Advances in the Treatment of Gynecologic Malignancies

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(Drug information on 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(Drug information on 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.