Concurrent definitive chemoradiation incorporating intensity-modulated radiotherapy followed by adjuvant chemotherapy in high risk locally advanced cervical squamous cancer: a phase II study.

BACKGROUND: Although the prognosis of locally advanced cervical cancer has improved dramatically, survival for those with stage IIIB-IVA disease or lymph nodes metastasis remains poor. It is believed that the incorporation of intensity-modulated radiotherapy into the treatment of cervical cancer might yield an improved loco-regional control, whereas more cycles of more potent chemotherapy after the completion of concurrent chemotherapy was associated with a diminished distant metastasis. We therefore initiated a non-randomized prospective phaseII study to evaluate the feasibility of incorporating both these two treatment modality into the treatment of high risk locally advanced cervical cancer. OBJECTIVES: To determine whether the incorporation of intensity-modulated radiotherapy and the addition of adjuvant paclitaxel plus cisplatin regimen into the treatment policy for patients with high risk locally advanced cervical cancer might improve their oncologic outcomes. STUDY DESIGN: Patients were enrolled if they had biopsy proven stage IIIA-IVA squamous cervical cancer or stage IIB disease with metastatic regional nodes. Intensity-modulated radiotherapy was delivered with dynamic multi-leaf collimators using 6MV photon beams. Prescription for PTV ranged from 45.0 ~ 50.0 Gy at 1.8 Gy ~ 2.0 Gy/fraction in 25 fractions. Enlarged nodes were contoured separately and PTV-nodes were boosted simultaneously to a total dose of 50.0-65 Gy at 2.0- 2.6 Gy/fraction in 25 fractions. A total dose of 28 ~ 35 Gy high-dose- rate brachytherapy was prescribed to point A in 4 ~ 5 weekly fractions using an iridium- 192 source. Concurrent weekly intravenous cisplatin at 30 mg/m2 was initiated on the first day of radiotherapy for over 1-h during external-beam radiotherapy. Adjuvant chemotherapy was scheduled within 4 weeks after the completion of concurrent chemo-radiotherapy and repeated 3 weeks later. Paclitaxel 150 mg/m2 was given as a 3-h infusion on day1, followed by cisplatin 35 mg/m2 with 1-h infusion on day1-2 (70 mg/m2 in total). RESULTS: Fifty patients achieved complete response 4 weeks after the completion of the treatment protocol, whereas 2 patients had persistent disease. After a median follow-up period of 66 months, loco-regional (including 2 persistent disease), distant, and synchronous treatment failure occurred in 4,5, and 1, respectively. The 5-year disease-free survival, loco-regional recurrence-free survival, distant-metastasis recurrence-free survival was 80.5%, 90.3%, and 88.0%, respectively. Four of the patients died of the disease, and the 5-year overall survival was 92.1%. Most of the toxicities reported during concurrent chemo-radiotherapy were mild and transient. The occurrence of hematological toxicities elevated mildly during adjuvant chemotherapy, as 32% (16/50) and 4% (2/50) patients experienced grade 3-4 leukopenia and thrombocytopenia, respectively. Grade 3-4 late toxicities were reported in 3 patients. CONCLUSIONS: The incorporation of intensity-modulated radiotherapy and adjuvant paclitaxel plus cisplatin chemotherapy were highly effective and well-tolerated in the treatment of high-risk locally advanced cervical cancer. The former yields an improved loco-regional control, whereas distant metastases could be effectively eradicated with mild toxicities when adjuvant regimen was prescribed.

Pooled analysis on the necessity of random 4-quadrant cervical biopsies and endocervical curettage in women with positive screening but negative colposcopy.

Controversy remains over whether random cervical biopsies and endocervical curettage (ECC) should be used in women with positive screening but negative colposcopy. Our paper aims to determine the indications for random biopsies and ECC among these screened positive women.Three thousand two hundred thirteen women with any positive screening test result but negative colposcopy, who received random 4-quadrant biopsies, were pooled from 17 population-based cervical cancer screening studies done in China from 1999 to 2008. The detection rates of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and CIN grade 3 or worse (CIN3+) stratified by cytology and high-risk human papillomavirus (HR-HPV) status were assessed, as well as the false negative rates for CIN2+ and CIN3+ by random biopsies without ECC.Compared with women with negative cytology and positive HR-HPV, those with atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion (ASC-US/LSIL) and negative HR-HPV had the equivalent lower risks of CIN2+ and CIN3+, but ascending risks were observed in the groups of ASC-US/LSIL and positive HR-HPV, and atypical glandular cells/atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion/high-grade squamous intraepithelial lesion or worse (AGC/ASC-H/HSIL+). If random biopsies were only taken without ECC, 9.3% of CIN2+ and 18.5% of CIN3+ would have been missed.For women with any positive screening but negative colposcopy, in areas with good cytological infrastructure, it was necessary to perform random biopsies plus ECC on those with cytological ASC-US/LSIL and positive HR-HPV, AGC, ASC-H, or HSIL+. In contrast, those with other results should be followed up.

[Study of the radiotherapy modality for patients with stage IIb-IIIb cervical stump cancer].

OBJECTIVE: To investigate the radiotherapy modality progress of stageIIb-IIIb cervical stump cancer. METHODS: The clinical data of 13 patients with stageIIb-IIIb cervical stump cancer undergoing radiotherapy from January 2000 to April 2012 was reviewed. Before 2006, 8 patients received conventional external beam radiotherapy and brachytherapy.Since 2006, 5 patients received intensity-modulated radiotherapy (IMRT) and brachytherapy. RESULTS: The median survival was 12-139 months. The median overall survivals and disease free survivals in the conventional radiotherapy (CRT) group were 57 months and 50 months, 3 cases of them recurred during 8-19 months and died of tumor progression.While, the median overall survivals and disease free survival in the IMRT group both were 21 months and nobody recurred. In the CRT group, 7 patients suffered toxicities, including 5 patients grade I-II acute rectum reaction, 2 patients grade I bladder reaction; and 3 had grade I-III, late rectum reaction, 2 patients for grade II bladder late reaction.In the IMRT group, toxicities including 1 case grade I acute or late rectum reaction, and no bladder reaction. CONCLUSION: In our experience, the recommended IMRT and interstitial brachytherapy for the selected patients with advanced cervical stump carcinoma may be obtain better tumor dose distribution and more sparing of the organ at risk.

A preliminary study of genes related to concomitant chemoradiotherapy resistance in advanced uterine cervical squamous cell carcinoma.

BACKGROUND: Tumor intrinsic chemoradiotherapy resistance is the primary factor in concomitant chemoradiotherapy failure in advanced uterine cervical squamous cell carcinoma. This study aims to identify a set of genes and molecular pathways related to this condition. METHODS: Forty patients with uterine cervical squamous cell carcinoma in International Federation of Gynecology and Obstetrics stage IIb or IIIb, treated with platinum-based concomitant chemoradiotherapy between May 2007 and December 2012, were enrolled in this trial. Patients included chemoradiotherapy resistant (n = 20) and sensitive (n = 20) groups. Total RNA was extracted from fresh tumor tissues obtained by biopsy before treatment and microarray analysis was performed to identify genes differentially expressed between the two groups. RESULTS: Microarray analysis identified 108 genes differentially expressed between concomitant chemoradiotherapy resistant and sensitive patients. Functional pathway cluster analysis of these genes revealed that DNA damage repair, apoptosis, cell cycle, Map kinase signal transduction, anaerobic glycolysis and glutathione metabolism were the most relevant pathways. Platelet-derived growth factor receptor alpha (PDGFRA) and protein kinase A type 1A (PRKAR1A) were significantly upregulated in the chemoradiosensitive group, while lactate dehydrogenase A (LDHA), bcl2 antagonist/killer 1 (BAK1), bcl2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3), single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1), and cyclin-dependent kinase 7 (CDK7) were upregulated in the chemoradiotherapy resistant group. CONCLUSION: We have identified seven genes that are differentially expressed in concomitant chemoradiotherapy resistant and sensitive uterine cervical squamous cell carcinomas, which may represent primary predictors for this condition.

Retrospective analysis of prognostic variables and clinical outcomes in surgically staged intermediate risk endometrial carcinoma.

OBJECTIVE: To identify independent prognostic variables for surgically staged intermediate risk endometrial carcinoma as defined by the Gynecologic Oncology Group 99 (GOG99) criteria. STUDY DESIGN: Retrospective study of 239 patients with FIGO stage IB-occult IIB endometrioid type endometrial cancer, who were primarily treated with comprehensive staging surgery. Data were collected on clinicopathological variables, extent of primary surgery, postoperative adjuvant treatment, and patterns of recurrences. Kaplan-Meier survival curves were used to estimate disease free survival (DFS) and overall survival (OS), and multivariate Cox regression models were used to identify independent prognostic variables. The median follow-up time was 67 months (range, 12-183 months). RESULTS: The 5-year DFS and OS were 91.0% and 93.0%, respectively. On univariate Kaplan-Meier analysis, age>60 years, deep myometrial invasion (MI), presence of lymph vascular invasion (LVSI), and negative progesterone receptor (PR) status were significantly associated with diminished 5-year DFS and OS. The univariate analysis on patterns of failures demonstrated that patients with older age or positive LVSI were more inclined to develop locoregional recurrence, while PR status and the depth of MI had a statistically significant impact on distant failure. On multivariate analysis, PR status, age, and the depth of MI were independent prognostic variables for 5-year DFS, and age was the only independent prognostic variable for 5-year OS. LVSI and age were independent prognostic variables for locoregional recurrence, while PR status and depth of MI were independent prognostic variables for distant recurrence. CONCLUSIONS: Age, depth of MI, PR status and presence of LVSI are of independent prognostic value for intermediate risk endometrial cancer. The presence of these variables warrants consideration when deciding upon treatment strategies.

[Comparative analysis of neoadjuvant therapies in stage Ib2 and IIa2 cervical carcinoma].

OBJECTIVE: To compare the clinical efficacy of neoadjuvant chemotherapy plus vaginal intracavitary irradiation, neoadjuvant chemotherapy alone and vaginal intracavitary irradiation alone followed by radical hysterectomy in patients with stage Ib2 and IIa2 bulkly cervical carcinoma. METHODS: Between January 2000 and December 2009, 224 patients with stage Ib2 and IIa2 bulkly cervical carcinoma (tumor diameter > 4 cm) received neoadjuvant therapy combined surgery in Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences were respectively analyzed, and they were divided into 3 groups according to the preoperative neoadjuvant therapy, the neoadjuvant chemotherapy combined vaginal intracavitary irradiation group (chemotherapy combined irradiation group, n = 86), the neoadjuvant chemotherapy alone group (chemotherapy group, n = 48), the vaginal intracavitary irradiation alone group (irradiation group, n = 90). The efficacy, postoperative risk factors, postoperative adjuvant therapy and survival were compared among the 3 groups. RESULTS: Among the chemotherapy combined irradiation group, chemotherapy group and irradiation group, the response rate (RR) were respectively 62% (53/86), 42% (20/48) and 37% (33/90), and there was significant difference (P = 0.003). The comparison of deep stromal invasion, lymph node metastases, lympho-vascular space involvement (LVSI) and other risk factors among the 3 groups, which showed that there were no statistically significant differences (P > 0.05). In chemotherapy combined irradiation group, the percentage of stromal invasion ≥ 1/2 was lower than that in chemotherapy group [53% (46/86) vs. 73% (35/48), P = 0.027], and the percentage of lymph node metastases was significantly lower than irradiation group [17% (15/86) vs. 29% (26/90), P = 0.046], and the risk factors-free rate was significantly higher than chemotherapy group [44% (38/86)vs. 25% (12/48), P = 0.028]. Among the chemotherapy combined irradiation group, chemotherapy group and irradiation group, the percentage of postoperative radiation therapy were respectively 47% (40/86), 67% (32/48) and 62% (56/90), and the differences were statistically significant (P = 0.035). The five-year disease free survival (DFS) was 79%, 75% and 78%, respectively. The five-year overall survival (OS) was respectively 81%, 78% and 81% among 3 groups, and there were no statistically significant differences (P > 0.05). Among 224 patients, the five-year DFS of the patients with 0, 1 and ≥ 2 risk factors after surgery were 90%, 75% and 57%, and OS were 95%, 82% and 65%, and there were no statistically significant differences (P < 0.01, respectively). Of patients without postoperative risk factors, the five-year OS in those without receiving postoperative radiation therapy was 96%, while 89% in received postoperative radiation therapy patients, there were no statistically significant differences (P = 0.263). CONCLUSION: There are no differences of DFS and OS among the neoadjuvant chemotherapy combined vaginal intracavitary irradiation group, the neoadjuvant chemotherapy alone group and the vaginal intracavitary irradiation alone group patients with stage Ib2 and IIa2. Patients without risk factors after neoadjuvant therapies have better prognosis.

[Analysis of 25 cases of brain metastasis from gynecological cancers].

OBJECTIVE: To discuss the clinical characteristics, treatment and prognostic factors of brain metastasis from gynecological cancers. METHODS: Clinical records of 25 brain metastasis patients from gynecological cancers admitted from January 1999 to January 2009 were reviewed retrospectively. The curative effects of different treatments were compared. The prognostic factors were determined using the Cox regression model. RESULTS: There were 14 cases ovarian malignant tumor, 6 cases cervical carcinoma and 5 cases uterine malignant tumor. Seven cases (28%, 7/25) had solitary metastatic lesion in the brain. Extracranial metastases were detected in 18 cases (72%, 18/25). Five patients only received one kind of treatment, and the mean survival time was 4.0 months (0.5 to 9.5 months). Sixteen patients received combined treatment, 3 of them received combined treatment including surgery, and the mean survival time was 8.4 months (4.1 to 13.4 months); 13 of them received chemotherapy and radiotherapy, and the mean survival time was 14.2 months (4.3 to 58.1 months). Four patients received only palliative supportive care, and the survival time was only 0.1 to 1.0 month. The Cox regression model showed that Karnofsky performance status scale, with or without extracranial metastases and the treatment method were the independent prognostic factors of brain metastasis from gynecological cancers (P < 0.05). CONCLUSION: The incidence of brain metastasis from gynecological cancers is low and the prognosis is very poor. Combined treatments may get better effects.

[Clinical analysis of 215 elderly patients with cervical cancer].

OBJECTIVE: To investigate the clinical features, treatment outcomes and possible prognostic factors in elderly patients with cervical cancer. METHODS: Clinical data of 215 elderly women (> or = 65-years-old) with cervical cancer were retrospectively analyzed. Most patients (89.3%) had advanced stage ( II b-IV) disease. Eight of the 215 patients (3.7%) underwent surgical treatment, and six of those received postoperative radiotherapy. 133 patients received radiotherapy alone, and 74 patients underwent concurrent chemotherapy and radiotherapy. RESULTS: The median follow-up time was 48 months (range: 12-102 months). The overall 5-year survival rate was 63.7%. The 5-year survival rate for stage I, II, III, IV were 83.2%, 76.4%, 39.0% and 0, respectively. There was no significant difference in 5-year survival rate between patients treated with concurrent chemotherapy combined with radiotherapy and radiotherapy alone. In multivariate analysis, lymph node metastasis, advanced stage, non-squamous histologies and poor differentiation were all negative prognostic factors for the overall survival. CONCLUSION: The treatment strategy for elderly cervical cancer patients should be individually planned according to the disease stage and performance status of the patients. Usually, one radical therapy modality can be chosen, and combined modality therapy is not suggested.

[The clinical significance and management of cervico-cytologically diagnosed ASCUS/LSIL].

PURPOSE: To investigate the clinical significance and management of ASCUS/LSIL. METHODS: 254 patients who were examined with cervical cytology in the Cancer Institute and Hospital Chinese Academy of Medical Sciences were ASCUS/LSIL, of whom 136 cases underwent colposcopy, Data were analyzed retrospectively according to the golden criterion of pathology outcome. RESULTS: 140 cases were ASCUS, and 114 cases were LSIL. Cervical intra-epithelial neoplasia (CIN) were diagnosed in 51.5% of patients with ASCUS, compared with 59.6% of patients with LSIL (P>0.05). High-grade cervical intraepithelial neoplasia were diagnosed in 22.9% of patients with ASCUS, compared with 30.7% of patients with LSIL (P >0.05). In the 136 patients examined with colposcopy, inflammation was found in 47 cases, low-grade intraepithelial lesion in 53 cases, High-grade intraepithelial lesion in 36 cases. The pathological results show inflammation in 55 cases, low-grade intraepithelial lesion in 41 cases, High-grade intraepithelial lesion in 40 cases (Kappa=0.314, U=0.064, P less than 0.05). CIN were diagnosed in 79% (67/84) of HPV-positive patients identified by pathology, compared with 43.5% (74/170) of HPV-negative patients (chi2=29.88 P less than 0.05). 83.5% of 254 patients were between 35 to 55 years old, and that was consistent with HPV-positive women age peak. CONCLUSION: Patients with ASCUS should be paid the same attention with LSIL patients and colposcopy examination should be done immediately to avoid missed diagnosis and missed follow-up examination, especially for HPV positive patients between 35 to 55 years old.

Colposcopically directed biopsy, random cervical biopsy, and endocervical curettage in the diagnosis of cervical intraepithelial neoplasia II or worse.

OBJECTIVES: The purpose of this study was to determine the relative importance of colposcopically directed biopsy, random biopsy, and endocervical curettage (ECC) in diagnosing > or =cervical intraepithelial neoplasia (CIN) II. Study design During a screening study, 364 women with satisfactory colposcopy and > or =CIN II were diagnosed. All colposcopically detected lesions were biopsied. If colposcopy showed no lesion in a cervical quadrant, a random biopsy was obtained at the squamocolumnar junction in that quadrant. ECC was then performed. RESULTS: The diagnosis of > or =CIN II was made on a colposcopically directed biopsy in 57.1%, random biopsy in 37.4%, and ECC in 5.5% of women. The yield of > or =CIN II for random biopsy when cytology was high grade (17.6%) exceeded that when cytology was low grade (2.8%). One of 20 women diagnosed solely by ECC had invasive cancer. CONCLUSION: Even when colposcopy is satisfactory, ECC should be performed. If cytology is high grade, random biopsies should be considered.

[Preliminary study on the relationship between loads of human papillomavirus in cervical carcinoma and cervical intraepithelial neoplasia].

OBJECTIVE: To explore the relationship between loads of human papillomavirus in cervical carcinoma and cervical intraepithelial neoplasia. METHODS: From December 2001 to May 2002, 9075 married women aged from 35 to 50 years who lived in the areas with a high incidence of cervical carcinoma of Shanxi Province were screened high risk types of human papillomavirus (HPV) infection using hybrid capture II (HC-II). Of them, 2087 women with positive human papillomavirus further underwent colposcopy and multi-focal directed punch biopsies plus endocervical currettage. RESULTS: Two thousand and eighty-seven women were found with positive human papillomavirus infection, comprising 1402 (67.2%) women who were diagnosed as cervicitis, 663 (31.8%) women diagnosed as cervical intraepithelial neoplasia [including cervical intraepithelial neoplasia (CIN) I to III], and 22 (1.1%) women diagnosed as cervical squamous cell carcinoma (SCC). HPV-DNA loads of women with chronic and acute cervicitis were 150 +/- 11 and 108 +/- 13, respectively, with no significant difference between two groups statistically (P = 0.225). HPV-DNA loads for women with CIN I, CIN II and CIN III were 332 +/- 29, 358 +/- 35, and 370 +/- 31, respectively, all significantly higher than that of women with cervicitis (P = 0.000), but there were no significant differences among three groups (P > 0.05). HPV-DNA loads of women with cervical squamous cell carcinoma was 593 +/- 86, much higher than those of women with varied grades of cervical intraepithelial neoplasia and cervicitis (P < 0.05 and P < 0.01). CONCLUSIONS: The new technology using HC-II is an effective method to detect HPV infection in cervix. Viral loads of HPV-DNA increase with severity of cervical neoplasia. So it could be used for screening primary cervical carcinoma.

[Population-based study of human papillomavirus infection in high-risk area for cervical cancer in Shanxi Province, China].

OBJECTIVES: To investigate the prevalence of oncogenic type of human papillomavirus (HPV) infection and identify the high risk population for conducting immuno/chemoprevention of cervical cancer. METHODS: All married women aged 30 to 50 with no history of hysterectomy, pelvic radiation and non-pregnant from certain villages of Xiangyuan and Yangcheng County were invited. This study was conducted through two phases. In phase one, subjects sampled the vaginal secretions using the collectors after signing the informed consent. And physicians sampled exfoliated cells from cervix in the phase two. All the specimens were tested with the Hybrid Capture 2 test. The data was managed and analyzed by VFP and SPSS software. RESULTS: There were 9,683 women participated in this study. Local women welcomed this study and population compliance rate was 75.4%. In tested population, we found 2,666 subjects of HPV DNA positive and HPV prevalence was 27.5%. The rates of different age group were 24.5% (30-34 yrs), 27.4% (35-39 yrs), 28.2% (40-44 yrs), 27.4% (45-50 yrs) respectively and had no significant differences (P = 0.604). The rates were slightly increased with the higher education level and had no differences (P = 0.106). The rate in mountain areas was higher than that in half-mountain areas (P = 0.001). CONCLUSIONS: The prevalence of HPV infection is indeed high in this region. Local women and health professionals welcome the activities of cervical cancer screening and prevention. It is an emergent task to improve their sanitary condition and prevent them from cervical cancer in these women. A women health cohort is established successfully among high HPV exposed women in rural China. The extensive biologic specimen repository has been successfully established to simultaneously study the etiology, early detection, and immuno/chemoprevention of cervical cancer.

[Clinical efficacy analysis of chemotherapy to lymph node metastasis in epithelial ovarian cancer].

BACKGROUND & OBJECTIVE: Epithelial ovarian cancer is moderate sensitivity to chemotherapy; the survival has been improved by aggressive cytoreductive surgery followed by combination chemotherapy with cisplatin-based regimen.However,there is a controversy about chemotherapeutic sensitivity of its lymph node metastasis. This study was designed to evaluate chemotherapeutic sensitivity and prognosis of lymph node metastases in epithelial ovarian cancer. METHODS: The authors retrospectively analyzed 50 cases of epithelial ovarian cancer with lymph node metastases in Cancer Hospital,Chinese Academy of Medical Sciences, Peking Union Medical College from June 1986 to February 2001, which included 32 cases with stage III-IV, and 18 with recurrent disease. All the 50 patients were with valuable metastatic lymph nodes,and among these patients 38 were also with valuable abdominal-pelvic tumor. Forty-six patients received 1-3 courses of neoadjuvant chemotherapy,cytoreductive surgery, and postoperative chemotherapy. The response rate was evaluated by the response criteria for solid tumor. The chemotherapy included neoadjuvant chemotherapy, and chemotherapy for patients with residual tumor after operation or recurrence. Forty-five patients received platinum-based chemotherapy regimens [including CP (cyclophosphamide+cisplatin), CAP (cyclophosphamide+epirubicin+cisplatin), TC (paclitaxel+carboplatin), TP (paclitaxel+cisplatin), cisplatin+mitomycin+vincristine+etoposide+carboplatin, gemcitabine+carboplatin,IEP(ifosphamide+etoposide+cisplatin regimens) and 1 patient received melphalan, 1 patient with CF(cyclophosphamide+5-fluorouracil)regimen, 3 patients with ifosphamide+etoposide. RESULTS: The overall response rates of lymph node metastasis and abdominal-pelvic tumor were 68.0% and 71.1%, respectively (P >0.05). The response rates of lymph node metastasis and abdominal-pelvic tumor for stage III-IV were 78.1% and 76.7%, respectively (P >0.05); both were 50% for recurrent patients with epithelial ovarian cancer. CONCLUSION: Either in stage III-IV or in recurrent patients with epithelial ovarian cancer, chemotherapeutic sensitivity of lymph node metastasis was similar to that of abdominal and pelvic tumor. The prognosis was related to the optimality of cytoreductive surgery, and the intensity of chemotherapy.