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Recent Developments in Chemoradiotherapy for Locally Advanced Cancer of the Cervix

Recent Developments in Chemoradiotherapy for Locally Advanced Cancer of the Cervix

ABSTRACT: Patients with locally advanced cervical cancer comprise a significant proportion of the total population with cervical cancer, particularly in developing countries. The inability to control pelvic tumors is still a significant concern. Although neoadjuvant chemotherapy is associated with a high response rate, data from randomized trials clearly do not support the use of neoadjuvant chemotherapy prior to definitive irradiation. However, the results of concurrent cisplatin (Platinol)-based chemotherapy and radiotherapy are highly promising 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 need to be developed. [ONCOLOGY 14(9):1327-1335, 2000]

Introduction

Radical surgery or definitive radiotherapy is effective treatment for
many women with nonbulky, early-stage cervical cancer (stage IB1 to
IIA). However, for women with bulky, early-stage (IB2) or late-stage
disease (stage IIB to IVA), treatment results are
unsatisfactory.[1,2] The patterns of failure are characterized by an
increase in both local and distant metastases related to increasing
tumor size. However, the main cause of failure is uncontrolled
disease within the pelvis. Local failure can be reduced with higher
doses of radiation, but this also causes an increase in
complications.[3,4]

Our previous study[5] demonstrated that strategies to augment tumor
shrinkage prior to intracavitary brachytherapy are necessary to
improve local control and increase survival because of the geometric
limitation of intracavitary brachytherapy. Strategies to enhance the
efficacy of irradiation, such as hyperbaric oxygen,[6,7] hypoxic cell
sensitization,[8] neutron therapy,[9] and hyperthermia,[10,11] have
been attempted, especially in late-stage disease, but have shown
little or no success in most studies. Many investigations are
currently being conducted to identify more effective treatments.

Chemotherapy combined with radiation is the logical choice to improve
local control as well as reduce distant failure. The use of
chemotherapy with radiation therapy in locally advanced cervical
cancer evolved as encouraging results were reported in trials
investigating chemoradiotherapy in squamous cell cancer of the head
and neck,[12] esophagus,[13] lung,[14] and anal canal.[15] The
utility of cytotoxic chemotherapy in patients with advanced cervical
cancer has been the subject of extensive clinical investigations,
with variable results. These studies can be categorized as: (1)
neoadjuvant chemotherapy administered prior to radiation; (2)
concurrent chemotherapy in which both chemotherapy and radiotherapy
are administered together; and (3) adjuvant chemotherapy in which
radiation is followed by chemotherapy.

The rationale of combining chemotherapy and radiotherapy has been
reviewed previously.[16] Despite the controversy concerning its
efficacy, the use of chemotherapy with irradiation appears to be
increasing rapidly.[17] Recently, the National Cancer Institute (NCI)
distributed a clinical announcement to physicians recommending the
use of concurrent cisplatin (Platinol)-based chemoradiotherapy for
the treatment of cervical cancer. This article presents an overview
of the results of phase III randomized trials of combined
chemoradiotherapy in locally advanced cancer of the cervix.

Neoadjuvant (Induction) Chemotherapy With Radiotherapy

Neoadjuvant chemotherapy has been used prior to local regional
radiotherapy for advanced cervical cancer. The theoretical rationale
for the use of cytoreductive systemic agents prior to radiation
therapy includes the following factors:

(1) Access of chemotherapy to the tumor may be optimal before local
treatment interferes with tumor vascularity;

(2) The efficacy of radiation treatment may be improved by reduced
cancer cell numbers and improved oxygenation; and

(3) Distant relapse may be reduced by effects on micrometastases.

Therefore, the potential exists for neoadjuvant chemotherapy to both
improve local cancer control and reduce distant metastasis.

Numerous studies of the combination of chemotherapy and radiation
therapy for advanced cancer of the cervix appear in the literature,
but most are uncontrolled phase II trials involving small numbers of
patients. Conclusions cannot be drawn about the relative merits of
these regimens without data from a large, well-designed phase III
trial.

Reports From Phase III Trials

Ten phase III trials of neoadjuvant chemoradiotherapy in advanced
cancer of the cervix have been reported (see Table
1
).[18-27] All were single-center trials except for those
reported by Sundfør et al and Tattersall et al. Many of the
trials were small, with fewer than 100 patients in each arm.
Cisplatin-based chemotherapy was utilized in all these trials. In
general, two or three courses were administered before radiation
treatment. Complete response rates achieved with neoadjuvant
chemotherapy prior to radiotherapy ranged from 0% to 26% (average,
7%). Complete response rates for radiotherapy alone and for
neoadjuvant chemotherapy followed by radiation treatment ranged from
33% to 89%, and 42% to 85%, respectively. Median follow-up in these
studies ranged from 1.3 years to 5.0 years.

None of these trials demonstrated a significant difference in
survival with neoadjuvant chemotherapy compared to radiotherapy
alone. Two studies reported a decreased survival rate and increased
treatment complication rate with neoadjuvant chemotherapy.[20,25]
This was due partially to the death of several patients in one study
from bleomycin (Blenoxane)-associated pulmonary toxicity.[20]

The failure of neoadjuvant chemotherapy to improve local control
indicates that partial regression after neoadjuvant chemotherapy was
not translated into better local control by subsequent radiotherapy.
The possibility of cross-resistance between cisplatin-based drugs and
radiation has also been proposed, but requires further exploration.
Accelerated repopulation of clonogenic cells in the tumor may provide
another possible explanation for the failure of neoadjuvant
chemotherapy.

As ineffective chemotherapy may prejudice response to radiation
simply by delaying its initiation, neoadjuvant therapy is potentially
risky. Until regimens are developed that produce a high complete
response rate, neoadjuvant chemotherapy is unlikely to be beneficial.[28-31]

Concurrent (Concomitant) Chemoradiotherapy

Using chemotherapy during radiation treatment as a radiation
“sensitizer” is an attractive approach. With this strategy,
the entire treatment course is not prolonged and, thus, the effects
of tumor proliferation are minimized. Unfortunately, these same
mechanisms apply to normal tissue and result in greater toxicity.

We analyzed nine phase III trials of concurrent chemoradiotherapy for
cervical cancer (Table 2).[32-40]
Seven of the nine trials were primarily radiotherapy trials, with or
without concurrent chemotherapy, for late-stage disease. Two other
trials utilized surgery as the primary approach for the treatment of
patients with early-stage disease; one employed preoperative
chemoradiotherapy for bulky stage IB disease, and the other employed
postoperative chemoradiotherapy in patients with high-risk factors.

Radiation With Concurrent Hydroxyurea

Of the seven trials using primary radiation therapy, the first
two[32,33] evaluated the concurrent use of hydroxyurea. Hydroxyurea
was advocated as a radiation sensitizer in earlier studies by Piver
et al.[33] In 1979, the Gynecologic Oncology Group (GOG) published
the results of a randomized, prospective trial favoring concurrent
hydroxyurea over radiation therapy alone.[32] However, hydroxyurea
has not been incorporated into general use because of its greater
hematologic toxicity and uncertainty about its real benefit.
Moreover, half of the patients in the 1979 GOG trial were inevaluable
due to protocol violations. The 3-year disease-free survival in this
trial was only 13% in the control arm and 26% in the hydroxyurea arm.

Nevertheless, on the basis of these data, three subsequent GOG trials
of concurrent chemoradiotherpy used hydroxyurea as a control arm (Table 3).[41-43]
First, Stehman et al[41] compared hydroxyurea with misonidazole and
reported no survival advantage for misonidazole. Next, Whitney et
al[42] compared hydroxyurea with cisplatin-based combination
chemotherapy and showed survival benefits for the cisplatin
combination.

When Rose et al[43] were designing their trial, the results of the
hydroxyurea vs cisplatin-based combined chemotherapy trial were not
available. Therefore, in a three-armed study, they compared treatment
with radiation plus hydroxyurea, radiation plus weekly cisplatin, and
radiation plus hydroxyurea, cisplatin, and fluorouracil (5-FU). These
investigators found that the relapse-free survival rate was
significantly higher in both regimens containing cisplatin. In
addition, patients treated with hydroxyurea had significant
hematologic toxicity: Grade III or IV neutropenia occurred in 24.5%
of patients receiving hydroxyurea and 3.6% of patients receiving
cisplatin/5-FU. Concurrent weekly cisplatin alone was a more
effective, less toxic regimen than radiation plus hydroxyurea.[42,43]

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