Advances in the Treatment of Gynecologic Malignancies
Advances in the Treatment of Gynecologic Malignancies
Part 1 of this article, which
appeared in last month’s issue of ONCOLOGY, summarized the outcome of major phase III trials in cervical and
vulvar cancer. This part will provide the outcome of phase III trials in uterine
and ovarian cancer.
Endometrial cancer is the most common female genital tract
cancer in the United States. The majority of cases are confined to the uterus.
Treatment of organ-confined uterine cancer usually comprises total abdominal
hysterectomy and bilateral salpingo-oophorectomy (TAH/BSO). In 1988, clinical
staging of endometrial cancer was replaced with surgical staging because of
inaccuracies associated with clinical staging. Over the past several decades, we
have learned more about the risk factors associated with the recurrence of
endometrial cancer. In recent years, few prospective phase III randomized
studies have been conducted in patients with endometrial carcinoma to answer
questions regarding the best management of these patients.
• GOG-33This Gynecologic Oncology Group (GOG) study
conducted by Creasman et al enrolled 621 patients with stage I/II cancer of the
endometrium. All patients underwent TAH/BSO, selective pelvic and para-aortic
lymphadenectomy, and peritoneal cytology. The depth of myometrial invasion and
grade of tumor were the most important factors predicting pelvic node and para-aortic
node metastases (Table 1).
Before 1988, endometrial cancer was clinically staged. However,
Creasman et al showed that, when a comprehensive staging procedure is performed,
22% of clinical stage I patients have disease outside the uterus. As a result,
the International Federation of Gynecology and Obstetrics (FIGO) mandated that
this disease be staged surgically.
The requirement for lymph node assessment has been the subject
of considerable debate. To different practitioners, this assessment may imply
observation, palpation, sampling, or dissection. GOG findings confirmed that
fewer than 10% of patients with nodal metastases have grossly positive nodes.
Therefore, visualization and palpation are inadequate to exclude lymph node
involvement. Pelvic lymph node dissection should be performed via multiple-sites
because retrospective evidence indicates that adequate pelvic lymph node
dissection may improve overall survival.[2,3]
• Risk GroupsIn general, patients can be divided into one of
three categories of risk for developing recurrent and metastatic disease: low
risk, intermediate risk, and high risk. When the patient’s tumor is confined
to the uterus, the primary risk factors are tumor grade, tumor histology, and
depth of invasion. Depending on the individual patient risk factors,
organ-confined endometrial cancer can be classified as either low risk (grade
1/2, endometrial invasion only, excluding clear cell and papillary serous cases)
or intermediate risk (grade 1-3, inner/middle myometrial invasion). Patients
at high risk have cervical involvement and tumor spread beyond the uterus.
Radiation is often administered to women at risk for
extrauterine spread when the status of the lymph nodes is unknown. However, the
adoption of surgical staging has led to questions regarding the role of pelvic
radiotherapy in patients with disease confined to the uterus.
Adjuvant Treatment of
• GOG-99Roberts et al evaluated surgery vs surgery plus
adjuvant radiotherapy in patients with intermediate-risk (stage IB, IC, and
occult stage II) endometrial cancer; clear cell and serous carcinomas were
excluded. All patients underwent complete surgical staging with pelvic and
para-aortic lymph node dissection and peritoneal cytology. Patients with
intermediate-risk, surgical stage I disease were then randomized to either no
further therapy or 50.4-Gy pelvic irradiation.
A preliminary report of this study showed that the pelvic
recurrence rate was 12% without radiotherapy vs 1.7% with radiotherapy.
Two-thirds of the pelvic recurrences were in the vagina alone (15/22, 68% of all
recurrences in the surgery-alone arm, as well as the only failure among patients
receiving radiation). Although the disease-free survival rate significantly
favored the radiotherapy arm93.7% vs 84.7%, respectively (P = .04)there
was no significant difference in the overall survival rate at 3 years (89% vs
96%, P = .09). This study will require further follow-up before a
final analysis of overall survival can be performed.
The intermediate-risk group represents a heterogeneous group of
patients. The patient population accrued in this study was much more favorable
than anticipated (< 18% had outer one-third myometrial invasion, and 81.6%
had grade 1 and 2 tumors), leaving the study insufficiently powered to observe
survival differences. Therefore, the role of pelvic irradiation in patients with
deep myometrial invasion and high-grade tumor is still unclear and needs to be
Since the main benefit of pelvic irradiation is a decrease in
the vaginal recurrence rate, it could be argued that women with
intermediate-risk tumors, especially those who are well staged, should receive
adjunctive vaginal vault radiation therapy only, which has fewer side effects.
Several retrospective studies have demonstrated excellent outcomes with this
approach.[5-8] Because of increased vaginal sequelae, treatment of the entire
length of the vagina is usually not recommended.
• NCIC trialAn ongoing trial being conducted by the National
Cancer Institute of Canada (NCIC) clinical trial group is similar to GOG-99. The
accrual goal is approximately 400 patients. The results of this study will help
clinicians make appropriate therapeutic decisions for this patient population.
• RTOG-99-05Recently, the Radiation Therapy Oncology Group (RTOG)
initiated a phase III study (99-05) of adjuvant postoperative irradiation
with or without cisplatin and paclitaxel following TAH/BSO in patients with
endometrial cancer. Selection criteria include uterine-confined cancer, but this
population (with stage IC and IIA/B disease) is at higher risk of disease
recurrence than were women enrolled in GOG-99. Regional lymph node sampling is
not necessary for this study population.
• Other Trials in Organ-Confined DiseaseTable 2 compares the
parameters of GOG-99 with those in two other randomized trials of clinically
organ-confined endometrial cancer.[4,9,10] In 1980, Aalders et al published a
report on a randomized trial of primary surgery and vaginal brachytherapy with
and without additional external-beam radiation in patients with endometrial
cancer. As expected, a significant reduction in vaginal and pelvic recurrences
was observed in the group receiving adjuvant radiotherapy (1.9% vs 6.9%).
However, the overall 5-year survival did not improve. In subset analysis, those
with grade 3 lesions and > 50% myometrial invasion showed a significant
increase in survival. Pelvic node dissection was not performed in this study.
In most European countries, lymphadenectomy is not considered a
standard procedure for stage I endometrial cancer. Recently, the Dutch
Postoperative Radiation Therapy in Endometrial Cancer (PORTEC) study group
investigated whether postoperative pelvic irradiation improved locoregional
control and survival in patients with stage I endometrial cancer. The 715
patients in the intermediate-risk group were randomized to pelvic radiotherapy
(46 Gy) or no further treatment, and pelvic node dissection was not performed.
The 5-year locoregional recurrence rates were 4% in the radiotherapy group and
14% in the control group, but there was no impact on overall survival. The
majority of recurrences (73%) were restricted to the vagina. As expected, the
incidence of late complications was higher in the radiotherapy group (25% vs
6%), although most were grade 1.
The results of both the Aalders and PORTEC trials[9,10] are
based on clinically staged patients and may not be relevant for surgically
staged patients. Another Dutch trial in which lymphadenectomy is being compared
to radiotherapy in high-risk endometrial cancer has recently been initiated, and
the results of that trial will clarify the future role of lymphadenectomy in