Clinical Study Received: October 29, 2014 Accepted after revision: February 27, 2015 Published online: April 29, 2015
Oncology 2015;89:103–110 DOI: 10.1159/000381461
Dose-Dense Neoadjuvant Chemotherapy plus Radical Surgery in Locally Advanced Cervical Cancer: A Phase II Study Pierluigi Benedetti Panici Innocenza Palaia Claudia Marchetti Ilary Ruscito Margherita Fischetti Angela Musella Violante Di Donato Giorgia Perniola Laura Vertechy Ludovico Muzii Department of Gynecology, Obstetrics and Urology, Sapienza University of Rome, Rome, Italy
Abstract Objective: To assess the efficacy and toxicity profile of dosedense cisplatin-based neoadjuvant chemotherapy (NACT) followed by radical surgery in patients affected by locally advanced cervical cancer. Methods: Patients affected by carcinoma of the uterine cervix FIGO (International Federation of Obstetrics and Gynecology) stage IB2–IIIB were enrolled into the study. The treatment schedule consisted of 5 cycles of intravenous paclitaxel 60 mg/m2 plus cisplatin 60 mg/m2 every 10 days; patients were then submitted to radical hysterectomy and pelvic lymphadenectomy. Results: From January 2011 to March 2013, 22 patients were enrolled. Median age was 47 (26–83) years. FIGO stages included 1 IIA, 15 IIB, 1 IIIA, and 5 IIIB. Ninety-one percent of patients completed all the 5 planned cycles of NACT. Three patients experienced allergic reactions to paclitaxel. Grade 3–4 hematological toxicity was observed in 18% of cases. In 3 cases, grade 3–4 extra-hematological adverse and life-threatening events were reported (1 ototoxicity, 1 transient ischemic attack, and 1 myocardial infarction). No treatment-related death oc-
© 2015 S. Karger AG, Basel 0030–2414/15/0892–0103$39.50/0 E-Mail [email protected] www.karger.com/ocl
curred. The operability rate was 86.4%. The overall response rate was 52.6%: 5 patients (26.3%) experienced clinical complete response, and 5 (26.3%) showed a clinical partial response. Stable disease was observed in 47.4% of patients, with no progressive disease recorded. Pathological response was observed in 57.9% of cases. Six out of 19 (31.6%) patients were submitted to adjuvant treatment. Conclusion: Dosedense cisplatin-based NACT showed a response rate in approximately half of patients. However, in consideration of the reported extra-hematological toxicity, further studies on and new strategies with dose-dense platinum-based NACT are required to improve outcome in cervical cancer patients. © 2015 S. Karger AG, Basel
Introduction
Cervical cancer is the second most common neoplasm among women worldwide, with an incidence of 529,800 new cases and 275,100 deaths per year [1]; more than half of these patients are affected by locally advanced cervical cancer (LACC) at diagnosis [International Federation of Obstetrics and Gynecology (FIGO) stage IB2–IIIB] [2]. Chemoradiation is considered the gold standard for the treatment of LACC [3]; however, in the last two decades, Dr. Innocenza Palaia Department of Gynecology, Obstetrics and Urology Sapienza University of Rome Viale Regina Elena, 324, IT–00161 Rome (Italy) E-Mail innocenza.palaia @ uniroma1.it
Downloaded by: Harvard University 198.143.38.97 - 7/26/2015 5:56:47 AM
Key Words Cervical cancer · Neoadjuvant chemotherapy · Dose intensity · Cisplatin · Paclitaxel · Radical hysterectomy
104
Oncology 2015;89:103–110 DOI: 10.1159/000381461
vanced ovarian cancer, paclitaxel and carboplatin given every 3 weeks has been compared to dose-dense weekly administration of paclitaxel. Median progression-free survival was longer in the dose-dense group (28 vs. 17.2 months), and overall survival at 3 years was higher in the dose-dense regimen group (72%) than in the conventional treatment group (65%). Neutropenia and anemia were more common in the dose-dense group [16]. As for cervical cancer, in 1993 Sardi et al. [17] first proposed a ‘quick’ neoadjuvant scheme of vincristine-bleomycin-cisplatin with encouraging results. Later on, Park et al. [18] published a pilot study on 43 patients affected by LACC submitted to NACT with cisplatin 60 mg/m2 plus paclitaxel 60 mg/m2 every 10 days administered before surgery or radiation therapy. They reported a response rate of about 91% and a favorable toxicity profile. However, they concluded that more studies were needed to confirm those results. On the basis of these previous experiences, we also hypothesized that the dose-dense administration of TP in patients affected by LACC scheduled for NACT and RS could be characterized by an equal or superior efficacy with respect to the TIP scheme, but with a less toxic profile. Therefore, the primary objective of the present prospective phase II study was to assess the efficacy and toxicity profile of the dose-dense administration of TP in this setting. The secondary end point was the survival analysis.
Materials and Methods Ethics committee approval was required and obtained for this study. The EUDRACT number of this study is 2014-001410-25. Between January 2011 and March 2013, consecutive patients referred to the Department of Gynecologic Oncology, Sapienza University, Rome, affected by histologically proven cervical cancer FIGO stage IB2–IIIB were enrolled into the study. Eligibility criteria were: age >18 years; histologically confirmed squamous, adenosquamous or adenocarcinoma of the uterine cervix; FIGO stage IB2–IIIB; normal hematological, renal, and hepatic function as determined by hemoglobin >9 g/dl, neutrophil count >1,500/μl, platelet count >100,000/μl, creatinine
Oncology 2015;89:103–110 DOI: 10.1159/000381461
Dose-Dense Neoadjuvant Chemotherapy plus Radical Surgery in Locally Advanced Cervical Cancer: A Phase II Study Pierluigi Benedetti Panici Innocenza Palaia Claudia Marchetti Ilary Ruscito Margherita Fischetti Angela Musella Violante Di Donato Giorgia Perniola Laura Vertechy Ludovico Muzii Department of Gynecology, Obstetrics and Urology, Sapienza University of Rome, Rome, Italy
Abstract Objective: To assess the efficacy and toxicity profile of dosedense cisplatin-based neoadjuvant chemotherapy (NACT) followed by radical surgery in patients affected by locally advanced cervical cancer. Methods: Patients affected by carcinoma of the uterine cervix FIGO (International Federation of Obstetrics and Gynecology) stage IB2–IIIB were enrolled into the study. The treatment schedule consisted of 5 cycles of intravenous paclitaxel 60 mg/m2 plus cisplatin 60 mg/m2 every 10 days; patients were then submitted to radical hysterectomy and pelvic lymphadenectomy. Results: From January 2011 to March 2013, 22 patients were enrolled. Median age was 47 (26–83) years. FIGO stages included 1 IIA, 15 IIB, 1 IIIA, and 5 IIIB. Ninety-one percent of patients completed all the 5 planned cycles of NACT. Three patients experienced allergic reactions to paclitaxel. Grade 3–4 hematological toxicity was observed in 18% of cases. In 3 cases, grade 3–4 extra-hematological adverse and life-threatening events were reported (1 ototoxicity, 1 transient ischemic attack, and 1 myocardial infarction). No treatment-related death oc-
© 2015 S. Karger AG, Basel 0030–2414/15/0892–0103$39.50/0 E-Mail [email protected] www.karger.com/ocl
curred. The operability rate was 86.4%. The overall response rate was 52.6%: 5 patients (26.3%) experienced clinical complete response, and 5 (26.3%) showed a clinical partial response. Stable disease was observed in 47.4% of patients, with no progressive disease recorded. Pathological response was observed in 57.9% of cases. Six out of 19 (31.6%) patients were submitted to adjuvant treatment. Conclusion: Dosedense cisplatin-based NACT showed a response rate in approximately half of patients. However, in consideration of the reported extra-hematological toxicity, further studies on and new strategies with dose-dense platinum-based NACT are required to improve outcome in cervical cancer patients. © 2015 S. Karger AG, Basel
Introduction
Cervical cancer is the second most common neoplasm among women worldwide, with an incidence of 529,800 new cases and 275,100 deaths per year [1]; more than half of these patients are affected by locally advanced cervical cancer (LACC) at diagnosis [International Federation of Obstetrics and Gynecology (FIGO) stage IB2–IIIB] [2]. Chemoradiation is considered the gold standard for the treatment of LACC [3]; however, in the last two decades, Dr. Innocenza Palaia Department of Gynecology, Obstetrics and Urology Sapienza University of Rome Viale Regina Elena, 324, IT–00161 Rome (Italy) E-Mail innocenza.palaia @ uniroma1.it
Downloaded by: Harvard University 198.143.38.97 - 7/26/2015 5:56:47 AM
Key Words Cervical cancer · Neoadjuvant chemotherapy · Dose intensity · Cisplatin · Paclitaxel · Radical hysterectomy
104
Oncology 2015;89:103–110 DOI: 10.1159/000381461
vanced ovarian cancer, paclitaxel and carboplatin given every 3 weeks has been compared to dose-dense weekly administration of paclitaxel. Median progression-free survival was longer in the dose-dense group (28 vs. 17.2 months), and overall survival at 3 years was higher in the dose-dense regimen group (72%) than in the conventional treatment group (65%). Neutropenia and anemia were more common in the dose-dense group [16]. As for cervical cancer, in 1993 Sardi et al. [17] first proposed a ‘quick’ neoadjuvant scheme of vincristine-bleomycin-cisplatin with encouraging results. Later on, Park et al. [18] published a pilot study on 43 patients affected by LACC submitted to NACT with cisplatin 60 mg/m2 plus paclitaxel 60 mg/m2 every 10 days administered before surgery or radiation therapy. They reported a response rate of about 91% and a favorable toxicity profile. However, they concluded that more studies were needed to confirm those results. On the basis of these previous experiences, we also hypothesized that the dose-dense administration of TP in patients affected by LACC scheduled for NACT and RS could be characterized by an equal or superior efficacy with respect to the TIP scheme, but with a less toxic profile. Therefore, the primary objective of the present prospective phase II study was to assess the efficacy and toxicity profile of the dose-dense administration of TP in this setting. The secondary end point was the survival analysis.
Materials and Methods Ethics committee approval was required and obtained for this study. The EUDRACT number of this study is 2014-001410-25. Between January 2011 and March 2013, consecutive patients referred to the Department of Gynecologic Oncology, Sapienza University, Rome, affected by histologically proven cervical cancer FIGO stage IB2–IIIB were enrolled into the study. Eligibility criteria were: age >18 years; histologically confirmed squamous, adenosquamous or adenocarcinoma of the uterine cervix; FIGO stage IB2–IIIB; normal hematological, renal, and hepatic function as determined by hemoglobin >9 g/dl, neutrophil count >1,500/μl, platelet count >100,000/μl, creatinine
