4 Versus 6 Courses of Adjuvant Chemotherapy in LACC Patients Previously Treated With NACT Plus Radical Surgery
4 Versus 6 Courses of Adjuvant Chemotherapy in LACC Patients Previously Treated With NACT Plus Radical Surgery
The investigators primary outcome was to evaluate the effectiveness in term of Overall
 Survival (OS) and disease free interval (DFI) of two different platinum-based chemotherapic
 regimen (3 and 6 cycles) for treatment of Locally Advanced Cervical Cancer (LACC) (IB2-IIB)
 previously treated with Neoadjuvant Chemotherapy Plus Radical Surgery (NACT+RS).

 The secondary outcome was to evaluate and compare safety, in term of toxicity profile, of the
 two treatment options.
Between February 2007 to January 2013, all patients with diagnosis of LAAC referred to the
 Division of Gynecologic Oncology of the Campus Bio-Medico University of Rome, were eligible
 for this protocol. The institutional internal review board approved the study. Inclusion
 criteria were: I) Patients with squamous cell, adenosquamous or adenocarcinoma of the cervix;
 II) Stage IB2-IIB according to the International Federation of Gynecology and Obstetrics
 (FIGO); III) age between 18 and 75 years; IV) Eastern Cooperative Oncology Group (ECOG)
 performance status 0-2; V) normal cardiac and respiratory functions; VI) absence of secondary
 malignancies; VII) no previous surgical, chemotherapic and/or radiotherapic treatment for
 secondary malignancies VIII) informed consent obtained from the patient.Exclusion criteria
 included: I) histological confirmation of papillary serous, mucinous, clear cell, squamous
 cell, mixed and undifferentiated carcinoma of the uterus; II) abnormal hepatic function
 (transaminases > 2.5 x upper limit, serum bilirubin > 1,5 x upper limit); III) abnormal renal
 function (creatinine clearance <60 mL/min and/or serum creatinine>2.0 mg/100 mL) function;
 IV) abnormal bone marrow function (absolute neutrophil count <1,5 x 109/L or platelet count <
 100 x 109/L or hemoglobin < 9 g/dL; V) severe or uncontrolled infection, other systemic
 diseases or mental illness; and VI) pregnant women. Clinical staging was performed according
 to the NCCN criteria, and included pelvic examination, cervical biopsy, abdomen-pelvis
 Computed Tomography, chest X-ray; examination under anesthesia, cystoscopy and/or proctoscopy
 if clinically indicated (National Comprehensive Cancer Network, Clinical Practicw Guidelines
 in Oncology. Cervical Cancer, Version 2.2015) All patients who met inclusion and exclusion
 criteria were enrolled and received 3 cycles of neoadjuvant chemotherapy (NACT) every three
 weeks according to the scheme Cisplatin 100 mg/mq and Paclitaxel 175 mg/mq.

 Complete response was defined as complete disappearance of all clinically detect able
 disease, determined by 2 observations not less than 4 weeks apart. Partial response was
 recorded as ≥50% reduction in total tumor size, determined by 2 observations not less than 4
 weeks apart. No response or stable disease was defined as <50% decrease in tumor size or <25%
 increase in the size of one or more measurable lesions. Progressive disease was defined >25%
 increase in size or the appearance of new lesions.

 After NACT all patients with stable or progressive disease were excluded from the protocol,
 all others were underwent to bilateral systematic pelvic lymph node dissection, classical
 radical hysterectomy and bilateral salpingo-oophorectomy. Aortic lymphadenectomy, up to the
 level of the inferior mesenteric artery, was reserved to patients with pelvic node disease at
 intraoperative examination or finding of bulky aortic nodes at the time of surgery. In case
 of positive aortic nodes, hysterectomy was not performed, patients were excluded from the
 protocol and referred to radiation oncologists. Similarly patients who presented positive
 surgical margins or close vaginal margins (<0.5 mm) at final pathology, were excluded from
 the study and referred to radiotherapist. After surgery were randomly allocated to undergo 4
 or 6 cycles of chemotherapy by using a predetermined computer-generated randomisation code.
 In Group A, all patients received 4 cycles of adjuvant chemotherapy every three weeks
 according to the scheme Cisplatin 100 mg/mq and Paclitaxel 175 mg/mq.In Group B, all patients
 received instead 6 cycles of adjuvant chemotherapy every three weeks according to the same
 chemotherapic regimen. Adjuvant chemotherapy started within 28 days after surgery. Follow-up
 procedures included physical examination and vaginal cytology every 3 months for 2 years,
 then every 6 months until the 5th year according the NCCN 2015 and total body CT.

 Therefore in all patients in whom there was suspicion of relapse, the total body CT was
 anticipated.

 To assess the sample size, in agreement with the investigators experience, the investigators
 estimated a 20% reduction of the toxicity profile for patients who received 4 cycles of
 adjuvant chemotherapy compared to those who received 6 cycles (11; 19). Considering a power
 of 80%, to detect a statistically significant difference (alpha = 0.5; P = 0.05 Long Rank
 Test), 100 patients were necessary for each treatment arm.

 OS and DFS curves were estimated using the Kaplan-Meier method and differences were compared
 by use of the log-rank test.

 The comparison of other variables between two groups was evaluated using the Mann-Whitney
 test, the chi-square test, Fisher test. Statistical significance was set at p <0.05.

 DFS, OS and recurrence rate were analyzed only in those patients who completed the study
 protocol; toxicity profile of the two treatment groups, however, were statistically analyzed
 considering all patients randomized and enrolled in the study protocol after treatment with
 NACT + RS.
Inclusion Criteria:

 -  patients with squamous cell, adenosquamous or adenocarcinoma of the cervix

 -  Stage IB2-IIB according to the Inyernational Federation of Gynecology and Obstetrics
 (FIGO)

 -  age between 18 and 75 years

 -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2

 -  normal cardiac and respiratory functions

 -  absence of secondary malignancies

 -  no previous surgical, chemotherapic and/or radiotherapic treatment for secondary
 malignancies

 -  informed consent obtained from the patient.

 Exclusion Criteria:

 -  histological confirmation of papillary serous, mucinous, clear cell, squamous cell,
 mixed and undifferentiated carcinoma of the uterus

 -  abnormal hepatic function (transaminases > 2.5 x upper limit, serum bilirubin > 1,5 x
 upper limit)

 -  abnormal renal function (creatinine clearance <60 mL/min and/or serum creatinine>2.0
 mg/100 mL) function

 -  abnormal bone marrow function (absolute neutrophil count <1,5 x 109/L or platelet
 count < 100 x 109/L or hemoglobin < 9 g/dL

 -  severe or uncontrolled infection, other systemic diseases or mental illness; and

 -  pregnant women. Clinical staging was performed according to the NCCN criteria, and
 included pelvic examination, cervical biopsy, abdomen-pelvis Computed Tomography,
 chest X-ray; examination under anesthesia, cystoscopy and/or proctoscopy if clinically
 indicated (National Comprehensive Cancer Network, Clinical Practicw Guidelines in
 Oncology. Cervical Cancer, Version 2.2015)