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International Journal of Gynecological Cancer & Volume 00, Number 00, Month 2016

Safety and Efficacy of Neoadjuvant Chemotherapy


Followed by Radical Surgery Versus Radical Surgery Alone in Locally
Advanced Cervical Cancer Patients

Lin Gong, MD, Jia-Wen Zhang, MD, Ru-Tie Yin, MD, Ping Wang, MD, Hui Liu, MD,
Ying Zheng, MD, Jiang-Yan Lou, MD, and Zhi-Lan Peng, MD

JOURNAL READING
disusun untuk melaksanakan tugas Kepaniteraan Klinik Madya
SMF/Lab. Obstetri dan Ginekologi RSD dr. Soebandi Jember

Oleh:
Nyoman Defriyana Suwandi
NIM 122011101012

Pembimbing
dr. Gogot Suhariyatno, Sp.OG

SMF/LAB. OBSTETRI DAN GINEKOLOGI RSD dr. SOEBANDI JEMBER


FAKULTAS KEDOKTERAN
UNIVERSITAS JEMBER
2016

ORIGINAL STUDY

Safety and Efficacy of Neoadjuvant Chemotherapy


Followed by Radical Surgery Versus Radical Surgery
Alone in Locally Advanced Cervical Cancer Patients
Lin Gong, MD, Jia-Wen Zhang, MD, Ru-Tie Yin, MD, Ping Wang, MD, Hui Liu, MD,

Ying Zheng, MD, Jiang-Yan Lou, MD, and Zhi-Lan Peng, MD

Objectives: This study aimed to evaluate the safety and efficacy of neoadjuvant chemo-therapy
(NACT) followed by radical surgery (RS) among patients with locally advanced cervical cancer
(LACC).

Methods: Eight hundred patients with LACC received either NACT followed by RS (NACTYRS) or RS
alone. The primary outcome measures assessed the efficacy and adverse effects of NACT. Secondary
outcome measures compared the preoperative clinical stage to the postoperative pathologic stage in
NACTYRS and RS patients, assessed intraoperative and postoperative complications, including the
adverse effects of postoperative radiotherapy and radiochemotherapy, and estimated the 5-year
progression-free survival and 5-year overall survival.

Results: The clinical response to NACT was 89.54%. Patients in the NACTYRS group had lower preoperative
hemoglobin levels (115.20 vs 122.04 g/L, P G 0.001), a longer operative time (mean, 233.66 vs 224.37 minutes, P =
0.008), more intraoperative bleeding (750.34 vs 684.41 mL, P = 0.011), a shorter duration of catheter use (mean, 29.84
vs 32.14 days, P = 0.036), and a lower incidence of postoperative complications (7.30% vs 13.62%, P = 0.002) and
postoperative radiotherapeutic and radiochemotherapeutic adverse effects (3.16% vs 4.63%, P G 0.001) compared to
patients in the RS group. The 5-year progression-free survival and 5-year overall survival were 80.30% and 81.10% in
the NACTYRS group and 81.00% and 78.50% in the RS group (P 9 0.05). Pathological poor differentia-tion,
nonsquamous cell carcinoma, parametrial invasion, positive pelvic lymph node, and lymphovascular invasion (P G 0.05)
were independent risk factors for recurrence.

Conclusions: Neoadjuvant chemotherapy may reduce RS-associated complications and postoperative


radiotherapeutic and radiochemotherapeutic adverse effects in Chinese pa-tients with LACC.

Key Words: Locally advanced cervical cancer, Neoadjuvant chemotherapy, Survival, Risk factors

Received March 17, 2015, and in revised form September 16, 2015.

Accepted for publication December 24, 2015.

(Int J Gynecol Cancer 2016;00: 00Y00)

Department of Obstetrics and Gynecology, West


China Second Hospital, West China Center of Medical
Sciences, Sichuan Uni-versity, Chengdu, China.

Address correspondence and reprint requests to Zhi-Lan


Peng, MD, Department of Obstetrics and Gynecology,
West China

Second Hospital, Sichuan University, No. 20, Section


3, South Peoples Rd, Chengdu, Sichuan 610041,
China. E-mail: pengzhilan1@163.com.

Copyright * 2016 by IGCS and ESGO

Supplemental digital contents are available for this


article. Direct URL citations appear in the printed text
and are provided in the HTML and PDF versions of
this article on the journals Web site (www.ijgc.net).

ISSN: 1048-891X

The authors declare no conflicts of interest.

DOI: 10.1097/IGC.0000000000000658

International Journal of Gynecological Cancer & Volume 00, Number 00, Month 2016

International Journal of Gynecological Cancer & Volume 00, Number 00, Month 2016

Gong et al

lactation; (4) hyster-ectomy; (5) incomplete clinical data; or


(6) discontinuation from the study.

Cervical cancer is the most common malignant tumor of the


female reproductive system. Globally, there are an estimated
530,000 new cases of cervical cancer each year.1Y3 One third
of these cases occur in China, where the average age of

The study was approved by the Research Ethics


Com-mittee of the local hospital, and all patients
provided written informed consent.

patients with cervical cancer is decreasing.1Y 3 Younger patients


with cervical cancer have characteristically high rates of
nonsquamous cell carcinoma, lymph node metastasis, and local
bulky tumors.4 Protection of ovarian and vaginal func-tion is a
primary objective of operative therapy in younger patients.5
Treatments for cervical cancer include traditional radical surgery
(RS) and radiotherapy, as well as cervical re-section,
neoadjuvant chemotherapy (NACT), concurrent radiochemotherapy (CCRT), and intensity-modulated radiotherapy.
Because of limited technologic development in south-west
China and with the development of chemotherapeutic

drugs, NACT followed by RS (NACTYRS) has become an


important part of the comprehensive treatment strategy for
young patients with locally advanced cervical cancer (LACC).
The objective of this study was to evaluate the safety and efficacy of NACT followed by RS among patients with LACC.

MATERIALS AND METHODS

Treatment

Preoperatively, chest and transvaginal ultrasonographic


measurements and ultrasonography of the urinary tract were
performed. Magnetic resonance imaging or abdominopelvic
computed tomography, intravenous pyelography, and colonoscopy were used when appropriate.

Patients were divided into 2 groups as follows: (1) RS (n = 389


cases), in which patients underwent type III radical
hysterectomy and direct lymphadenectomy; and (2) NACTYRS
(n = 411 cases), in which patients with no contraindication to
chemotherapy received between 1 and 3 cycles of platinum-

Selection Criteria

This retrospective study included 800 patients with LACC


who attended the local hospital from January 2008 to
December 2012. Inclusion criteria were as follows: (1) stage
IB2, IIA2, and IIB LACC diagnosed according to the staging
system for cervical cancer recommended by the International Federation of Gynecology and Obstetrics (histologically confirmed with a tumor diameter of more than 4 cm by
at least 2 gynecological clinical oncologists during a vaginorecto-abdominal examination); (2) willing to tolerate radi-cal
hysterectomy; (3) hemoglobin level of 80 g/L or higher,
leukocyte count of 3000 per mm3 or higher, platelet count of

based NACT intravenously every 10 to 21 days, followed by RS


within 10 to 14 days. NACT regimens included carboplatin and
cisplatin, bleomycin and pingyangmycin, ifosfamide, 57,8

fluorouracil, paclitaxel, and vincristine (Table 1). For pa-tients


younger than 45 years with squamous cell cancer, healthy
ovaries were translocated to the external side of the iliac fossae
to prevent radiation damage during the operation.

Postoperative therapy included chemotherapy, radiotherapy, or radiochemotherapy, as appropriate.

100,000 per mm or higher before surgery; (4) normal renal


(serum creatinine G 133 Kmol/L) and hepatic (transaminase
G 50 U/mL) function; (5) normal chest x-ray; and (6)
provision of informed consent. Exclusion criteria were as
follows: (1) metastatic tumor or combination of other
cancers; (2) exist-ing chronic disease; (3) pregnancy or

Outcome Measures

The primary outcome measures assessed the clinical efficacy and


adverse effects of NACT. The chemotherapeu-tic response was
evaluated 7 to 10 days after every cycle by pelvic examination and
ultrasound according to World Health Organization criteria, which
included complete response (tu-mor completely disappeared),
partial response (tumor size re-duced more than 50%), stable
disease (tumor size reduced less than 50%, or increased less than
25% without new lesions), and progressive disease (tumor size

BP/BVP
323
11

increased more than 25% or had new lesions). Clinical response


was defined as com-plete or partial response. Adverse effects
associated with NACT were graded and evaluated in accordance
9

with World Health Organization criteria. Secondary outcome


measures (1) com-pared the preoperative clinical stage to the
postoperative path-ologic stage in NACTYRS and RS patients; (2)
compared the preoperative hemoglobin level, operative time,
intraoperative blood loss, rate of blood transfusion, postoperative
complica-tions, time to recovery of bladder function, and adverse effects of postoperative radiotherapy and radiochemotherapy in
NACTYRS and RS patients; and (3) estimated 5-year progressionfree survival (PFS) and 5-year overall survival (OS).

5
FBP/FIP
11
13
1
TP/TC
26
11

Statistical Analysis

4
Total

All statistical analyses were performed with SPSS ver-sion 19.0


(SPSS, Chicago, IL). Descriptive data are expressed as mean T
standard deviation. Between-group comparisons were
performed using an unpaired 2-tailed Student t test with

360
35
10

TABLE 1. NACT regimens (unit: case)


*Special: neuroendocrine small cell carcinoma and combined type. BP,
cisplatin (50 mg/m2, day 1), plus bleomycin (15 mg) or pingyangmycin
(16 mg, days 1Y2); BVP, BP plus vincristine (1 mg/m2, day 1); FBP, 5-

Regimen

fluorouracil (500 mg, days 1Y3), plus cisplatin (50 mg/m2, day 1), plus
bleomycin (15 mg) or pingyangmycin (16 mg, days 1Y2); FIP, 5-

Squamous

fluorouracil (1000 mg, days 1Y3), plus cisplatin (50 mg/m2, day 1), plus
ifosfamide (1 g/m2) and mesna (200 mg/m2, at 0, 4, and 8 hours);

Adenocarcinoma
Special*

TP/TC, paclitaxel (135Y175 mg/m2, day 1), plus cisplatin (50 mg/m2) or
carboplatin (area under the concentration time curve, 5.0Y7.5,

day 1).

* 2016 IGCS and ESGO

International Journal of Gynecological Cancer & Volume 00, Number 00, Month 2016

NACT for Cervical Cancer

In the NACTYRS group, the clinical response rate to NACT was


89.54% (368/411), and the complete response rate was 2.43%
(10/411). No patients had stable disease. The

a pooled estimator of variance. Overall survival was


calculated by the KaplanYMeier procedure, and differences
in survival were evaluated via the log-rank test. The log-rank
test for univariate analysis, hazard ratio (HR), and 95%
confidence interval (CI) of mortality from cancer were
calculated using the Cox hazards regression model analysis
based on multivariate clinicopathologic characteristics of risk
factors. Statistical sig-nificance was defined as P G 0.05.

RESULTS

From January 1, 2008, to December 30, 2012, 800 patients


with stage IB2, IIA2, and IIB cervical cancer (tumor diameter
9 4 cm) were referred to the West China Second Hospital of
Sichuan University for treatment. Patients were between 20
and 70 years old (mean, 43.38 T 8.24 years); 67.4%
(539/800) of patients were 45 years or younger.

Patient clinical and pathological characteristics are summarized in Table 2. Patients in the NACTYRS group
experienced more severe disease compared to the RS
group. Patients in the NACTYRS group had larger tumors
(mean diameter, 5.53 vs 4.78 cm, respectively, P G 0.001), a
higher rate of stage IIA2, IIB LACC (80.29% vs 54.5%,
respectively, P G 0.001), and a higher rate of preoperative
anemia (32.85% vs 18.25%, re-spectively, P G 0.001).

overall clinical response rate for squamous cell cancer and


adenocarcinoma were 89.53% (325/363) and 86.49% (32/37),
respectively. Mean tumor volume was significantly decreased
after chemotherapy (mean diameter, 5.53 vs 3.16 cm, respectively, P G 0.001). Neoadjuvant chemotherapy was associated with grade 1 or grade 2 adverse events, including bone
marrow suppression in 93 patients and nausea, vomiting, and
transient diarrhea in 165 patients. Some patients experi-enced
alopecia (55 women) and rash (1 woman). There were no grade
3 or grade 4 adverse events.
Patients in the NACTYRS group had lower preopera-tive
hemoglobin levels (115.20 vs 122.04 g/L, respectively, P G
0.001), a longer operative time (mean, 233.66 vs 224.37
minutes, respectively, P = 0.008), more intraoperative bleeding
(750.34 vs 684.41 mL, respectively, P = 0.011), a shorter
duration of catheter use (mean, 29.84 vs 32.14 days,
respectively, P = 0.036), and a lower incidence of postopera-tive
complications (7.30% vs 13.62%, respectively, P = 0.002) and
postoperative radiotherapeutic or radiochemotherapeu-tic
adverse effects (3.16% vs 4.63%, respectively, P G 0.001)
compared to patients in the RS group (Table 3).

There was no significant difference in the incidence of risk


factors for recurrence, including lymph node metastasis,
positive surgical margin, parametrial infiltration, deep cervical
stromal invasion, and lymphovascular invasion (LVSI) in the
NACT-RS compared to the RS group (P 9 0.05) (Table 1, Supplemental Digital Content 1, http://links.lww.com/IGC/A350).
Parametrial infiltration was significantly reduced in responders

TABLE 2. Clinical characteristics of the NACTYRS and RS groups (n = 800) (mean T SD or % unless otherwise stated)

NACTYRS

RS

411

389
P

Age, y
20Y67 (43.72 T 7.94)
23Y70 (43.02 T 8.53)
0.230
Tumor diameter, cm

Before chemotherapy
5.53 T 1.00
4.78 T 0.52
G0.001
After chemotherapy
3.16 T 1.05

Stage

IB2
81
(19.71)

177
(45.50)
G0.001
IIA2 (IIB)
330 (52) (80.29)

162
(50) (54.5)

Pathological types

Squamous
363

(88.32)

327
(84.06)
0.367
Adenocarcinoma
19
(4.62)

24
(6.17)

Adenosquamous
18
(4.38)

25
(6.43)

Special*
11
(2.68)

13
(3.34)

Grade

G1
6
(1.46)

15
(3.86)
0.017
G2
68
(16.55)

74
(19.02)

G3
320
(77.86)

294
(75.58)

Not stated
17
(4.14)

6
(1.54)

Anemia before surgery


135
(32.85)

71
(18.25)
G0.001

*Special: neuroendocrine small cell carcinoma and combined type.

Not stated: pathological report prompted that could not be graded or no residual foci.

* 2016 IGCS and ESGO

Copyright 2016 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.

Gong et al

International Journal of Gynecological Cancer & Volume 00, Number 00, Month 2016

TABLE 3. Comparison of surgery conditions and radiochemotherapeutic adverse effects between the NACTYRS
and RS groups (mean T SD or % unless otherwise stated)

NACTYRS
RS
P

Time, min
233.66
T 48.88
224.37
T 50.65
0.008
Hb before surgery, g/L
115.20
T 13.30
122.04
T 15.37
G0.001
Transfusion number
261
(63.50)
195 (50.13)
G0.001

Catheter time, d
29.84
T 19.60
32.14
T 19.43
0.036
No. postoperative complications
30
(7.30)
53 (13.62)
0.002
No. radiochemotherapeutic adverse effects
13
(3.16)
18 (4.63)
G0.001

Hb, Hemoglobin
postoperative radiotherapy or CCRT. The 5-year PFS and 5year OS were 78.80% (95% CI, 0.29Y1.00) and

compared to nonresponders in the NACTYRS group (5.98%


vs 16.28%, respectively, P = 0.029) (Table 2, Supplemental
Digital Content 2, http://links.lww.com/IGC/A350).

In the overall median follow-up time of 30 months (range, 6Y66


months), 308 (74.94%) patients in the NACTYRS group and
289 (74.29%) patients in the RS group voluntarily continued to
participate in the study (P 9 0.05). The 5-year PFS was 80.30%
(95% CI, 0.65Y0.95) and 81.00% (95% CI, 0.66Y0.96) in the
NACTYRS and RS groups, respectively (P = 0.561) (Fig. 1).
The 5-year OS was 81.10% (95% CI, 0.66Y0.96) and 78.50%
(95% CI, 0.64Y0.93) in the NACTYRS and RS groups,
respectively (P = 0.511) (Fig. 2).

In the NACTYRS group, 38.40% (91/237) of patients 45 years


or younger with tumors 4 cm or less after chemo-therapy had
deep cervical stromal invasion or LVSI at the postoperative
pathological examination. Twenty-nine of the 91 patients
received no treatment or chemotherapy. The 5-year PFS and 5year OS were 90.60% (95% CI, 0.59Y1.00) and 90.70% (95%
CI, 0.59Y1.00), respectively. Sixty-two patients received

77.60% (95% CI, 0.27Y1.00), respectively. There was


no sig-nificant difference in survival rates.

Log-rank test and Cox hazards regression model analysis showed that a high level of pathological
differentiation (HR, 1.648, P = 0.020), nonsquamous cell
carcinoma (HR, 1.603, P G 0.001), parametric infiltration
(HR, 4.078, P G 0.001), lymph node metastasis (HR,
2.825, P G 0.001), and LVSI (HR, 1.804, P = 0.003) were
independent risk factors for recurrence (Table 4).

DISCUSSION

Neoadjuvant chemotherapy, defined as systemic chemotherapy before comprehensive and local therapy (radiotherapy or surgery) for locally advanced metastatic disease, is

indicated for stage IB2 and IIA2 cervical tumors with poor
10

prognosis, and for down-staging of stage IIBYIVA tumors. In


the current study, the 5-year PFS and 5-year OS were not

significant differently between the NACTYRS and RS groups.


However, the clinical response to NACT was 89.54%, and
postoperative complications and postoperative radiochemotherapeutic adverse effects were significantly lower in the

FIGURE 1. Progression-free survival in the NACTYRS and NACT groups. The 5-year PFS was 80.30% (95% CI,
0.65Y0.95) in the NACTYRS group and 81.00% (95% CI, 0.66Y0.96) in the RS group (P = 0.561).

* 2016 IGCS and ESGO

Copyright 2016 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.

International Journal of Gynecological Cancer & Volume 00, Number 00, Month 2016

NACT for Cervical Cancer

FIGURE 2. Overall survival in the NACTYRS and NACT groups. The OS was 81.10% (95% CI, 0.66Y0.96) in the
NACTYRS group and 78.50% (95% CI, 0.64Y0.93) in the RS group (P = 0.511).
only associated with grade 1/2 toxicities, including bone marrow suppression and gastrointestinal reactions.
NACTYRS group, despite an increased frequency of intraoperative complications caused by large lesions and local inflammation. The complete response to NACT was only 2.43%
(10/411), which may be due to few preoperative chemotherapy
cycles and local bulky lesions. Neoadjuvant chemotherapy was

More than two thirds of the patients included in this study were
younger than 45 years, indicating a high incidence of LACC in
young patients. In the NACTYRS group, the prevalence of bulky

tumors, stage IIA2 and IIB LACC, and anemia before surgery
was higher compared to the RS group. Recent research
indicates that local bulky tumors, clinically advanced cervical
cancer, and anemia are predictors of poor

Current studies using platinum-based combination


chemotherapy to treat LACC report a 67.0% to 90.7% response rate, a 9% to 18% complete response rate, and a 42%
14Y16

prognosis and survival.11Y13 Therefore, the patients in the


NACTYRS group were expected to have a poorer prognosis
than the patients in the RS group, suggesting that any
positive outcomes of NACTYRS are especially beneficial.

to 67% clinical response rate for adenocarcinoma.


In the
current study, chemotherapeutic drugs were selected based on
the clinical characteristics of the LACC being treated, in an

TABLE 4. Univariate and multivariate analysis of recurrence for all patients

Univariate Analysis

Multivariate Analysis

Factors
P

P
HR
95% CI

17

attempt to improve efficacy. The BP (cisplatin plus bleomycin


or pingyangmycin) or BVP (BP plus vincristine) regimen was
used for squamous cell cancer, and attained an 89.53%
response rate, whereas the TP or TC (paclitaxel plus

Age
0.637

0.852
0.977
0.766Y1.247
Tumor size before treatment
0.179

0.150
1.179
0.942Y1.474
FIGO stage
0.063

0.349
1.137
0.869Y1.487
Grade
0.028

0.020
1.648
1.082Y2.509
Pathology
G0.001
G0.001
1.603
1.324Y1.942
Deep cervical stromal 9 0.5

0.001

0.600
1.161
0.665Y2.025
Positive surgical margin
0.268

0.326
0.647
0.271Y1.545
Parametric infiltration
G0.001
G0.001
4.078
2.508Y6.631
Lymph node metastasis
G0.001
G0.001
2.825
1.887Y4.227
LVSI
G0.001
0.003
1.804
1.229Y2.648

FIGO, International Federation of Gynecology and Obstetrics.

* 2016 IGCS and ESGO

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Gong et al

International Journal of Gynecological Cancer & Volume 00, Number 00, Month 2016

cisplatin or carboplatin) regimen was used for adenocarcinoma, and attained an 86.49% response rate.

BVMP regimen) and an RS group to investigate risk factors for


poor survival and postoperative radiotherapy (in-cluding lymph
node metastasis, parametrial infiltration and deep cervical
stromal invasion). The results showed that NACT did not
improve the 5-year OS (NACT vs RS, 70% vs 74.4%,

6
Previous reports indicate that retroperitoneal lymph node
metastasis, parametrial infiltration, positive surgical mar-gins,
LVSI, deep cervical stromal invasion, and local bulky lesions are
18Y20

risk factors for cervical cancer relapse.


The current study
showed that poor differentiation, pathological type, parametrial
infiltration, lymph node metastasis, and LVSI were independent
risk factors for recurrence. Notably, NACT resulted in a
significant reduction in parametrial infiltra-tion in responders
compared to nonresponders. Taken together, these data
suggest that NACT prevents the progression of cervical lesions
and residual tumor metastasis, and reduces parametrial
infiltration in responders. Neoadjuvant chemo-therapy combined
with surgery may allow early tumor eradi-cation without drug
resistance and reduce the risk factors for recurrence.

21,22

According to the 2014 National Comprehensive Cancer Network


recommendations for the management of patients with stage IB2
and IIA2 cervical cancer, LACC should be treated with pelvic
radiation therapy plus concurrent platinum-based chemotherapy
plus brachytherapy (dose, Q85 Gy), or type III radical hysterectomy
plus pelvic lymph node dissec-tion plus or minus para-aortic lymph
node sampling, or pelvic radiation therapy plus brachytherapy
(dose, 75Y80 Gy) plus concurrent platinum-based chemotherapy as
a radiation sensi-tizer and treatment for recurrence and metastasis

P = 0.85). However, significantly fewer patients in the


NACTYRS group required postoperative radiotherapy (NACT vs
RS, 58% vs 80 %, P = 0.015); therefore, the occurrence of
26

radiotherapeutic adverse effects was reduced. In accordance


with these data, the current study showed that the incidence of
postoperative and radiochemotherapeutic complications were
lower and the duration of catheter use was shorter in the NACT
plus RS group. In the NACT plus RS group, the survival rate of
patients who received chemotherapy or follow-up after surgery
was greater than 90%, whereas the survival rate of patients
who received radiochemotherapy after surgery was less than
90%. Although the difference was not statistically sig-nificant, it
indicates that patients with deep cervical stromal invasion or
LVSI have the option for regular follow-up after postoperative
chemotherapy. This may alleviate the expense of radiotherapy,
protect the ovarian and vaginal function of young patients, and
avoid the adverse effects associated with radiotherapy. Further
investigations in studies with a larger sample size are required
to substantiate these findings.

23

plus adju-vant hysterectomy. However, in southwest China, there


is a relative lack of radiotherapy equipment and technology;
therefore, NACT represents an effective treatment for younger
patients who wish to retain their ovarian and vaginal functions. In
these patients, NACT can shrink tumors; reduce deep cer-vical
stromal invasion, parametrial infiltration, positive surgi-cal margins,
24,25

and LVSI; and contribute to the success of radical resection.


In
the current study, nearly two thirds of the patient population was
younger than 45 years. Our data suggest that NACTYRS may be a
suitable therapy for younger patients.

In our study, the overall median follow-up time was 30 months.


The 5-year PFS was 80.30% and 81.00% in the NACTYRS and
RS groups (P = 0.561), respectively, and the 5-year OS was
81.10% and 78.50% in the NACTYRS and RS groups (P =
0.511), respectively. Previous reports suggest that the 5-year
survival rate of patients with stage IB1 can reach 80% to 90%,
whereas the 5-year survival rate of patients with stage IB2YIIA
(tumor diameter, 4 cm) with local bulky tumors is only 30% to
60%, and even lower if the patients have lymph node
27Y29

Patients who have lymph node metastasis, positive sur-gical


margins, or parametrial infiltration, according to the pathological
reports, should receive supplemental CCRT plus or minus
vaginal brachytherapy. If patients have a large pri-mary tumor
(94 cm) with deep cervical stromal invasion or LVSI, they may
receive supplemental pelvic radiotherapy plus or minus
23

concurrent cisplatin-based chemotherapy or follow-up. In the


current study, 91 responders in the NACTYRS group had deep
cervical stromal invasion (90.5) or LVSI according to the
postoperative pathological examination. Of these, 29 patients
received chemotherapy or just follow-up, whereas the rest (62
patients) received radiotherapy or CCRT. There was no
significant difference in survival between these groups.
Katsumata et al reported a stage III randomized clin-ical trial in
which 134 patients with stage IB2, IIA2, and IIB cervical
squamous cell carcinoma were randomly divided into an NACT
plus RS group (bleomycin, vincristine, mitomycin, cisplatin,

metastasis.
However, these outcomes have changed
dramatically with the emergence of NACT. In 252 patients with
LACC who received NACT including nedaplatin and paclitaxel
(NP) or paclitaxel and cisplatin (PC) followed by radical
hysterectomy, there was a high response rate (80.77% and
68.24%) and good long-term PFS (81.41% and 67.28%) and
30

OS (93.89% and 81.54%). Yin et al reported a retro-spective


study which analyzed the PFS and OS of 476 patients with
stage IB2YIIB who received NACT plus RS, RS, or CCRT and
were followed up for 54 to 114 months (median, 82.8 months).
The 5-year PFS of the NACT plus RS, RS, and CCRT groups
were 85.00%, 77.44%, and 52.94%, respectively (P G 0.0001),
and the 5-year OS were 88.67%, 80.21%, and 64.37%,
respectively (P G 0.0001). Compared with RS and CCRT, NACT
plus RS improved PFS and OS of the patients with stage
IB2YIIB cervical cancer. In addition, the TP regimen improved
31

PFS and OS compared to the BVP regimen. In a metaanalysis of 1078 patients with stage IB included in 6
randomized controlled trials, Rydzewska et al

25

showed that

NACT significantly improved the OS (HR, 0.77; 95% CI,


0.62Y0.96, P = 0.02) and PFS (HR, 0.75; 95% CI, 0.61Y0.93, P
= 0.008) of patients with early stage and local bulky cervical
cancer compared to surgery only.

Although the standard treatment for LACC is cisplatin-based


CCRT, in southwest China, CCRT is not performed
effectively. This study suggests that NACTYRS is a safe and

efficacious treatment for patients with LACC in China, and


may be especially suitable for patients younger than 45
years. The present single institutional study provides a
rationale for further studies to assess NACTYRS in a
multicenter ran-domized clinical trial.

* 2016 IGCS and ESGO

Copyright 2016 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.

International Journal of Gynecological Cancer & Volume 00, Number 00, Month 2016

NACT for Cervical Cancer

Shanbhogue AK, Karnad AB, Prasad SR. Tumor response


evaluation in oncology: current update. J Comput Assist
Tomogr. 2010;34:479Y484.

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Introduksi
Kanker serviks adalah tumor ganas yang paling sering terjadi pada sistem reproduksi wanita. Secara
global, diperkirakan terdapat 530.000 kasus baru kanker serviks setiap tahunnya. Sepertiga dari kasus ini
terjadi di China, di mana rata-rata usia penderita kanker serviks mengalami penurunan. Pada pasien muda
dengan kanker serviks memiliki ciri khas dengan karsinoma sel non squamous yang tinggi, metastasis
kelenjar getah bening, serta tumor lokal yang besar. Proteksi terhadap fungsi ovarium dan vagina adalah
tujuan utama terapi operatif pada pasien muda.Terapi untuk kanker serviks meliputi radical surgery (RS),
radioterapi, reseksi serviks, neoadjuvant chemotherapy (NACT), concurrent radiochemotherapy (CCRT),
dan intensity-modulated radiotherapy. Karena perkembangan teknologi terbatas di barat daya Cina dan
adanya perkembangan kemoterapi, NACT follow by RS (NACTYRS) yang telah menjadi bagian penting
pada strategi perawatan yang komprehensif untuk pasien muda dengan kanker serviks stadium lanjut/
locally advanced cervical cancer (LACC) Tujuan dari penelitian ini adalah untuk mengevaluasi keamanan
dan efektivitas pada NACT diikuti oleh RS antara pasien dengan LACC.

METODE DAN MATERIAL


Kriteria Seleksi
Studi retrospektif ini mencakup 800 pasien dengan LACC yang masuk pada rumah sakit local dari
Januari 2008-Desember 2012. Penelitian disetujui oleh Research Ethics Comitee pada rumah sakit local
dan pasien yang telah mengsisi surat inform consent. Kriteria inklusi dan eksklusi meliputi:
Kriteria Inklusi
Kriteria Eksklusi

Stage IB2, IIA2, IIB LACC (klasifikasi

FIGO)
Bersedia
untuk
menoleransi
radikal

histerektomi
Kadar Hemoglobin 80 g/L atau lebih tinggi

sebelum operasi,
Jumlah leukosit yaitu 3000 per mm3 atau
lebih tinggi sebelum operasi,
Jumlah platelet 100,000 per mm3 atau lenoh
besar sebelum operasi
Fungsi Normal

Renal (serum creatinine < 133 Kmol/L)


Hepatic (transaminase <50 U/mL)
Rontgen dada normal

Informed Consent

Tumor metastasis atau kombinasi dengan


kanker lain
Terdapat penyakit kronik lain
Hamil atau laktasi

Histerektomi

Data klinik yang tidak lengkap


Tidak bersedia mengikuti penelitian secara
penuh

TERAPI
Sebelum operasi, dilakukan pengukuran ultrasonografi dada, transvaginal, dan saluran kemih.
Magnetic Resonance Imaging atau abdominopelvic computed tomography, pyelography intravena, dan
kolonoskopi digunakan pada saat yang tepat. Pasien dibagi menjadi 2 kelompok sebagai berikut:
1. RS (N=389 kasus): pasien menjalani radikal histerektomi tipe III dan limfadenektomi langsung; dan
2. NACTYRS (N=411 kasus), dimana pasien tanpa kontraindikasi kemoterapi dan menerima NACT
intravena setiap 10 sampai 21 hari, diikuti oleh RS dalam waktu 10 sampai 14 hari.
Regimen NACT termasuk carboplatindan, cisplatin, bleomycin dan pingyangmycin, ifosfamide, 5fluorouracil, paclitaxel, dan vincristine. Untuk pasien yang lebih muda dari 45 tahun dengan kanker sel
skuamosa, ovarium sehat ditranslokasikan ke sisi eksternal dari fossa illiaca untuk mencegah kerusakan
akibat radiasi selama operasi.
HASIL
Pengukuran primer menilai efikasi klinis dan efek samping pada NACT. Respon kemoterapi
dievaluasi 7 sampai 10 hari setelah setiap siklus dengan pemeriksaan panggul dan ultrasound menurut
kriteria WHO. Kriteria termasuk respon lengkap (tumor benar-benar menghilang), respon parsial (ukuran
tumor berkurang lebih dari 50%), penyakit stabil (ukuran tumor berkurang yaitu kurang dari 50%, atau
meningkat kurang dari 25% tanpa lesi baru),dan penyakit progresif (ukuran tumor meningkat lebih dari
25% atau memiliki lesi baru). Respons klinis didefinisikan sebagai respon lengkap atau respon parsial.
Efek samping terkait dengan NACT dinilai dan dievaluasi sesuai dengan kriteria WHO.
Pengukuran sekunder menilai yaitu (1) membandingkan tahap klinis pra operasi dengan tahap
patologis pasca operasi pada pasien dengan NACTYRS dan RS; (2) membandingkan tingkat hemoglobin
pra operasi, waktu operasi, intraoperatif, kehilangan darah, laju transfusi darah, komplikasi pasca operasi,
waktu untuk pemulihan fungsi kandung kemih, dan efek samping radioterapi pasca operasi dan
radiokemoterapi pada pasien NACTYRS dan RS; dan (3) memperkirakan 5 tahun bebas tanpa
progresifitas dari penyakit (PFS) dan 5-tahun kelangsungan hidup secara keseluruhan (OS).
HASIL PENELITIAN
Mulai 1 Januari 2008, sampai 30 Desember 2012, 800 pasien dengan stadium IB2, IIA2, dan
kanker serviks IIB (tumor diameter> 4 cm) dirujuk keWest China Second Hospital of Sichuan University
untuk pengobatan. Pasien berusia antara 20 dan 70 tahun, 67,4% yaitu pasien 45 tahun atau lebih muda.
Karakteristik klinis dan patologis pasien dirangkum pada Tabel 2. Pasien dalam kelompok
NACTYRS mengalami penyakit yang lebih berat dibandingkan dengan kelompok RS. Pasien dalam
kelompok NACTYRS memiliki tumor yang lebih besar (berarti diameter, 5,53 vs 4,78 cm, masingmasing, P <0,001), tingkat yang lebih tinggi pada tahap IIA2, IIB LACC (80,29% vs 54,5%, masingmasing, P <0,001), dan memiliki nilai lebih tinggi pada angka anemia pra operasi (32,85% vs 18,25%,
masing-masing, P <0,001).
Pada kelompok NACTYRS, tingkat respons klinis terhadap NACT adalah 89,54% (368/411), dan
tingkat respons lengkap adalah 2,43% (10/411). Tidak ada pasien memiliki penyakit stabil. Tingkat
respon klinis secara keseluruhan untuk kanker sel skuamosa dan adenokarsinoma adalah 89,53%
(325/363) dan 86,49% (32/37), masing-masing. Berarti volume tumor menurun secara signifikan setelah
kemoterapi (berarti diameter, 5,53 vs 3,16 cm, masing-masing, P <0,001). Kemoterapi neoadjuvant
berhubungan dengan timbulnya efek samping pada kelas 1 atau kelas 2 yaitu penekanan sumsum tulang

pada 93 pasien serta mual, muntah, dan diare sementara pada 165 pasien. Beberapa pasien mengalami
alopecia (55 perempuan) dan ruam (1 wanita). Sedangkan, kelas 3 atau kelas 4 tidak ada efek samping.
Pasien dalam kelompok NACTYRS memipunyai tingkat hemoglobin pra operasi yang lebih
rendah (115.20 vs 122,04 g / L, masing-masing, PG 0,001), waktu yang lebih lama untuk operasi (berarti,
233,66 vs 224,37 menit, masing-masing, P = 0,008), perdarahan intraoperatif lebih banyak (750,34 vs
684,41 mL, masing-masing, P = 0,011), durasi yang lebih singkat pada penggunaan kateter (berarti, 29,84
vs 32,14 hari, masing-masing, P = 0,036), dan insiden lebih rendah terhadap pasca operasi (7.30% vs
13,62%, masing-masing, P = 0,002) dan efek samping rendah pasca operasi radioterapi atau
radiochemotherapeutic efek samping (3,16% vs 4,63%, masing-masing, PG 0,001) dibandingkan dengan
pasien dalam kelompok RS (Tabel 3).
Tidak ada perbedaan yang signifikan dalam kejadian faktor risiko kekambuhan, termasuk
metastasis kelenjar getah bening, batas bedah positif, infiltrasi parametrium, dalam invasi stroma serviks
dalam, dan invasi lymphovascular (Lvsi) di NACT-RS dibandingkan dengan kelompok RS (P> 0,05)
(Tabel 1). Infiltrasi parametrium berkurang secara signifikan pada pasien dengan respon dibandingkan
dengan nonresponders pada kelompok NACTYRS (5,98% 16,28%, masing-masing, P = 0,029) (Tabel 2).
Pada waktu follow up/tindak lanjut yaitu 30 bulan, 308 (74,94%) pasien dalam kelompok
NACTYRS dan 289 (74,29%) pasien dalam kelompok RS sukarela terus berpartisipasi dalam studi (P 9
0,05). 5 tahun PFS pada masing-masing kelompok NACTYRS dan RS adalah 80,30% (95% CI,
0.65Y0.95) dan 81.00% (95% CI, 0.66Y0.96) (P = 0,561) (Gambar. 1). 5 tahun OS pada masing-masing
kelompok NACTYRS dan RS adalah 81,10% (95% CI, 0.66Y0.96) dan 78,50% (95% CI, 0.64Y0.93) (P
= 0,511) (Gambar. 2).
Pada kelompok NACTYRS, 38,40% (91/237) pada pasien 45 tahun atau lebih muda dengan
tumor 4 cm atau kurang setelah kemoterapi memiliki invasi stroma servix yang dalam atau Lvsi pada
pemeriksaan patologis pasca operasi. Dua puluh sembilan dari 91 pasien tidak menerima pengobatan atau
kemoterapi. 5 tahun PFS dan 5 tahun OS adalah 90,60% (95% CI, 0.59Y1.00) dan 90,70% (95% CI,
0.59Y1.00), masing-masing. Enam puluh dua pasien menerima radioterapi pasca operasi atau CCRT. 5
tahun PFS dan 5 tahun OS adalah 78,80% (95% CI, 0.29Y1.00) dan 77,60% (95% CI, 0.27Y1.00),
masing-masing. Tidak ada perbedaan yang signifikan dalam tingkat kelangsungan hidup.
PEMBAHASAN
Kemoterapi neoadjuvan didefinisikan sebagai kemoterapi sistemik yang digunakan sebelum
melakukan terapi komprehensif dan lokal (radioterapi atau pembedahan) yang digunakan untuk penyakit
dengan metastasis lanjut yang sifatnya local. Kemoterapi ini diindikasikan pada kanker serviks tahap IB2
dan IIA2 dengan prognosis buruk. Dalam penelitian ini, 5 years PFS dan 5 years OS tidak berbeda secara
signifikan dengan kelompok NACTYRS dan RS. Namun, respons klinis terhadap NACT adalah 89,54%,
dan komplikasi pasca operasi serta efek samping radiokemoterapi pasca operasi secara signifikan lebih
rendah pada kelompok NACTYRS. Respon lengkap untuk NACT hanya 2,43% (10/411), yang mungkin
disebabkan akibat beberapa siklus kemoterapi pra operasi dan lesi lokal yang besar. Kemoterapi
neoadjuvant hanya dikaitkan dengan grade 1/2 toxicities, meliputi penekanan sumsum tulang dan reaksi
gastrointestinal.
Lebih dari dua pertiga dari pasien yang dilibatkan dalam penelitian ini berusia lebih muda dari 45
tahun, menunjukkan tingginya insiden LACC pada pasien muda. Pada kelompok NACTYRS, prevalensi
tumor berukuran besar, stadium IIA2 dan IIB LACC, dan anemia sebelum operasi lebih tinggi

dibandingkan dengan kelompok RS. Penelitian terbaru menunjukkan bahwa tumor besar lokal, klinis
kanker serviks, dan anemia adalah prediktor buruknya prognosis dan kelangsungan hidup. Oleh karena
itu, pasien dalam kelompok NACTYRS diperkirakan memiliki prognosis yang lebih buruk daripada
pasien dalam kelompok RS, ini menunjukkan bahwa setiap hasil positif dari NACTYRS sangatlah
bermanfaat.
Dalam penelitian ini, obat-obat kemoterapi yang dipilih berdasarkan karakteristik klinis LACC
yang sedang dirawat, dalam upaya untuk meningkatkan efikasi. Regimen BP (cisplatin ditambah
bleomycin atau pingyangmycin) atau BVP (BP ditambah vincristine) yang digunakan untuk terapi kanker
sel skuamosa mencapai respon sebesar 89,53%, sedangkan regimen TP atau TC (paclitaxel ditambah
cisplatin atau carboplatin) yang digunakan untuk adenokarsinoma mencapai respon sebesar 86,49%.
Laporan sebelumnya menunjukkan bahwa metastasis kelenjar getah bening retroperitoneal,
infiltrasi parametrium, margin bedah positif, Lvsi, invasi stroma serviks dalam, dan lesi lokal besar
merupakan faktor risiko untuk relapsnya kanker serviks relapse. Studi saat ini menunjukkan bahwa
buruknya diferensiasi, tipe kerusakan, infiltrasi parametrium, metastasis kelenjar getah bening, dan LVSI
merupakan faktor risiko independen untuk terjadinya kekambuhan. Secara khusus, NACT mengakibatkan
penurunan yang signifikan dalam infiltrasi parametrium pada responden dibandingkan dengan
nonresponden. Secara bersama-sama, data ini menunjukkan bahwa NACT dapat mencegah
perkembangan lesi serviks dan sisa metastasis tumor, serta mengurangi infiltrasi parametrium pada
responden. Kemoterapi neoadjuvan dikombinasikan dengan operasi dapat memungkinkan pemberantasan
tumor awal tanpa resistensi obat dan mengurangi faktor risiko kekambuhan.
Menurut rekomendasi National Comprehensive Cancer Network tahun 2014, untuk pengelolaan
pasien dengan stadium IB2 dan kanker serviks IIA2 LACC harus ditangani dengan terapi radiasi panggul
ditambah kemoterapi. Kemudian ditambah brachytherapy (dosis, 85 Gy), atau radikal histerektomi tipe
III ditambah diseksi limfonodi panggul plus atau minus sampling limfonodi para-aorta. Selain itu dapat
diterapi dengan radiasi panggul ditambah brachytherapy (dosis, 75-80 Gy) ditambah kemoterapi berbasis
platinum sebagai radiation sensitizer dan pengobatan untuk kekambuhan dan metastasis ditambah
histerektomi adjuvant.
Berdasarkan laporan patologis, pasien yang memiliki metastasis limfonodi, margin bedah positif,
atau infiltrasi parametrium, harus menerima CCRT tambahan plus atau minus brachytherapy vagina. Jika
pasien memiliki tumor primer yang besar (>4 cm) dengan invasi stroma serviks dalam atau Lvsi, mereka
kemungkinan akan menerima radioterapi panggul tambahan plus atau minus kemoterapi berbasis
cisplatin. Dalam penelitian ini, 91 responden pada kelompok NACTYRS memiliki invasi stroma servix
dalam(> 0,5) atau Lvsi sesuai dengan pemeriksaan patologis pasca operasi.Dari jumlah tersebut, 29
pasien menerima kemoterapi atau hanya tindak lanjut, sedangkan sisanya (62 pasien) menerima
radioterapi atau CCRT. Tidak ada perbedaan signifikan dalam kelangsungan hidup antara kelompokkelompok ini. Katsumata et al melaporkan uji klinis tahap III secara acak di mana 134 pasien dengan
stadium IB2, IIA2, dan IIB karsinoma sel skuamosa serviks dibagi secara acak menjadi kelompok NACT
ditambah kelompok RS (bleomycin, vincristine, mitomycin, cisplatin, BVMP rejimen) dan kelompok RS
untuk menyelidiki faktor risiko untuk rendahnya kelangsungan hidup dan radioterapi pasca operasi
(termasuk kelenjar getah bening metastasis, infiltrasi parametrium dan mendalam serviks invasi stroma).
Hasil penelitian menunjukkan bahwa NACT tidak meningkatkan OS 5 tahun (NACT vs RS, 70% vs
74,4%, P = 0,85). Namun, secara signifikan lebih sedikit pasien dikelompok NACTYRS yang

memerrlukan radioterapi pasca operasi (NACT vs RS, 58% vs 80%, P = 0,015); Oleh karena itu,
terjadinya efek samping radioterapi dapat berkurang.
Sesuai dengan data ini, penelitian kali ini menunjukkan bahwa kejadian komplikasi pasca operasi
dan radiochemotherapeutic lebih rendah dan durasi penggunaan kateter lebih pendek di NACT ditambah
RS kelompok. Pada kelompok NACT ditambah RS, tingkat kelangsungan hidup pasien yang menerima
kemoterapi atau tindak lanjut setelah operasi lebih besar dari 90%, sedangkan tingkat kelangsungan hidup
pasien yang menerima radiochemotherapy setelah operasi kurang dari 90%. Meskipun perbedaannya
tidak signifikan secara statistik, hal ini menunjukkan bahwa pasien dengan invasi stroma serviks dalam
atau LVSI memiliki pilihan untuk tindak lanjut setelah kemoterapi pasca operasi. Hal ini dapat
meringankan beban radioterapi, melindungi fungsi ovarium dan vagina pasien muda, dan menghindari
efek buruk yang terkait dengan radioterapi. Penyelidikan lebih lanjut dalam studi dengan ukuran sampel
yang lebih besar diperlukan untuk mendukung temuan ini. Meskipun pengobatan standar untuk LACC
adalah cisplatin berbasis CCRT, di kawasan barat daya Cina, CCRT tidak dilakukan secara efektif. Studi
ini menunjukkan bahwa NACTYRS aman dan berkhasiat untuk pasien dengan LACC di Cina serta
mungkin sangat cocok untuk pasien yang lebih muda dari 45 tahun. Sekarang studi institusional tunggal
memberikan alasan untuk studi lebih lanjut untuk menilai NACTYRS dalam percobaan klinis multicsnter
acak.