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REVIEW ARTICLE
CURRENT TRENDS IN TREATING CERVICAL CANCER
Kung-Liahng Wang1,2,3*
1
Department of Obstetrics and Gynecology, Mackay Memorial Hospital, 2National Taipei College of
Nursing, and 3Mackay Medicine, Nursing and Management College, Taipei, Taiwan.
SUMMARY
Cervical cancer is the most common gynecologic malignancy worldwide. Squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma are the three major histologic types, and this cancer develops slowly
and locally. Radical hysterectomy plus pelvic lymph node dissection or concurrent chemoradiation therapy
(CCRT) is the standard treatment when the disease is at an early stage. CCRT remains the standard for locally
advanced disease, and systemic chemotherapy plays a major role in disease with distant metastases. In recent
decades, some new trends in treating this cancer have been discussed and applied. A series of clinical trials and
retrospective studies support a more conservative surgical treatment in early-stage disease. Sentinel lymph
node mapping is used to decrease the morbidities after nodal dissection. Some new concurrent chemotherapeutic agents and schedules have been developed to replace the traditional cisplatin-base agents in order to
decrease the toxicity during CCRT. Consolidation chemotherapy after CCRT can help improve the outcome.
Neoadjuvant chemotherapy plus radiotherapy has revealed itself as the potential application as part of a new
therapeutic trend in treating locally advanced cervical cancer patients. In the Gynecologic Oncology Group
(GOG) phase III trial (GOG-179), cisplatin plus topotecan was proved to prolong the patients’ survival time.
Vaccines, both prophylactic and therapeutic, will be the trend in the future. This article intends to review
recent reports and update the available information relating to the current trends in the management of cervical cancer. [International Journal of Gerontology 2007; 1(2): 98–102]
Key Words: cervical cancer, chemotherapy, concurrent chemoradiation therapy (CCRT), surgery, vaccine
Introduction
Cervical cancer is the most common gynecologic malignancy in Taiwan. The incidence of cervical cancer is
51.88/100,000 women in 20021. Over 99% of cervical
cancers are caused by the high-risk group of human
papillomavirus (HPV)2, which includes types 16 and 18
that are responsible for over 70% of cervical cancer.
Quadrivalent (Gardasil®; Merck & Co., NJ, USA) and
bivalent (Cervarix®; GlaxoSmithKline, London, UK) HPV
vaccines are recently available treatments for prevention of cervical infection of the two high-risk HPV
*Correspondence to: Dr Kung-Liahng Wang, Division of Gynecologic
Oncology, Department of Obstetrics and Gynecology, Mackay
Memorial Hospital, 92, Section 2, Chung-Shan North Road, Taipei
104, Taiwan.
E-mail: kl421229@ms6.hinet.net
Accepted: March 20, 2007
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types before the onset of pre-cancer lesion (cervical
intraepithelial neoplasm [CIN]). Cervical cancer is also
a slowly progressing local disease, which occurs 5–30
years after the development of CIN lesions. CIN lesions
can be detected by Papanicolaou smear and treated
with local excision procedure or simple hysterectomy.
Unfortunately, if CIN lesions develop into invasive cancer, the treating modalities become more complicated, and usually at a sacrifice to the quality of life
of these cervical cancer patients. We would like to
review the modern trends in the treatment of invasive
cervical cancer.
Trend 1: More Conservative Treatment in
Early Stage Disease
The early stage of cervical cancer is defined as FIGO
clinical stages IA1 to IIA, where the lesion is confined
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Current Trends in Treating Cervical Cancer
within the cervical portion to the upper vagina without
parametrial involvement. There are 3 main histologic
types of cervical cancer: squamous cell carcinoma (SCC),
adenocarcinoma, and adenosquamous cell carcinoma.
SCC offers a better prognosis and allows for more conservative modalities than the other two types. Stage IA1
SCC cervical cancer can be treated by conization with the
intention of preserving the uterus if fertility is desired,
because the possibility of pelvic lymph node metastases
is < 1%3. Simple hysterectomy without pelvic lymph node
dissection is acceptable if fertility is no longer a concern.
On the other hand, the management of adenocarcinoma and adenosquamous cell carcinoma remains as
conization followed by hysterectomy, for fear of a skip
lesion in the cervical portion.
The traditional treatment of stage IA2 cervical cancer
is class 2 radical hysterectomy (modified radical hysterectomy) with pelvic lymph node dissection. Alternatively,
unlike adenocarcinoma or adenosquamous carcinoma,
radical trachelectomy with pelvic node dissection is
acceptable for SCC cervical cancer if fertility preservation
is desired, because the probability of a nodal metastasis
averages 7.3%4.
The conventional treatment of stage IB1 or IIA
tumors (4 cm or less in diameter) requires class III
Wertheim’s radical hysterectomy plus bilateral pelvic
lymph node dissection. Yang et al.5 suggested a more
conservative modality, which employed class II radical
hysterectomy (modified radical hysterectomy) and
yielded results comparable to the traditional surgical
method with low voiding or defecation dysfunction.
The local failure rate was not increased and the complication rate was decreased if postoperative radiotherapy was required. The local recurrence in one
adenocarcinoma patient revealed that conservative
modalities were unsuitable for histologic types other
than SCC.
Patients with stage IB2 or IIA tumors (4 cm or more
in diameter) were favorably treated with concurrent
chemoradiation therapy (CCRT) than those receiving
large-scale surgeries6,7. There was a 30–40% possibility of
pelvic lymph node metastases, and postoperative radiotherapy was eventually unavoidable. The morbidity of
surgery plus CCRT was higher than surgery or CCRT alone.
The quality of life became worse in the combination
group. It has been suggested that pelvic lymph node
dissection will not increase the complication during consecutive CCRT and that the excision of existing bulky
nodes is beneficial.
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Trend 2: CCRT
Ever since 1988, CCRT has replaced the traditional radiotherapy and become the standard primary treatment
of locally advanced cervical cancer (stages IIB–IVA). When
a combination of cisplatin and 5-fluorouracil (5-FU)
was used as radiosensitizers during pelvic radiation and
brachytherapy, the local control rate, progressive-free
survival, and overall survival were improved. Although
the cisplatin–5-FU combination incurred other treatment morbidities such as severe bone marrow suppression, this morbidity had been shown to be acceptable
in a recent literature8.
CCRT was also shown to be applicable in earlystage cervical cancer patients who were not suitable
for radical surgery or had major risk factors after radical
surgery. The schedule of chemotherapy during radiotherapy is cisplatin plus 5-FU for three courses with
a 21-day interval between the courses, or a singleagent cisplatin (40 mg/m2) given weekly for six courses.
Ikushima et al.9 reported that the reduction of the
weekly cisplatin dose to 30 mg/m2 significantly reduced
hematologic toxicity. A new chemotherapeutic schedule of daily cisplatin (20 mg/m2/d for 5 consecutive
days) for a total of two courses during radiotherapy has
been developed, and it was reported to have a better
outcome10. Other chemotherapeutic agents, such as
gemcitabine, oxaliplatin, etoposide, liposomal doxorubicin, carboplatin and tagafur, or paclitaxel, and carboplatin, were tested as radiosensitizers, but cisplatin
remains the most effective agent in treating cervical
cancer11.
Trend 3: Sentinel Lymph Node-Mapping
Sentinel lymph node mapping is well developed for the
surgery of breast cancer, for the reduction of morbidity
after total axillary lymph node dissection. Similarly, this
procedure is currently applied during radical surgery
of cervical cancer to reduce the lower-extremity lymphedema, lymphagitis or pelvic lymphocyst after pelvic
lymph node dissection and is often coupled with postoperative pelvic radiotherapy. Metastable technetium99 (Tc-99m) lymphoscintigraphy and blue dye injection
are used to investigate the sentinel lymph node distribution during pelvic node dissection. A recent study by
Wydra et al.12 reported the sensitivity (86.4%), negative
predictive value (95.5%), and specificity (100%) using a
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combination of these two methods in 100 patients
with early cervical cancer.
Trend 4: Consolidation Chemotherapy After
CCRT in Locally Advanced Cervical Cancer
CCRT is the standard treatment in locally advanced
cervical cancer. Although CCRT improves the survival rate
by 30–50%, the 5-year survival rate in these patients
remains < 65%. Local failure and distant metastases
often happen after treatment. The concept of postradiotherapy consolidation chemotherapy originates
from maintenance chemotherapy of advanced ovarian cancer, which can either suppress the microscopic
circulating cancer cells in the systemic circulation or
achieve the anti-angiogenesis effects (metronomic
therapy) by maintaining the blood concentration of
the chemotherapeutic agent. Vrdoljak et al.13 reported
a clinical trial in which locally advanced cervical cancer
patients who received external beam pelvic radiation
therapy without chemotherapeutic agent concurrently.
A combination of ifosfamide (2 g/m2) and cisplatin (75
mg/m2) was used concurrently during two low-dose rate
brachytherapy applications. After completing concomitant chemoradiation therapy, four courses of systemic
chemotherapy with the same two-drug regimen were
given as consolidation therapy. The results showed a high
response rate (nearly 100%) and high recurrence-free
rate (88.7%) during a follow-up of 49 months. The trial
also demonstrated acceptable morbidity rate (25%
grade 3, 11% grade 4 hematologic toxicities). Only 16%
of the patients developed delayed major complications.
This protocol may become more promising than the
traditional CCRT schedule.
Trend 5: Neoadjuvant Chemotherapy
(NACT)
NACT plus surgery have demonstrated itself on phase
II trials to be feasible as a valid replacement for conventional radiotherapy or surgery14–16. However, most
phase III trials of NACT plus radiotherapy have failed to
show further benefit than those of radiotherapy alone17.
In contrast, a recent meta-analysis by Medical Research
Council (UK)18 showed the benefit of a more intensive
chemotherapy at shorter cycle length or higher dose
intensity for the NACT plus radiotherapy treatment.
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K.L. Wang
This meta-analysis included 2,074 patients from 18
different trials with a median follow-up analysis of 5.7
years. Sardi et al.19, in a recent review article, drew
attention to the significance of this meta-analysis and
highlighted the potential application of NACT plus
radiotherapy as part of a new therapeutic trend in treating locally advanced cervical cancer patients. Further
research is required to verify and conclude this finding.
Trend 6: Improvement of Systemic
Chemotherapy
Single-agent cisplatin (50 mg/m2) administered every 3
weeks apart has been the standard systemic chemotherapeutic agent for the treatment of advanced/recurrent
and metastatic SCC of the uterine cervix. It demonstrated a 50% objective response rate in previously
untreated patients20. Several new single agents with
antineoplastic activity were trialed in combination with
cisplatin, including ifosfamide21, oxaliplatin, paclitaxel22,
and gemcitabine23. Ifosfamide plus cisplatin demonstrated a significant improvement in response rate and
progressive-free survival but failed to improve the overall
survival24. The combination of ifosfamide and cisplatin
showed limited improvement on the progressive-free
survival (1.4 months). A recent Gynecologic Oncology
Group (GOG)-169 study25 demonstrated that a combination of paclitaxel and cisplatin also showed limited
improvement in progressive-free survival without any
improvement in overall survival. The abovementioned
trials once again reinforce the role of single-agent cisplatin as the current standard systemic therapy for cervical cancer. There have been two new trends in multiple
chemotherapeutic agent combinations recently, the
first is the combination of methotrexate, vinblastine,
doxorubicin, and cisplatin (MVAC)26, and the other is
cisplatin plus topotecan (GOG-179)27. The three-arm
clinical trial involving the MVAC regimen was forced to
close prematurely because of many treatment-related
deaths. In the comparison between cisplatin plus
topotecan and single-agent cisplatin, the combination
group showed a statistically significant improvement in
response rate (27% vs. 13%), progressive-free survival (4.6
months vs. 2.9 months) and overall survival (9.4 months
vs. 6.5 months). The combination of cisplatin plus
topotecan has now replaced the single-agent cisplatin to
become the most effective systemic chemotherapeutic
combination agents.
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Current Trends in Treating Cervical Cancer
Trend 7: Prophylactic and Therapeutic
Vaccines
Oncogenic HPV are epitheliotropic and detectable in over
99% of cervical cancers. The vaccines of HPV are classified into two major groups: prophylactic and therapeutic vaccines. The prophylactic vaccine protects against
HPV infection, and the therapeutic vaccine kills previously infected or transformed keratinocytes. Prophylactic
vaccines can induce a high titer of blood antibodies
against oncogenic HPV 16 and 18. They can retard the
progression of cervical cancer or prevent the cancer
from occurring. Two types of prophylactic vaccines are
recently under investigation. However, the quadrivalent
vaccine (Gardasil) has already been approved for marketing, while the bi-valent HPV vaccine (Cervarix) is still
pending approval. On the other hand, therapeutic vaccines are currently being developed in order to
increase anti-HPV natural CD4+ and CD8+ T-cell immunity in women infected during their sexual activity.
Researchers have designed these vaccines to target the
activity of the E6 and E7 oncoproteins28. These therapeutic vaccines can be divided to several subgroups29, such
as viral-vector, bacterial-vector, peptide, protein, DNA,
dendrite cell-based, and tumor cell-based. A number of
approaches have shown significant therapeutic benefit in
preclinical papillomavirus models16. Although the therapeutic vaccines might have efficiency similar to surgical treatment of CIN30, the current therapeutic vaccine
trials are still less mature with respect to disease clearance. Further testing in patient populations is required
to determine the most effective curative strategy.
are now undergoing further experiments. Target therapy can play either a major or an assistant role in the
future treatments of cancers, including cervical cancer
and other gynecologic malignancies.
Conclusion
This review summarizes the current trends in the management of cervical cancer. Although the results of
some clinical trials are still inconclusive, many clinical
improvements have been observed in recent years. It
is the author’s belief that the investigation of alternate
treatment modalities that are more conservative, less
toxic, less harmful, and more effective is an ongoing
objective in the field of gynecologic oncology.
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