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Advances in the Treatment of Gynecologic Malignancies

Advances in the Treatment of Gynecologic Malignancies

ABSTRACT: Two recent multicenter randomized trials have greatly advanced our understanding of the role of postoperative radiation therapy in operable cervical cancer. In locally advanced cervical cancer, such studies have shown a significant improvement in survival with the use of concurrent cisplatin-based chemoradiotherapy and have redefined standard therapy for women with this presentation. In vulvar cancer, adjuvant chemoradiotherapy is emerging as an effective therapeutic approach, permitting less morbid surgery. Although the results of treatment with concurrent chemoradiotherapy are encouraging in both cervical and vulvar cancer, efforts to minimize the associated toxicity are needed. [ONCOLOGY 16:1510-1530, 2002]

The ideas generated from
phase I/II studies and other sources of information are subsequently tested in
randomized phase III trials in disease-specific sites. There they are compared
to the best therapy in current clinical practice or other concurrent controls.
Large multicenter phase III trials such as those conducted by the Gynecologic
Oncology Group (GOG) are essential for putting potential therapeutic advances in
proper perspective.

This paper summarizes the outcome of major phase III trials of treatment for
gynecologic cancers and outlines some of the current and/or recently closed
protocols as well as important surgical/pathologic studies in this setting.
Trials dealing with recurrent disease are not included. Discussions of each
disease site are divided into early-stage and locally advanced cancer. Part 1 of
this two-part article will focus on cervical and vulvar cancer, and part 2 will
address uterine corpus and ovarian cancers.

Early-Stage Cervical Cancer

Although the general consensus is that surgery and radiation therapy produce
equivalent cure rates in early-stage cervical cancer, radical hysterectomy is
often recommended for younger, healthier patients, based on the opportunity to
preserve the ovaries and the patient’s ability to tolerate surgical and
anesthetic complications.

Surgical/Pathologic Studies

GOG-19—In this protocol, Lagasse et al addressed the
surgical/pathologic staging of para-aortic lymph nodes in 290 patients with
invasive cancer of the cervix.[1] By means of surgical staging, a substantial
portion of patients with cervical cancer have been found to have disease outside
the standard pelvic radiation field: This is true for 5% of women with stage IB
disease, 18% of those with stage IIA, 33% of those with stage IIB, and 31% of
those with stage IIIB. In the absence of an adequate noninvasive technique for
determining nodal metastases, surgical staging has been incorporated into the
design of all GOG cervical studies conducted after GOG-4.

GOG-49—Conducted by Delgado et al, this study was a
prospective surgical/pathologic study that assessed correlations with
disease-free interval in 732 patients with stage IB cervical cancer.[2] The
study found that, in addition to positive pelvic nodes, clinical tumor size,
capillary-lymphatic space invasion, and depth of cervical stromal invasion were
independent predictive factors. Results suggested that patients could be
classified as having a low, intermediate, or high risk of recurrence, and that
therapeutic interventions could be planned accordingly.

Surgical Treatment

GOG-92: Postoperative Radiotherapy—Sedlis et al
sought to define the role of adjuvant radiation therapy in a patient population
considered to be at intermediate risk of relapse.[3] As mentioned, GOG-49
identified an intermediate-risk group based on tumor size, capillary lymphatic
space invasion, and depth of cervical stromal invasion, in varying combinations,
and that carried a recurrence risk of approximately 30%, despite the absence of
nodal metastases (Figure 1).[3]

A total of 277 patients were randomized to pelvic irradiation or no further
therapy. The actuarial 2-year, recurrence-free rates for pelvic radiotherapy and
no further therapy were 88% and 79%, respectively (P = .008). Although survival data were not yet mature at the time of
publication, a preliminary analysis indicated a 36% reduction in overall
mortality for patients receiving radiation. Among patients who underwent pelvic
irradiation, nine (7%) experienced severe or life-threatening toxicity, compared
to three (3%) in the no-further-therapy group.

• GOG-141: Preoperative Chemotherapy—The use of induction
chemotherapy prior to surgery has a sound basis biologically, as surgery may
eliminate residual disease that otherwise could be resistant to radiation. High
initial clinical response rates have been reported with cisplatin-containing
regimens in numerous phase II trials, but whether these responses will translate
into reproducible improvements in relapse-free and/or overall survival remains
to be determined. Sardi et al[4] reported an overall survival advantage for
neoadjuvant cisplatin, vincristine, and bleomycin prior to surgery in 209
patients with stage IB disease. Benedetti-Panici et al[5] and Chang et al[6]
reported conflicting results with the use of neoadjuvant chemotherapy followed
by surgery vs radiation therapy alone.

GOG-141 was a phase III trial designed to assess the role of neoadjuvant
chemotherapy in patients with bulky stage IB cervical cancer, who were
randomized to primary surgery vs three cycles of cisplatin and vincristine
followed by surgery. The study was closed prematurely because the majority of
patients needed further therapy (radiotherapy or chemoradiotherapy) despite the
use of neoadjuvant chemotherapy prior to surgery. At a future date, with more
effective chemotherapy, it might be appropriate to reevaluate this strategy.

• GOG-109/SWOG/RTOG: Postoperative Chemoradiation—For patients
with positive pelvic lymph nodes following radical hysterectomy, pelvic
irradiation reduces the pelvic failure rate from approximately 50% to 25% but
does not affect survival. This phase III Intergroup trial (conducted by
Peters et al for the GOG, Southwest Oncology Group [SWOG], and Radiation Therapy
Oncology Group [RTOG]) was initiated to determine whether the efficacy of
adjuvant radiotherapy following radical hysterectomy and lymphadenectomy in
high-risk early-stage cervical cancer patients might be improved by concomitant
chemotherapy.[7] The high-risk group includes one or more of three
histologically defined poor prognostic factors (positive pelvic lymph nodes,
positive parametrial involvement, and positive surgical margins).

Patients were randomized to receive adjuvant radiotherapy alone or combined
concurrent chemoradiotherapy (Figure 2)[7]; 85% had positive pelvic nodes, 34%
had positive parametrial involvement, and 5% had positive margins. The estimated
4-year, disease-free survival (81% vs 63%) and overall survival rates were
significantly higher with chemoradiotherapy, compared to radiotherapy alone (81%
vs 71%).

With its impressive results, combined adjuvant chemoradiotherapy has become
the current standard treatment after radical hysterectomy for patients with
selected high-risk factors, particularly positive pelvic nodes. Although
grade 3/4 toxicity—notably, acute hematologic and gastrointestinal
effects—were more common in patients who received combined chemoradiotherapy,
these reactions were considered manageable. Because the combination of radical
surgery and irradiation is associated with greater morbidity than either
modality above, complete preoperative assessment is crucial to minimize the need
for both.

Radiation Therapy

In the radiotherapeutic management of stage IB cervical cancer, bulky disease
(the so-called "barrel shaped" cervix) is associated with a high local
failure rate. Definitions of bulky stage IB disease have ranged from greater
than 2.0 cm to greater than 6.0 cm; the GOG definition is ³
4.0 cm in size. Management of this entity is controversial. Recently, the
International Federation of Gynecology and Obstetrics (FIGO) staging system
divided stage IB disease into stages IB1 (£ 4.0 cm) and IB2
(> 4.0 cm). One way to improve definitive radiotherapy is with the
use of planned extrafascial hysterectomy after irradiation.[8]

• GOG-71/GOG-123: Preoperative Radiotherapy—In two studies for the
GOG, Keys et al examined the use of preoperative radiotherapy in women with
early-stage cervical cancer. GOG-71 compared definitive radiotherapy vs
moderate-dose irradiation (75 Gy to point A) followed by extrafascial
hysterectomy in 256 patients with stage IB bulky disease.[9] GOG-123 examined
whether a regimen of weekly cisplatin (40 mg/m²) during external-beam
radiation therapy improved survival compared with that achieved with irradiation
alone in 369 patients with stage IB/IIA cervical cancer.[10] Both arms of
GOG-123 included completion of extrafascial hysterectomy, because the results of
GOG-71 were not yet available when the later study was initiated.

The results of GOG-71 showed that the addition of surgery did not improve
survival. In GOG-123, survival was significantly improved in patients who
received concurrent cisplatin and radiation, compared with those who received
radiation alone prior to extrafascial hysterectomy. At a median follow-up of 36
months, survival rates were 83% and 74% (P = .008) for the chemoradiation
arm and the radiotherapy-alone arm, respectively. Although the rate of severe
adverse effects was higher in the cisplatin-and-radiotherapy group (35%)
compared to the radiotherapy-alone group (13%), no treatment-related deaths
occurred. The improved survival associated with the use of concurrent cisplatin
and radiation is attributable to a reduction in pelvic recurrence.

Surgery vs Radiotherapy

Landoni et al[11] reported the only randomized phase III trial to compare
primary radiotherapy alone with radical hysterectomy followed by postoperative
pelvic radiotherapy in this setting. A total of 337 high-risk (positive nodal
metastases, parametrial involvement, cut-through, and < 3.0 mm of uninvolved
cervical stromal margins) stage IB/IIA cervical cancer patients were included in
the intention-to-treat analysis. Based on the qualifying pathologic risk factor
identified after radical hysterectomy, 62 of 114 (54%) patients with a tumor
diameter of 4.0 cm or less, and a remarkable 46 of 55 (84%) patients with a
tumor diameter greater than 4.0 cm received postoperative radiotherapy.

The relapse-free and overall survival rates were identical in both groups,
but the complication rate was higher among patients undergoing surgery (28% vs
12%, P = .0004). Therefore, patients selected for radical hysterectomy
should have small-volume disease, to minimize the need for adjuvant pelvic
radiation.

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