Elsevier

Gynecologic Oncology

Volume 110, Issue 3, September 2008, Pages 308-315
Gynecologic Oncology

Clinical efficacy of modified preoperative neoadjuvant chemotherapy in the treatment of locally advanced (stage IB2 to IIB) cervical cancer: A randomized study

https://doi.org/10.1016/j.ygyno.2008.05.026Get rights and content

Abstract

Objectives

The use of preoperative neoadjuvant chemotherapy (NAC) in locally advanced cervical cancer (LACC) was hindered by the disadvantages of a delay of curative treatment for nonresponders and the development of radioresistant cells. However, these disadvantages may be overcome by a ‘quick’ high-dose scheme administered in a short period before surgery. Our purpose is to assess the efficacy of NAC with short cycle-length, high-dose agents for LACC.

Method

From 1999 to 2004, 142 of patients with LACC (stage IB2IIB, tumor diameter ≥ 4 cm) were assigned to randomly receive either NAC followed by surgery or primary surgery directly. A modified NAC scheme with short cycle-length, high-dose agents was used.

Results

The overall clinical response rate was 69.4%. The chemotherapeutic response was more favorable in the squamous carcinoma and the tumors smaller than 8 cmP = 0.005, P = 0.029). Pathologic findings showed that the pelvic metastasis and parametrial infiltration rates were significantly lower in NAC group than in the primary surgery group (P = 0.025; P = 0.038). Among patients who received NAC, the lymph node metastasis rate was still as high as 45.5% in non-NAC responders, and it decreased to 16.0% in NAC responders (P = 0.008). The same thing also occurred with parametrial infiltration: 45.5% in non-NAC responders compared with 16.0% in NAC responders (P = 0.008). Survival analysis revealed that although test showed a longer survival in NAC group than in the primary surgery group (P = 0.041), Cox hazard analysis did not indicate the therapy modality as a prognostic predictor (P = 0.074). However, after further subdivision, we found that NAC responders had longer survival and lower recurrence rate than non-NAC responders (P = 0.000; P = 0.013). NAC response was also an independent prognostic predictor (P = 0.005).

Conclusion

The modified preoperative NAC is well tolerated and beneficial in reducing tumor size, eliminating pathological risk factors, and improving prognosis for responders. It also avoids the delay of effective treatment for non-NAC responders.

Introduction

For early-stage cervical cancer, radical surgery is accepted as the standard treatment. However, there is still no agreement on the best approach for bulky (≥ 4 cm in the diameter of tumor) or locally advanced cervical cancer (LACC). The prognosis of patients with such disease has not been improved since 1950, despite the therapeutic advances [1]. Various factors may contribute to therapeutic failure, and the most important one is perhaps the tumor size [2]. The survival rate of patients with early-stage cervical cancer is 80–90% in non-bulky tumors, but decreases to 50–60% in bulky tumors [3], [4], [5], [6]. Therefore, a new therapeutic modality targeted to LACC should be developed.

Recently, neoadjuvant chemotherapy (NAC) prior to surgery or radiotherapy has been applied as a new therapeutic strategy for bulky or locally advanced disease. This treatment often uses cisplatin-based agents and repeats for three to five cycles at 3-week intervals as a standard regimen. Some studies supported its effectiveness in shrinking tumor size, controlling micrometastasis and increasing operability rate [7], [8], [9], [10], [11]. Although the response rate of NAC in LACC could reach up to 73.1–95.0% [8], [9], [10], [11], [12], [13], [14], [15], the use of it remains controversial. Several studies failed to demonstrate a survival benefit of NAC over conventional treatments [16], [17]. It was suggested that only the chemotherapeutic responders who underwent surgery would benefit from NAC. To those non-NAC responders, the delay of surgery could lead to the acceleration of tumor growth [18]. A recent systematic review of 21 trials which enrolled more than 3,000 patients failed to show the conclusive results whether NAC could benefit the survival of patients [19]. Sardi suggested that the major disadvantages of NAC included the delay in curative treatment, the development of radioresistant cellular clones, and cross-resistance with radiotherapy [20]. Most of the reported studies applied more than 3 cycles of chemotherapy which lasted over months. Since NAC is only an adjuvant treatment rather than a final therapy, we reason that patients with poor response may miss the optimal surgery time and have a delayed treatment process. This could ultimately affect the survival.

How to make use of the advantages that NAC offers, and at the same time avoid the delay of effective therapy for non-NAC responders is a very important topic in current cervical cancer therapy. A recent review demonstrated that trials using cycle-lengths shorter than 14 days or the cisplatin dose greater than 25 mg/m2 per week exhibited an advantage of NAC on the survival of patients with LACC. It indicates that the timing and dose intensity may greatly impact the curative effect of NAC [21]. Based on these studies, we hypothesized that NAC might be improved if we could make a more efficient balance between chemotherapy time and surgery time. To test it, we conducted a randomized study by applying a). By systematically assessing the curative efficacy, we conclude that the modified preoperative NAC is well tolerated and beneficial in reducing the tumor size, eliminating pathological risk factors and improving prognosis for responders. Most importantly, it avoids the delay of effective treatment for non-NAC responders.

Section snippets

Patients

From January 1999 to April 2004, 184 patients with IB2IIB stage cervical cancer were referred to the Gynecologic Oncology Department, Zhongnan Hospital of Wuhan University. Prior to entry, patients received a standard evaluation, including physical and gynecologic examination, cytological examination, colposcopy, biopsy, hemotology and chemistry profiles. Patients also received other instrumental examinations including chest X-ray, intravenous pyelography (IVP), hepatic and pelvic

Clinical response to NAC

In NAC group, 58 patients (80.5%) showed a reduction in tumor size after chemotherapy. Clinical hemotherapeutic response evaluation identified fifty patients as NAC responders (50/72, 69.4%), including CR in 6 patients (8.3%) and PR in 44 patients (61.1%); twenty-two patients were identified as non-NAC responders, including nineteen patients with SD (26.4%), and three with PD (4.2%). Six patients with CR were further evaluated by pathological examination of surgical specimens. Four of them were

Discussion

NAC represents a promising alternative to surgery or radiotherapy as the initial treatment of LACC due to its ability to reduce the tumor size and increase the tumor resectability. However, the efficiency of this approach is currently controversial. Some studies reported survival benefits of applying NAC prior to surgery over the traditional therapies [11], [23], [24]; while others showed the opposite results [16], [17], [25], [26]. Since most of previous NAC performed more than 3 cycles with a

Conflict of interest

The authors declare that there are no conflicts of interest.

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