have
reported promising response rates [17–23]. The use of neoadju-
vant chemotherapy as part of a multimodal treatment offers
some theoretical advantages in high-risk diseases. Chemother-
apy may shrink bulky tumors and microscopic spread of tumor
cells and may also reduce the incidence of lymph node metas-
tases. Accordingly, radical surgery can remove residual cervical
tumor after neoadjuvant chemotherapy. More importantly,
patients are thought to attain a superior survival rate compared
with a control group given conventional therapy [17,23].
Only three randomized trials using iv. neoadjuvant chemo-
therapy combined with surgery have been reported thus far
(TABLE 2). In one of the first prospective randomized studies of
neoadjuvant chemotherapy in early-stage cervical cancer, Sardi
et al. reported their final results in 205 stage IB carcinoma of
the cervix [17]. Patients were treated with radical hysterectomy
followed by 50 Gy radiotherapy to the pelvis with or without
neoadjuvant chemotherapy. In patients with stage IB1, neoad-
juvant chemotherapy did not improve overall response or sur-
vival compared with those not receiving chemotherapy. In
patients with stage IB2, there was 83.6% (51 of 61) partial or
complete response to chemotherapy. The authors reported a
higher response rate (100 vs. 85%) and overall survival after
9 years of follow-up was 61% for the control group and 80%
for the neoadjuvant group (p < 0.01). After 7 years of follow-
up, the outcome of the unresectable bulky control group of
patients is significantly worse (14%) than that of the resectable
group (69%; p < 0.001). With regard to recurrences, a signifi-
cant decrease in pelvic failures in the neoadjuvant chemother-
apy group was observed (p < 0.001). Survival was improved in
bulky resectable cases (p < 0.05). Pathological findings for the
surgical specimens revealed differences between both groups
because all the risk factors, such as parametrial and lymph
node metastases, tumor bulk and vascular embolism had been

Table 1. Randomized clinical trials of neoadjuvant chemotherapy combined with radiation in cervical cancer.
Authors N Regimen Response (%) Survival (%) Ref.
CT/RT RT CT/RT RT p
Chavergne 138 POMTXC 84.9 88.9 63 60 NS
Tobias 66 BIP 75 56 NS [11]

Souhami 107 BOMP 47 32.5 23 39 NS [8]

Cardenas 28 PECy 5 86 36 50 NS [12]

Kumar 177 BIP 70 69 38 43 NS [13]

Leborgne 130 BOP 68 65 38 49 NS [4]

Tatersall 260 EpP 72 92 47 70 0.02 [9]

Sundfor 94 CI 53 57.5 38 40 NS [14]

Chiara 58 C 78 81 72 83 NS [15]

B: Bleomycin; C: Chlorambucil; Cy: Cyclophophamide; Ep: Epirubicin; I: Ifosphamide; M: Mitomycin C; MTX: Methotrexate; O: Vincristine; P: Cisplatin.

74 Expert Rev. Anticancer Ther. 2(1), (2002)


decreased (p < 0.001). They concluded that neoadjuvant
chemotherapy was able to improve survival because of
increased operability with free survival margins and a decrease
in pathologic risk factors in unselected, stage IB2 patients.
In another trial, Benedetti-Panici et al. randomized 441
patients with stage IB2–III cervical squamous cell carcinoma
to neoadjuvant chemotherapy and radical surgery versus radia-
tion therapy alone [23]. Progression-free survival and overall
survival were reported to be improved with neoadjuvant chem-
otherapy, where the 4-year overall survival and progression-free
survival rates were 62 and 59%, and 48 and 45% for neoadju-
vant chemotherapy arm and the radiotherapy arm (p = 0.007
and 0.01), respectively. Subgroup survival analysis revealed an
overall and progression-free survival of; 66% and 62.5% (stage
IB2–IIB, neoadjuvant arm), 51 and 47% (stage IB2–IIB, radi-
ation arm) (p = 0.0005 and 0.02); 48 and 47% (stage III, neo-
adjuvant arm), 37 and 36% (stage III, radiation arm), respec-
tively. They concluded that although more evident for the
stage IB2–IIB than for the stage III group, a survival benefit
might be associated with the neoadjuvant chemotherapy com-
bined with radical surgery. But in this study, only 70 Gy to
point A of the total radiation dose was used for patients treated
with radiation alone, which is well below current standards in
the USA.
More recently, Chang et al. also reported that 124 women
with previously untreated bulky (primary tumor > 4 cm) stage
IB or IIA non-small cell carcinoma of the uterine cervix were
randomly assigned to receive either cisplatin 50 mg/m2 and vin-
cristine 1 mg/m2 for 1 day and bleomycin 25 mg/m2 for 3 days
for three cycles followed by radical hysterectomy or receive pri-
mary pelvic radiotherapy only [20]. The median duration of fol-
low-up was 39 months. Thirty-one percent of patients in the
neoadjuvant chemotherapy arm and 27% in the radiotherapy
arm had relapse or persistent diseases after treatment and 21%
in each group died of disease. Estimated cumulative survival
rates at 2 years were 81% for the neoadjuvant chemotherapy
arm and 84% for the radiotherapy arm; the 5-year rates were 70
and 61%, respectively. There were no significant differences in
disease-free survival and overall survival. They concluded that
neoadjuvant chemotherapy followed by radical hysterectomy
and primary radiation therapy showed similar efficacy for bulky
stage IB or IIA cervical cancer. Although these results are of
interest, it may be ultimately necessary to identify patient sub-
groups better suited for either treatment modality and to com-
pare the efficacy and toxicity of this trimodal approach with
optimal dose and schedule concurrent use of chemotherapy and
radiation without routine hysterectomy.
Moreover, two randomized studies of intra-arterial neoadju-
vant chemotherapy have been reported thus far. Park et al. per-
formed a Phase III study of intra-arterial (arm 1), or systemic
(arm 2) neoadjuvant chemotherapy versus radiation therapy
only (arm 3) for stage IIb bulky carcinoma of the uterine cervix
[24]. A combination of mitomycin-C, vincristine and cisplatin
was used in arms 1 and 2. The mean volume reduction rate was
not statistically different but pathologic complete response rate
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Neoadjuvant chemotherapy in cervical cancer
(50% in arm 1 vs. 0% in arm 2, p = 0.038) was significantly
higher in arm 1. They suggested that neoadjuvant intra-arterial
chemotherapy was effective in increasing pathologic complete
response rate and decreasing the requirement of postoperative
radiotherapy in most patients with stage IIb bulky cervical can-
cer. Kigawa et al. performed randomized study using intra-arte-
rial infusion chemotherapy on the cure rate in advanced cervi-
cal cancer with bulky tumor in 50 patients [25]. They concluded
that neoadjuvant intra-arterial infusion chemotherapy did not
improve the prognosis of patients with advanced cervical cancer
compared to radiation therapy alone and only responders who
underwent surgery obtained an advantage in survival.
In these trials, since most of patients received adjuvant radio-
therapy as well as neoadjuvant chemotherapy and surgery, it
may complicate the interpretation of the results. Furthermore,
most investigators addressed that the use of neoadjuvant chem-
otherapy for cervical cancer was not justified in small tumors
(<3–4 cm in diameter) because in those cases, survival was not
improved with this new strategy [17]. However, it has previously
been reported that the incidence of lymph node metastasis was
significantly high in younger (<50 years) cervical cancer
patients with deep stromal invasion (outer 1/3 or parametrial
infiltration), even with cervical tumors less than 4 cm in diame-
ter. Also it was concluded that the 5-year survival rate of
patients with lymph node metastasis accompanied by deep stro-
mal invasion was significantly poorer in younger patients com-
pared with patients of 50 years or older [26,27]. Therefore, a trial
was performed to assess the efficacy of neoadjuvant chemother-
apy for the improvement of prognosis in this subgroup of
patients. In our study, we used PVP (cisplatin 60 mg/m2 on
day 1, vinblastine 4 mg/m2/day on days 1, 2 and peplomycin
10 mg/day on days 1, 8, 15) regimen for younger (<50 years)
patients with locally advanced cervical carcinoma – including
stage IB1 with deep stromal invasion – in a neoadjuvant setting
[22]. An 86% response rate was acheived (0 CR, 18 PR), which
was almost equal or higher than those reported previously by
others [17–20]. Histological examination revealed mild-to-mod-
erate chemotherapy effects in primary tumor site. Pathological
findings for the surgical specimens revealed differences between
both groups because all the risk factors, such as parametrial and
lymph node metastases, tumor bulk and vascular embolism had
been decreased. The neoadjuvant chemotherapy in this study
reduced the size of the bulky tumor as well as tumor infiltration
to deep cervical stroma or parametrium, to allow radical sur-
gery with a final pathological diagnosis of negative parametrial
and vaginal margins in all patients. This treatment may be of
benefit to the patients in that regard. With regard to recur-
rences, all four were distant recurrence in our neoadjuvant
chemotherapy group, while in the control group there were
three local, three distant and two combined recurrences. A
decrease in pelvic failure in the neoadjuvant chemotherapy
group was observed, which might be due to an increased opera-
bility with the neoadjuvant chemotherapy and an effect of post-
operative adjuvant radiotherapy. Previous reports described that
a significant reduction in the local relapse rate was observed in
75
Aoki & Tanaka
patients treated with neoadjuvant chemotherapy plus radical
hysterectomy plus adjuvant radiotherapy [17,18]. In our study,
three patients died of disease and the median survival period
was 36 months. The overall 5-year estimated survival rate was
significantly higher than that in the control group, although the
relatively small number of patients in this study and a short
time period of follow-up in some patients does limit the power
of the assessment. The neoadjuvant chemotherapy using PVP
for younger patients with locally advanced cervical carcinoma is
thought to be safe, well-tolerated and effective. It may be useful
to increase operability, decrease pathological risk factors and
improve survival. Nevertheless, further studies are required
before the PVP regimen is proposed for these patients.
Concurrent chemoradiation
Radical pelvic irradiation has constituted the definitive therapy
for patients with large cervical cancers. No substantial improve-
ments have been made in treatment outcomes. In the past year,
however, a series of large, well-conducted randomized trials has
evaluated the role of concurrent chemotherapy with pelvic irra-
diation in cervical cancer. These trials include definitive treat-
ment of patients with stage IB2–IVA disease and adjuvant
treatment after radical surgery in stage IB2–IIA disease
(TABLE 2). Five landmark trials have shown a consistent 30–50%
reduction in the risk of death from disease when concurrent
chemotherapy is used.
The Gynecologic Oncology Group (GOG) performed a ran-
domized trial of radiotherapy in combination with three con-
current chemotherapy regimens – cisplatin alone; cisplatin,
fluorouracil and hydroxyurea; and hydroxyurea alone – in
patients with locally advanced cervical cancer [28]. Women with
primary untreated invasive squamous-cell carcinoma, adenosq-
uamous carcinoma, or adenocarcinoma of the cervix of stage
IIB, III or IVA, without involvement of the para-aortic lymph
nodes, were enrolled. All 526 patients received external-beam
radiotherapy and were randomly assigned to receive one of the
three chemotherapy regimens: 40 mg/m2/week of cisplatin for
6 weeks (group 1); 50 mg/m2 of cisplatin on days 1 and 29, fol-
lowed by 4 g/m2 of fluorouracil given as a 96-h infusion on
days 1 and 29, and 2 g/m2 of oral hydroxyurea twice weekly for
Table 2. Randomized clinical trials of iv. neoadjuvant
chemotherapy followed by radical surgery.
Authors N Stage Response Survival (%)
(%)
CT/ RT p hysterectomy. Women with evidence of lymphadenopathy on
RS
Sardi 205 IB 83.6 63 60 <0.01
BenedetP 441 IB-2-III 62 48 0.0007
anici
Chang 124 IB, IIA 86.2 70 61 NS
bulky
CT: Chemotherapy; RS: Radical surgery; RT: Radiation therapy.
76
6 weeks (group 2); or 3 g/m2 of oral hydroxyurea twice weekly
for 6 weeks (group 3). The median duration of follow-up was
35 months. Both groups that received cisplatin had a higher
rate of progression-free survival than the group that received
hydroxyurea alone (p < 0.001 for both comparisons). The rela-
tive risks of progression of disease or death were 0.57 in group 1
and 0.55 in group 2, as compared with group 3. The overall
survival rate was significantly higher in groups 1 and 2 than in
group 3, with relative risks of death of 0.61 and 0.58, respec-
tively. The authors concluded that regimens of radiotherapy
and chemotherapy that contain cisplatin improve the rates of
survival and progression-free survival among women with
locally advanced cervical cancer.
In a subsequent trial by the Radiation Therapy Oncology
Group (RTOG) [29], 403 women with advanced cervical cancer
confined to the pelvis (stage IIB–IVA or stage IB or IIA with a
tumor diameter of at least 5 cm or involvement of pelvic lymph
nodes) were randomly assigned to receive either 45 Gy of radia-
tion to the pelvis and para-aortic lymph nodes or 45 Gy of radi-
ation to the pelvis alone plus two cycles of fluorouracil and cis-
platin (days 1 through 5 and days 22 through 26 of radiation).
Patients were then to receive one or two applications of low-
dose-rate intracavitary radiation, with a third cycle of chemo-
therapy planned for the second intracavitary procedure in the
combined-therapy group. The median duration of follow-up
was 43 months. Estimated cumulative rates of survival at
5 years were 73% among patients treated with radiotherapy
and chemotherapy and 58% among patients treated with radio-
therapy alone (p = 0.004). Cumulative rates of disease-free sur-
vival at 5 years were 67% among patients in the combined-
therapy group and 40% among patients in the radiotherapy
group (p < 0.001). The rates of both distant metastases (p <
0.001) and locoregional recurrences (p < 0.001) were signifi-
cantly higher among patients treated with radiotherapy alone.
The seriousness of side effects was similar in the two groups,
with a higher rate of reversible hematologic effects in the com-
bined-therapy group. Therefore, the addition of chemotherapy
with fluorouracil and cisplatin to treatment with external-beam
and intracavitary radiation significantly improved survival
among women with locally advanced cervical cancer.
The GOG conducted a trial to determine whether weekly
cisplatin during radiotherapy improves progression-free and
overall survival among patients with bulky stage IB cervical
cancer [30]. Women with bulky stage IB cervical cancers (tumor,
Ref. >4 cm in diameter) were randomly assigned to receive radio-
therapy alone or in combination with cisplatin (40 mg/m2 once
a week for up to six doses), followed in all patients by adjuvant
computed tomographic scanning or lymphangiography were
[17]
ineligible unless histologic analysis showed that there was no
lymph node involvement. The cumulative dose of external pel-
vic and intracavitary radiation was 75 Gy to point A and 55 Gy
[20] to point B. Cisplatin was administered during external radio-
therapy and adjuvant hysterectomy was performed 3–6 weeks
later. The relative risks of progression of disease and death
Expert Rev. Anticancer Ther. 2(1), (2002)

among the 183 women assigned to receive radiotherapy and
chemotherapy with cisplatin, as compared with the 186 women
assigned to receive radiotherapy alone, were 0.51 and 0.54,
respectively. The rates of both progression-free survival (p <
0.001) and overall survival (p = 0.008) were significantly higher
in the combined-therapy group at 4 years. In the combined-
therapy group, there were higher frequencies of transient grade
3 and grade 4 adverse hematologic effects (21 vs. 2% in the
radiotherapy group) and adverse gastrointestinal effects (14 vs.
5%). They demonstrated that adding weekly infusions of cispl-
atin to pelvic radiotherapy followed by hysterectomy signifi-
cantly reduced the risk of disease recurrence and death in
women with bulky stage IB cervical cancers.
The GOG also initiated a protocol comparing primary radia-
tion therapy plus hydroxyurea with irradiation plus 5-fluorour-
acil and cisplatin for the treatment of patients with locally
advanced cervical carcinoma. The goals of the protocol were to
determine the superior chemoradiation regimen and to quanti-
tate the relative toxicities [31]. All patients had biopsy-proven
invasive squamous cell carcinoma, adenocarcinoma, or adenos-
quamous carcinoma of the uterine cervix with stages IIB, III or
IVA. Negative cytologic washings and para-aortic lymph nodes
were required for entry. The 388 patients were randomized to
receive either standard whole pelvic radiation therapy with con-
current 5-fluorouracil infusion and bolus 5-fluorouracil and
cisplatin, or the same radiation therapy plus oral hydroxyurea.
Of the patients, 368 were eligible; 177 were randomized to 5-
fluorouracil and cisplatin and 191 to hydroxyurea. Adverse
effects were predominantly hematologic or gastrointestinal in
both regimens. Severe or life-threatening leukopenia was more
common in the hydroxyurea group (24%) than in the 5-fluor-
ouracil and cisplatin group (4%). The difference in progres-
sion-free survival was statistically significant in favor of the 5-
fluorouracil and cisplatin group (p = 0.033). Survival was sig-
nificantly better for the patients randomized to 5-fluorouracil
and cisplatin (p = 0.018). This study demonstrated that for
patients with locally advanced carcinoma of the cervix, the
combination of 5-fluorouracil and cisplatin with radiation ther-
apy offered patients better progression-free survival and overall
survival than hydroxyurea and with manageable toxicity.
Lastly, in a trial by the Southwest Oncology Group (SWOG)
[32], 268 patients with clinical stage IA2, IB and IIA with high-
risk factors, such as nodal metastasis, parametrial extension, or
involved margins of resection after radical hysterectomy, were
randomized to radiation therapy with cisplatin and 5-fluorour-
acil or to radiation alone. This trial differed from the other four
trials in that chemotherapy was given both concurrently during
radiation therapy for two cycle and for two cycles after radia-
tion completion. Survival favored the chemoradiation arm
(81%) versus radiation alone (63%).
Collectively, all five trials comparing cisplatin-based chemo-
radiation with radiation alone demonstrate a significant reduc-
tion in the risk for recurrence and death with chemoradiation.
The five randomized cervical cancer trials involved a total of
1894 women with a variety of disease stages of cervical cancer
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Neoadjuvant chemotherapy in cervical cancer
in which radiation therapy would be used. There is remarkable
symmetry in the reduction of relative risk for relapse or death
by 30–50%. On the basis of the results of these five trials, the
National Cancer Institute released a Clinical Announcement
stating ‘strong consideration should be given to the incorpora-
tion of concurrent chemotherapy with radiation for the
patients who require radiation therapy for the management of
cervical cancer.’ Since these studies suggest that cisplatin alone
appears to be as effective as combination chemotherapy, con-
comitant cisplatin with radiation therapy now emerges as the
treatment of choice when radiation is used in cervical cancer.
However, questions still remain as to what constitutes the
best chemotherapy dose and schedule. In all of the positive tri-
als, cisplatin was used but three also used 5-fluorouracil. The
level of survival improvement that occurs when chemotherapy
is added to optimal irradiation and whether patients with stage
IIIB and IVA benefit are also unclear. Improvements in survival
rates for patients with solid tumors occur slowly. Based on the
evidence, it is likely that concurrent chemotherapy with radia-
tion will become the new standard of care for bulky and
advanced cervix cancer. However, the results of concurrent cis-
platin-based chemotherapy and radiotherapy are highly prom-
ising for locally advanced cancer of the cervix and should be
considered as a treatment option. To decrease the risk of distant
metastasis and improve survival, more effective drugs or drug
combinations must be developed.
More recently, Green et al. performed an excellent systemic
review and meta-analysis [33]. They carried out a systemic
review of all known randomized controlled trials performed
between 1981 and 2000 (17 published, two unpublished) of
chemoradiation for cervical cancer. This review suggests not
only an improvement in survival and local control but also a
reduction in the rate of metastases whether platinum is used or
not. A great beneficial effect is seen in trials that included a
high proportion of stage I and II patients. Therefore, it may not
be the case that new drugs or drug combinations are required,
but rather the optimization of those already available.
Neoadjuvant chemotherapy for adenocarcinoma of
the uterine cervix
Of its histological subtypes, squamous cell carcinoma is the
most common, while adenocarcinoma represents a minority,
but increasing number, of cervical cancers, accounting for
approximately 5–15% of all cases. Adenocarcinoma of the cer-
vix carries a worse prognosis than its squamous counterpart, in
particular when cancer cells spread beyond the uterine cervix.
In particular, tumors with lymph node metastasis have a miser-
ably poor prognosis. This is derived from the observation that
adenocarcinoma is less sensitive to radiation therapy and has a
tendency to spread into lymphatic drainage even in early-stage
disease [21,34–38].
In recent years, systemic trial of neoadjuvant chemother-
apy for adenocarcinooma of the cervix has been reported
(TABLE 1). Due to the rarity of adenocarcinoma of the cervix,
most reports have focused on squamous cell carcinoma and
77
Aoki & Tanaka

so far, few data are available for patients with cervical adeno- small number of patients in this study limits the power of the
carcinoma. Zanetta et al. examined the effects of neoadjuvant assessment, a survival advantage was not clear.
chemotherapy with a combination of cisplatin and epiru- The increased frequency and poor prognosis of cervical aden-
bicin in 21 patients with locally advanced adenocarcinoma of ocarcinoma calls for new therapeutic strategies, especially in
the cervix and the vagina [39]. They observed four CRs clini- locally advanced disease. Lissoni et al. reported that chemother-
cally and ten PRs (total response rate, 67%). Fujiwaki et al. apy regimen consisting of epirubicin 70 mg/m2, paclitaxel
found that patients with endometrial carcinoma have a favo- (175 mg/m2, 3 h) and cisplatin (50 mg/m2) in 19 patients with
rable clinical response rate (87.5%) to intra-arterial neoadju- cervical adenocarcinoma showed clinical and pathological
vant chemotherapy with cisplatin and doxorubicin but that response rates of 64 and 62%, respectively [45]. The GOG con-
those with cervical adenocarcinoma have disappointing ducted a Phase II trial of paclitaxel for advanced nonsquamous
results (58.3%). No CR was observed in the group of cervical carcinoma of the cervix to determine its activity in patients who
adenocarcinoma [40]. Iwasaka et al. have reported that neoad- had failed standard chemotherapy [46]. The starting dose of
juvant chemotherapy consisting of cisplatin, mitomycin and paclitaxel was 170 mg/m2 (135 mg/m2 for patients with prior
etoposide for adenocarcinoma of the cervix showed three CR pelvic radiation) given as a 24-h continuous iv. infusion with
and five PR (50%) and the mean survival period of respond- courses repeated every 3 weeks. In this trial, 42 assessable
ers was 47.5 months while that of nonresponders was patients were initially entered onto the study and 13 responses
28.3 months [35]. were observed; four patients had a CR and nine patients had a
In our study, cisplatin was used in combination with 5- PR. The overall response rate was 31%. The response rate to
fluorouracil of low-dose consecutive intra-arterial infusion for paclitaxel exceeds the rates reported using other single agents in
patients with cervical adenocarcinoma in a neoadjuvant setting nonsquamous carcinoma of the cervix. The overall response
[21]. Low-dose consecutive infusion has been reported to result rate of 31% is a notable finding considering the relative lack of
in a higher area under the time–concentration curve, although effective chemotherapeutic agents available to treat recurrent or
lower maximum concentration of cisplatin, as compared with advanced nonsquamous carcinoma of the cervix. The applica-
bolus infusion [41,42], which led to superior clinical response tion of paclitaxel in a neoadjuvant seting for high-risk cervical
with milder adverse effects. The antitumor effect of cisplatin cancer should be considered in the future.
depends on the area under the time–concentration curve of fil-
terable platinum obtained following an administration of the Cellular mechanisms regulating the responsiveness of
agent but not on maximum concentration of the agent [41]. A neoadjuvant chemotherapy
64% response rate was achieved (0 CR, seven PR), which was Neoadjuvant chemotherapy appears to work in the surgical
almost greater than or equal to those reported previously by and concomitant settings, but not in the radiotherapy setting.
others [35,39,40,43,44]. Also, even in three SD patients, tumor vol- Our speculation on this is as follows. Cisplatin is the most
ume showed a 25–50% reduction but no CR was found. Pre- effective cytotoxic agent against metastatic cervical carcinoma
vious reports addressed that chemoresponsiveness is the most [47] and has been shown in cell lines to enhance the effect of
potent predictor of cure in patients with locally advanced cer- radiotherapy. Mechanisms that underlie the interaction
vical adenocarcinoma treated with neoadjuvant chemotherapy between drugs and radiation may include inhibition of poten-
[35,44]. Histological examination in our study, however, tially lethal or sublethal damage repair and an increase in the
revealed only mild effects even in PR patients. Despite the rel- radiosensitivity of hypoxic cells [48]. That is why concurrent
atively high response rate, no CR was observed, which indi- chemoradiation appears to work better than chemotherapy
cates that the chemotherapy regimen used may not effectively with subsequent radiotherapy. After chemotherapy comple-
lead to the cure from adenocarcinoma of the cervix. Accord- tion, chemotherapy resistant cancer cells survive and generally
ingly, two patients with negative lymph nodes survived with-
out evidence of recurrence (63, 65 months). One is alive and
has been free of disease after resection of pulmonary recurrence Table 3. Randomized trials of concurrent chemoradiation
for 24 months. The remaining seven patients died because of in cervical carcinoma.
disease. In nine recurrences, three were local recurrence and Authors N Drugs Survival (%) Ref.
five subjects were distant. The remaining one was progressive
peritoneal carcinomatosis during neoadjuvant chemotherapy. CT/RT RT p
Rose 526 C vs. H 64 C 39 H 0.02 [28]
The relatively high rate of distant recurrence implies that low-
dose intra-arterial cisplatin combined with 5-fluorouracil infu- Morris CHF vs. H 66 CHF 39 H 0.002 [29]
sion may not be an appropriate strategy for bulky or locally
Keys 386 CF 73 58 0.004 [30]
advanced adenocarcinoma of the cervix. However, since the
regimen we used reduced the size of the bulky tumor to allow Whitney 388 CF vs. H 50.8 CF 39.8 H 0.018 [31]
radical surgery with a final pathological diagnosis of negative [32]
Peters 241 CF 81 63 0.01
parametrial and vaginal margins, this treatment might be of
benefit to the patients in that regard. Although the relatively C: Cisplatin; CT: Chemotherapy; F: 5-FU; H: Hydroxyurea; RT: Radiation therapy.

78 Expert Rev. Anticancer Ther. 2(1), (2002)


Table 4. Response rates to neoadjuvant chemotherapy
in adenocarcinoma and adenosqumous carcinoma of the
cervix.
Authors N Drugs RR (%) CR (%) Ref.
Zanetta 21 CEpi 67
Fujiwaki 12 CDox 58.3
Iwasaka 16 MEC 50
Aoki 11 CF ia. 64
C: Cisplatin; Dox: Doxorubicin; Epi: Epirubicin; E: Etoposide; F: 5-FU; M:
Methotrexate; ia.: intra-arterial infusion.
those cells are thought to be also resistant to radiotherapy.
Radical surgery can remove a residual cervical tumor after
neoadjuvant chemotherapy but it is thought to be difficult to
remove all of the residual cancer cells with radiotherapy.
Accordingly, neoadjuvant chemotherapy combined with radi-
cal surgery seems to work better than that with subsequent
radiation.
Recently, a number of studies have been published in which
the cellular mechanisms regulating the responsiveness of patients
to neoadjuvant chemotherapy has been evaluated [49–56].
Scambia et al. reported that a squamous cell carcinoma
antigen assay may provide useful information to improve the
prognostic characterization and disease monitoring of
patients with locally advanced cervical cancer undergoing
neoadjuvant chemotherapy [49]. Furthermore, pretreatment
serum levels of squamous cell carcinoma antigen, together
with the CA 15.3 assay, may be a useful tool in the determi-
nation of response to chemotherapy, while the CA 125 assay
could be evaluated as a prognostic risk factor in these
patients [50]. Kim et al. demonstrated that although the
serum squamous cell carcinoma antigen level did not have a
direct linear relationship to tumor volume, reduction in
serum squamous cell carcinoma antigen level had a linear
correlation with that of tumor volume after neoadjuvant
chemotherapy in patients with cervical carcinoma and ele-
vated prechemotherapy squamous cell carcinoma antigen lev-
els [51]. Garzetti’s study seemed to define the relationship
between p53 expression and sensitivity to cisplatin-based
chemotherapy in locally advanced cervical carcinoma, sup-
porting the notion that the cytotoxic action of cisplatin
could activate p53-mediated apoptosis [52]. However, the lim-
ited number of patients in our series does not permit judge-
ment on the clinical implications of the expression of p53 in
patients undergoing neoadjuvant combination chemotherapy
for locally advanced cervical carcinoma. Fujiwaki et al.
reported that the PCNA index in cervical adenocarcinomas
appeared to be potentially useful in predicting the immediate
response to chemotherapy [53]. Konishi et al. also demon-
strated that assessment of the expression of P-glycoprotein
and PCNA was potentially useful for the prediction of
tumor response to neoadjuvant chemotherapy for cervical
www.future-drugs.com
Neoadjuvant chemotherapy in cervical cancer
carcinomas [54]. Cosiski Marana et al. focused on NK-cells
and IL-12, showing that patients with a poor response had
lower lytic activity per NK-cell and were refractory to IL-12
stimulation, probably as a result of the reduced expression of
IL-12 receptors or of an intracellular defect in the mecha-
nism of transduction [55]. More recently, Costa et al. reported
19 [39]
that CD44 isoform 6 (CD44v6) was involved in the response
0 [40] to neoadjuvant chemotherapy and eventually in disease out-
[35]
come [56]. This implicated that the assessment of CD44v6
19
expression may help in selecting patients who were likely to
0 [21] respond to neoadjuvant chemotherapy. Uncovering these
mechanisms could be important in predicting women who
would eventually benefit from this type of therapy.
Expert opinion & five-year view
The results of randomized clinical trails of neoadjuvant chemo-
therapy combined sequentially with radiation in cervix cancer
have been disappointing. To date, no study in cervical carci-
noma has suggested benefits of neoadjuvant chemoradiation
versus radiation alone.
It may be ultimately necessary to identify patient subgroups
better suited for neoadjuvant chemotherapy combined with
radical surgery, compare the efficacy and toxicity with optimal
dose, and schedule concurrent use of chemotherapy and radia-
tion without routine hysterectomy, before it can be considered
standard treatment.
Based on the evidence, it is likely that concurrent chemother-
apy with radiation will become the new standard of care for
bulky and advanced cervix cancer.
Since the effectiveness of concurrent chemoradiation modal-
ity for nonsquamous cell carcinoma of the cervix remains
unclear, the increased frequency and poor prognosis of cervical
adenocarcinoma calls for new therapeutic strategies, especially
in locally advanced disease.
Key issues
• The results of randomized clinical trails of neoadjuvant
chemotherapy combined sequentially with radiation in the
cancer of the cervix have been disappointing.
• Although the results of neoadjuvant chemotherapy followed
by radical surgery are of interest, randomized trials in
comparison with concurrent chemoradiation are required,
before it can be considered standard treatment.
• It is likely that concurrent chemotherapy with radiation will
become the new standard of care for bulky and advanced
cervix cancer. To decrease the risk of distant metastasis and
improve survival, more effective drugs or drug combinations
might be developed.
• The increased frequency and poor prognosis of cervical
adenocarcinoma call for the establishment of efficacy of
concurrent chemoradiation and new therapeutic strategies,
especially in locally advanced disease.
79
Aoki & Tanaka
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Affiliations
• Yoichi Aoki, MD
Assistant Professor
Division of Obstetrics and Gynecology,
Department of Obstetrics and Gynecology,
Niigata University Graduate School of
Medical and Dental Sciences,
1-757 Asahimachi dori Niigata,
951-8510 Japan
Tel.: 81 25 227 2321
Fax +81 25 227 0789
yoichi@med.niigata-u.ac.jp
• Kenichi Tanaka, MD
Professor
Division of Obstetrics and Gynecology,
Department of Obstetrics and Gynecology,
Niigata University Graduate School of
Medical and Dental Sciences,
1-757 Asahimachi dori Niigata,
951-8510 Japan
Tel.: +81 25 227 2317
Fax: +81 25 227 0789
tanaken@med.niigata-u.ac.jp
Expert Rev. Anticancer Ther. 2(1), (2002)