Which clinical/pathologic factors matter in the era of chemoradiation as treatment for locally advanced cervical carcinoma?: Analysis of two Gynecologic Oncology Group (GOG) trials

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Abstract

Purpose.

To explore clinical/pathologic factors associated with prognosis of patients with locally advanced cervical carcinoma treated with weekly cisplatin and pelvic radiation.

Methods.

We retrospectively reviewed data from 335 women who received weekly cisplatin and radiation while participating in similar arms of two GOG studies (protocols 120 and 165). Progression-free survival (PFS) and overall survival (OS) were evaluated for associations between clinical/pathologic factors and prognosis. Prognosis and selected toxicities were also compared between studies.

Results.

Four-year PFS and OS for stage II patients were 64.2% and 68.1%, respectively for those treated on GOG 120 and 65.8% and 73.9% for those treated on GOG 165, compared to 51.4% and 55.4% for stage III/IV patients respectively treated on GOG 120 and 37.7% and 42.7% respectively for those treated on GOG 165. In multivariate analysis, stage, tumor grade, race and age were independently predictive of PFS and OS (for all, p < 0.05). Prolonged (delayed for any cause) radiation was associated with poorer PFS (hazard ratio [HR], 1.98; 95% confidence interval [CI], 1.16–3.38; p = 0.012) and OS (HR, 1.88; 95% CI, 1.08–3.26; p = 0.024) in GOG 165 but not GOG 120.

Conclusions.

FIGO stage, tumor grade, race and age are prognostic in patients with locally advanced cervical carcinoma treated with concurrent cisplatin and radiation. This exploratory analysis has generated a hypothesis that clinical staging (as per GOG 165) is less sensitive in detecting aortic nodal metastases compared to surgical staging (as per GOG 120) and may be associated with poorer prognosis particularly when radiation is prolonged. Prospective clinical studies are needed to test this hypothesis.

Introduction

In the United States, the majority of cervical carcinoma patients are diagnosed with early stage disease. Among the 13,458 staged patients with cervical carcinoma registered by the SEER program between 1973 and 1987, 71% were diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage I–IIA tumors [1]. Most of these women with early lesions are cured with surgery or radiation (RT) alone. However, patients with more advanced lesions are at greater risk of recurrence and account for the majority of cervical cancer deaths [2].

The standard prescription for RT used to treat bulky or locally advanced cervical cancer has been dictated by common practice and Patterns of Care Studies [3], [4], [5]. In contrast, the addition of concomitant chemotherapy to RT has been studied in a number of randomized prospective trials [6], [7], [8], [9], [10]. When added to RT, cisplatin reduces the relative risk of death from cervical carcinoma by approximately 50% by decreasing local/pelvic failure and distant metastases. In 1999, weekly intravenous cisplatin 40 mg/m2 for 6 weeks in combination with RT was established as a new standard for the treatment of locally advanced cervical carcinoma [6], [7]. This dose and schedule were favored because Gynecologic Oncology Group (GOG) protocol 120 showed it to be more convenient, equally efficacious and less toxic than other cisplatin regimens or combinations using 5-fluorouracil (5-FU) and/or hydroxyurea [8]. Indeed, all subsequent GOG randomized trials in this disease have used this dose and schedule as the standard arm, including GOG 165 [9] which compared protracted venous infusion 5-FU and RT to standard cisplatin and RT in patients with stage IIB, IIIB and IVA cervical cancer.

There is a renewed interest and need to reevaluate the effects of common clinical and pathologic factors in today's era of concomitant therapy; some of these were previously studied prior to the development of contemporary RT protocols that include chemotherapy [10], [11]. The current report describes an exploratory analysis of selected patients on GOG 120 and GOG 165 who were treated with weekly cisplatin/pelvic RT in order to investigate the association between common clinical and pathological factors and progression-free survival (PFS) and overall survival (OS). We were also interested in assessing the association between RT duration and prognosis, stratified by these two protocols.

Section snippets

Methods

GOG 120 and GOG 165 were randomized prospective studies treating eligible patients with primary, previously untreated, histologically confirmed invasive (stage IIB to IVA) squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma of the uterine cervix. Patients on GOG 120 were enrolled in the study from April 1992 to April 1997 and patients on GOG 165 were enrolled in the study from October 1997 to July 2000. Arm 1 in each protocol consisted of intravenous cisplatin 40 mg/m2 weekly for

Results

One hundred seventy-six patients treated on GOG 120 and 159 treated on GOG 165 who received weekly cisplatin plus RT were included for this study. Patient characteristics are shown in Table 1. Patient characteristics were comparable between the studies except that women on GOG 165 had better performance status than those on GOG 120. Additionally, there was a difference between protocols regarding staging methods, such that surgical staging was required in GOG 120 but optional in GOG 165

Discussion

According to the National Comprehensive Cancer Network [12], the current standard treatment of women with FIGO stage IB2 to IVA cervical carcinoma with clinically negative aortic nodes is pelvic RT (external and internal techniques delivering approximately 85 Gy to Point A) plus concurrent chemotherapy (cisplatin 40 mg/m2 weekly for 6 cycles) [6]. Although the importance of adding cisplatin to RT is well established, there have been no randomized trials investigating variations in the dose or

Acknowledgments

This study was supported by National Cancer Institute grants to Dr. Monk (K23 CA87558), and to the Gynecologic Oncology Group (GOG) Administrative Office (CA 27469) and the GOG Statistical and Data Center (CA 37517). The following GOG member institutions participated in this study: University of Mississippi Medical Center, University of Oklahoma, Indiana University School of Medicine, Duke University Medical Center, Wayne State University, SUNY-Downstate Medical Center, University of California

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