Concomitant Radiochemotherapy plus Surgery in Locally Advanced Cervical Cancer: Update of Clinical Outcome and Cyclooxygenase-2 as Predictor of Treatment Susceptibility

Objective: We have updated our findings on the efficacy of concomitant radiochemotherapy plus radical surgery in a larger series of patients (n = 54) with locally advanced cervical cancer (LACC). We also investigated the role of cyclooxygenase-2 (COX-2) in this clinical setting. Methods: Radiotherapy was administered to the whole pelvic region (1.8 Gy/day, totaling 39.6 Gy) in combination with cisplatin (20 mg/m2) and 5-fluorouracil (1,000 mg/m2) (both on days 1–4 and 27–30). Radical surgery was performed 5–6 weeks after the end of treatment. Results: A clinical complete or partial response was observed in all 53 evaluable patients (75.5 and 24.5%, respectively). At pathological examination, 23 of 51 patients (45.1%) undergoing radical surgery showed complete response to treatment, 18 patients (35.3%) only had microscopic residual disease, 6 patients (11.7%) had a partial response and 4 (7.8%) had no change in their disease. When logistic regression was applied, the FIGO stage (χ2 = 5.28, p = 0.021) and tumor to stroma COX-2 ratio (χ2 = 4.72, p = 0.029) retained an independent role in the prediction of the pathologic response to treatment. The 3-year disease-free survival (DFS) was 75.2%, with local relapse-free survival of 86.2% and metastasis-free interval of 89.9% at 3 years. Cases with a high COX-2 ratio showed a shorter DFS than cases with a low COX-2 ratio (p = 0.016). A direct association was shown between COX-2 ratio values and risk of recurrence, as assessed by Cox analysis using COX-2 ratio values as a continuous covariate (χ2 = 3.94, p = 0.047). Conclusion: This study confirms the possibility of achieving a very high rate of pathological responses in LACC patients administered chemoradiation plus surgery (3-year DFS 75.2%). Moreover, COX-2 status may play a role in the prognostic characterization and prediction of tumor response.

[1]  G. Scambia,et al.  Cyclooxygenase-2 (COX-2) expression in locally advanced cervical cancer patients undergoing chemoradiation plus surgery. , 2003, International journal of radiation oncology, biology, physics.

[2]  N. Maggiano,et al.  Expression of cyclooxygenase-2 (COX-2) in tumour and stroma compartments in cervical cancer: clinical implications , 2002, British Journal of Cancer.

[3]  C. Suh,et al.  Overexpression of cyclooxygenase‐2 is associated with a poor prognosis in patients with squamous cell carcinoma of the uterine cervix treated with radiation and concurrent chemotherapy , 2002, Cancer.

[4]  N. Maggiano,et al.  Increased cyclooxygenase-2 expression is associated with chemotherapy resistance and poor survival in cervical cancer patients. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  L Souhami,et al.  Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  J. Isola,et al.  Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. , 2002, Cancer research.

[7]  F. Landoni,et al.  Neoadjuvant chemotherapy and radical surgery versus exclusive radiotherapy in locally advanced squamous cell cervical cancer: results from the Italian multicenter randomized study. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  G. Scambia,et al.  Is there a place for a less extensive radical surgery in locally advanced cervical cancer patients? , 2001, Gynecologic oncology.

[9]  A. Hsu,et al.  Apoptosis signaling pathways mediated by cyclooxygenase-2 inhibitors in prostate cancer cells. , 2001, Advances in enzyme regulation.

[10]  D. Beer,et al.  Selective inhibition of cyclooxygenase-2 suppresses growth and induces apoptosis in human esophageal adenocarcinoma cells. , 2000, Cancer research.

[11]  V. Valentini,et al.  Phase I-II trial of preoperative chemoradiation in locally advanced cervical carcinoma. , 2000, Gynecologic oncology.

[12]  P. Grigsby,et al.  Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  J. García-Foncillas,et al.  Pilot study of concurrent cisplatin, 5-fluorouracil, and external beam radiotherapy prior to radical surgery +/- intraoperative electron beam radiotherapy in locally advanced cervical cancer. , 1999, Gynecologic oncology.

[14]  B N Bundy,et al.  Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  B N Bundy,et al.  Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. , 1999, The New England journal of medicine.

[16]  P J Eifel,et al.  Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. , 1999, The New England journal of medicine.

[17]  K. Blank,et al.  Concurrent Cisplatin-Based Radiotherapy and Chemotherapy for Locally Advanced Cervical Cancer , 1999 .

[18]  R. Manfredi,et al.  Cervical cancer response to neoadjuvant therapy: MR imaging assessment. , 1998, Radiology.

[19]  R. DuBois,et al.  Prostaglandin endoperoxide synthase: why two isoforms? , 1996, The American journal of physiology.

[20]  M. Gamerre,et al.  Concomitant chemoradiation prior to surgery in the treatment of advanced cervical carcinoma. , 1994, Gynecologic oncology.

[21]  W. Sauerbrei,et al.  Dangers of using "optimal" cutpoints in the evaluation of prognostic factors. , 1994, Journal of the National Cancer Institute.

[22]  M. Piver,et al.  Five Classes of Extended Hysterectomy for Women With Cervical Cancer , 1974, Obstetrics and gynecology.

[23]  David R. Cox The analysis of binary data , 1970 .

[24]  N. Mantel Evaluation of survival data and two new rank order statistics arising in its consideration. , 1966, Cancer chemotherapy reports.

[25]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .