Completed versus aborted radical hysterectomy for node-positive stage IB cervical cancer in the modern era of chemoradiation therapy

Objective

Debate continues about optimal management of patients with node-positive stage I cervical cancer. Our objective was to determine if patient outcomes are affected by radical hysterectomy in the modern era of adjuvant chemoradiation.

Methods

Cervical cancer patients diagnosed from 2000 to 2008 were identified. Demographics, therapy, clinicopathologic data, progression free survival (PFS), overall survival (OS), total radiation exposure, and grade 3-4 complications were analyzed by student t, Mann-Whitney, Fisher's exact, Kaplan-Meier, and log rank tests.

Results

This single-institution review evaluated forty-one of 334 (13.4%) patients scheduled to undergo radical hysterectomy that had gross nodal disease diagnosed intraoperatively. 15 underwent aborted radical hysterectomy following lymphadenectomy; the remaining 26 underwent radical hysterectomy and lymphadenectomy. Eleven patients undergoing radical hysterectomy underwent whole pelvic radiation therapy (WPRT) while 8 (30.7%) patients underwent WPRT and postoperative vaginal brachytherapy (BT) for local treatment secondary to close margins. All patients undergoing aborted radical hysterectomy underwent WPRT and BT. With mean follow-up of 42.3 months, there were no significant differences in urinary, gastrointestinal, or hematologic complications between groups. When comparing those undergoing radical hysterectomy to aborted radical hysterectomy, there were no significant differences in local recurrence (11.5% vs 26.7%, p = 0.39) or distant recurrence (19.2% vs. 33.3%, p = 0.45), PFS (74.9 months vs 46.8 months, p = 0.106), or OS (91.8 months vs 69.4 months, p = 0.886).

Conclusions

Treatment of patients with early stage cervical cancer and nodal metastasis may be tailored intraoperatively. Completion of radical hysterectomy and lymphadenectomy decreases radiation exposure without apparently compromising safety or outcome in the era of adjuvant chemoradiation.     

Vesicovaginal fistula formation in patients with Stage IVA cervical carcinoma

OBJECTIVES: To evaluate the rate of vesicovaginal fistula formation and mortality in women with Stage IVA cervical carcinoma. METHODS: Data were abstracted from the clinical records of women diagnosed with Stage IVA cervical cancer at the time of examination under anesthesia, cystoscopy, and proctoscopy (EUA/C/P) at a single institution from 1994 to 2004. Demographic and treatment characteristics were compared using either Fisher's exact test or Student's t-test, as appropriate. Survival was calculated using the Kaplan-Meier method. RESULTS: Twenty-three patients were diagnosed with Stage IVA cervical cancer. All were diagnosed with extension of disease into the bladder; one patient had rectal involvement as well. Concurrent chemotherapy and radiation was used in 60.8%, while 30.4% received radiation alone and 8.7% elected no treatment. Fifty-six percent of the patients were smokers. Eleven patients (47.8%) developed a fistula at a median time of 2.9 months from cancer diagnosis. Fistula formation was significantly increased among smokers as compared to non-smokers (73 vs 27%; p=0.03). Two patients (8.7%) are alive without evidence of disease at a median follow-up of 19 months. The disease-specific survival is 23.1 months. Patients who developed a vesicovaginal fistula had a median survival of 11.2 months after fistula formation. CONCLUSIONS: High rates of vesicovaginal fistula formation can be expected when treating women with extension of cervical cancer into the bladder, particularly among women who smoke. The routine use of EUA/C/P at the time of initial diagnosis aids in counseling women about the likelihood of this complication. Novel strategies for managing vesicovaginal fistulae after chemoradiation are needed.     

Quality of life and survival in advanced cervical cancer: a Gynecologic Oncology Group study

Purpose

To determine associations between pretreatment health-related quality of life subscales with progression-free (PFS) and overall survival (OS) in advanced and recurrent cervical cancer.

Patients and Methods

Patients included those participating in Gynecologic Oncology Group advanced or recurrent cervical cancer phase III treatment trials who completed the Functional Assessment of Cancer Therapy for patients with cervical cancer (FACT-Cx) and a single-item pain scale at study entry. The FACT-Cx includes five domains: physical (PWB), emotional (EWB), social (SWB), functional well being (FWB), and cervix cancer subscale (CCS). A high quality of life (QoL) score reflects better QoL. After stratifying by protocol and adjusting for patient and disease characteristics, a Cox proportional hazards model was fitted for each subscale as a continuous variable. If statistically significant, (p < 0.05), an analysis on mean item scores (MIS) was performed.

Results

Nine-hundred-ninety-one patients were enrolled from 1997 to 2007. The majority (87%) had recurrent disease. After adjustment for covariates and predictors, only the PWB domain (better physical QoL) was associated with improved OS [HR 0.96 95% CI 0.95-0.98; p < 0.001]. When classifying patients based on the MIS of each subscale, the patients with the lowest risk of death were likely to report less compromised QoL (MIS > 3) for PWB [HR 0.44 (0.33-0.58) P < 0.001], FWB [0.49 (0.38-0.62) P < 0.001], and CCS [0.48 (0.38-0.61) P < 0.001].

Conclusion

The pretreatment patient-reported PWB as measured by the PWB subscale of the FACT-Cx, is significantly associated with survival in advanced cervical cancer trials, even after controlling for known prognostic factors.     

The impact of disease distribution on survival in patients with stage III epithelial ovarian cancer cytoreduced to microscopic residual: a Gynecologic Oncology Group study

Objective

To assess the survival impact of initial disease distribution on patients with stage III epithelial ovarian cancer (EOC) cytoreduced to microscopic residual.

Methods

We reviewed data from 417 stage III EOC patients cytoreduced to microscopic disease and given adjuvant intravenous platinum/paclitaxel on one of three randomized Gynecologic Oncology Group (GOG) trials. We subdivided patients into three groups based on preoperative disease burden: (1) minimal disease (MD) defined by pelvic tumor and retroperitoneal metastasis (2) abdominal peritoneal disease (APD) with disease limited to the pelvis, retroperitoneum, lower abdomen and omentum; and (3) upper abdominal disease (UAD) with disease affecting the diaphragm, spleen, liver or pancreas. We assessed the survival impact of potential prognostic factors, focusing on initial disease distribution using a proportional hazards model and estimated Kaplan-Meier survival curves.

Results

The study groups had similar clinicopathologic characteristics. Median overall survival (OS) was not reached in MD patients compared to 80 and 56 months in the APD and UAD groups (P < 0.05). The five-year survival percentages for MD, APD, and UAD were 67%, 63%, and 45%. In multivariate analysis, the UAD group had a significantly worse prognosis than MD and APD both individually and combined (Progression Free Survival (PFS) Hazards Ratio (HR) 1.44; P = 0.008 and OS HR 1.77; P = 0.0004 compared to MD + APD).

Conclusion

Stage III EOC patients with initial disease in the upper abdomen have a worse prognosis despite cytoreductive surgery to microscopic residual implying that factors beyond cytoreductive effort are important in predicting survival.     

Radiation therapy with concomitant paclitaxel and cisplatin chemotherapy in cervical carcinoma limited to the pelvis: a phase I/II study of the Gynecologic Oncology Group

OBJECTIVES: To determine the maximum tolerated dose (MTD) of weekly paclitaxel and cisplatin chemotherapy concurrent with whole pelvic irradiation in women with locally advanced cervical cancer. METHODS: Consenting patients with stage IB2, IIA, IIB, IIIB and IVA carcinoma of the cervix (all cell types) were eligible for this phase I/II trial. Chemotherapy agents were administered in escalating doses to cohorts of three patients at each dose level, pending evaluation of toxicities from the previous dose level. RESULTS: Thirty-five eligible women were enrolled on this study, of whom 13 comprised the phase I component. The MTD was determined to be cisplatin 40 mg/m2 and paclitaxel 40 mg/m2 administered weekly for six cycles with external beam radiation therapy. An additional 21 patients were enrolled in the phase II component at the previously determined MTD, yielding a total of 22 patients at the MTD, of whom 19 were evaluable. Among the evaluable patients treated at the MTD, two had grade 3 or 4 gastrointestinal (GI) toxicities (representing 5 of 113 cycles administered to this cohort) and seven experienced grade 3 or 4 neutrophil toxicity, none occurring prior to the fourth cycle. Thrombocytopenia was rare. Radiation therapy was successfully completed in 52% of patients at 8 weeks and in 79% of patients at 9 weeks, with a median of 59 days. CONCLUSIONS: Paclitaxel and cisplatin combination chemotherapy concurrent with whole pelvic irradiation can be safely administered at the described MTD.     

Neoadjuvant cisplatin plus ifosfamide in patients with stage IIB cervical cancer: a single center phase II study

The objective of this study was to evaluate cisplatin plus ifosfamide as neoadjuvant chemotherapy with regard to toxicity and clinical response in patients with stage IIB cervical cancer. Sixty-eight patients with previously untreated stage IIB cervical cancer were given two cycles of chemotherapy: cisplatin 20 mg m⁻² on Days 1–5, infused over 1 h; ifosfamide 1.2 g m⁻² on Days 1–5 infused over 30 min. Mesna 120 mg m⁻² was administered as a bolus 15 min before ifosfamide, and a continuous infusion, delivering Mesna 1.2 g m⁻², was given subsequently over the next 16 hours. The treatment cycle was repeated on day 21. Responders were then randomized to surgery or radiation therapy. All 68 patients were evaluable for toxicity. Toxicity was found to be acceptable. One patient died at home one month after completion of the second treatment cycle. There was one grade 4 thrombocytopenia. Grade 3 toxicities included anemia in four patients, leucopenia and nausea and vomiting in one patient each. Sixty-two patients were evaluable for response. A clinical response was documented in 44 of the 55 evaluable patients (80%), with 17 complete responses (31%) and 27 partial responses (49%) (95% confidence limits 69%–91%, 19%–43%, and 36%–62% respectively). The intent-to-treat response rate was 64.7%. Twenty-one patients were randomized to surgery and 23 patients to radiation therapy. Amongst the eight patients with a complete clinical response, one patient had a complete pathological response and one patient had residual intra-epithelial neoplasia. The drug combination of cisplatin plus ifosfamide had acceptable toxicity and gave a clinical response rate of 80% in previously untreated patients with stage IIB cervical cancer.     

Outcome of early stage cervical cancer patients treated according to a radiosurgical approach: Clinical results and prognostic factors

Objective

To report clinical results of a multimodal strategy based on preoperative brachytherapy followed with surgery in early stage cervical cancer.

Association between cigarette smoking and prognosis in locally advanced cervical carcinoma treated with chemoradiation: a Gynecologic Oncology Group study

OBJECTIVE: To determine if smoking, a known risk factor for a number of cancers including cervical cancer, is associated with poor prognosis in patients with locally advanced cervical carcinoma treated with chemoradiation. METHODS: Patients with primary, previously untreated, histologically confirmed stage II-B, III-B or IV-A cervical carcinoma participated in a Gynecologic Oncology Group (GOG) phase III study (GOG 165) and were randomly allocated to receive radiation plus either cisplatin or 5-fluorouracil. Smoking behavior was ascertained using an administered questionnaire and by quantifying urine cotinine concentration. Disease progression was defined as a >or=50% increase in the cross product of the existing tumor compared with previous assessments. Patients were followed until death. RESULTS: Of 328 enrolled patients, 12 were ineligible, one was inevaluable for reported smoking status and 40 others were inevaluable for cotinine-derived smoking status. Among evaluable patients, 133 (42%) were reported smokers and 111 (40%) were cotinine-derived smokers. The kappa for agreement between the groups was 0.872 (P<0.01). Compared with non-smokers, median survival was 15 months shorter for reported smokers and 20 months shorter for cotinine-derived smokers (P<0.01). After adjusting for covariates, a significant increase in the risk of death (but not disease progression) was observed for reported smokers (hazard ratio [HR]: 1.51; 95% confidence interval [CI]: 1.01-2.27; P=0.04) and cotinine-derived smokers (HR: 1.57; 95% CI: 1.03-2.38; P=0.04). CONCLUSIONS: Smoking predicts worse overall survival in women with locally advanced cervical carcinoma treated with chemoradiation.     

Phase II trial of paclitaxel and nedaplatin in patients with advanced/recurrent uterine cervical cancer: a Kansai Clinical Oncology Group study

Objective

A multicenter phase II trial was conducted to evaluate the activity and toxicity of paclitaxel and nedaplatin (cis-diammineglycolatoplatonum) in patients with advanced/recurrent uterine cervical cancer.

Methods

Patients were required to have measurable disease. Histologic confirmation of the primary diagnosis as uterine cervical cancer was mandatory. The treatment consisted of paclitaxel 175 mg/m² over 3 hours and nedaplatin 80 mg/m² intravenously over 1 hour on day 1 every 28 days until progressive disease or adverse effects prohibited further therapy.

Results

Fifty patients were enrolled into the study protocol from October 2007 to February 2010. 45 patients(90%) were eligible for assessment of response (RECIST version 1.0) to treatment; 31 patients (62%) received prior radiotherapy and 23 patients (46%) received prior chemotherapy. The overall response rate was 44.4% (11 complete responses and 8 partial responses) with 22.2% of patients having stable disease. Grades 3 or 4 adverse events (NCI-CTCAE ver 3) included neutropenia (n = 16, 32.7%), febrile neutropenia (n = 1, 2.0%), anemia (n = 9, 18.4%), but there was no significant thrombocytopenia. Non-hematologic toxicity was generally not serious and without a dominant pattern. The median progression-free survival was 7.5 months (95% C.I., 5.7, 9.4) and overall survival was 15.7 months (95% C.I., 9.4, 21.9).

Conclusions

Paclitaxel 175 mg/m² and nedaplatin 80 mg/m² intravenously on day 1 every 28 days in patients with advanced/recurrence uterine cervical cancer demonstrated easy administration, favorable antitumor activity, and the toxicity profile of this regimen would be decreased compared with cisplatin-containing combinations. Evaluation of this regimen in phase III trials is warranted.     

Gynecologic Oncology Group risk groups for vulvar carcinoma: improvement in survival in the modern era

OBJECTIVE: Patients with vulvar cancer were stratified into risk groups for survival based on surgicopathologic findings from a prospective study conducted by the Gynecologic Oncology Group from 1977-1984. The purpose of this study is to reassess these risk groups in patients treated in an era of contemporary management. METHODS: Patients with vulvar carcinoma were identified from 1990-2005 for retrospective analysis. Charts were abstracted for clinical, histopathologic and surgical data, and patients stratified into four risk groups for survival based on the clinical size of tumor and extent of lymph node metastasis. Univariate and multivariate characteristics were evaluated and 5-year survival determined by Kaplan-Meier method. RESULTS: 175 patients were identified that underwent surgical management with a median age at diagnosis of 59.9 years. Stage distribution included: I (n=89, 51%), II (n=53, 30%), III (n=29, 17%), and IV (n=4, 2%). Stratification into risk groups included: minimal (n=89, 51%), low (n=69, 40%), intermediate (n=11, 6%), and high (n=6; 3%). The survival rate was 100%, 97%, 82% and 100%, respectively, at median follow-up of 54.5 months. Comparatively, the survival rates for historic groups were 97.9%, 87.4%, 74.8% and 29.0%. Using multivariate analysis, age (p=0.04) and lymph node metastasis (p=0.009) were predictive of survival. CONCLUSIONS: Survival among the minimal and low risk groups is preserved in spite of less radical surgery. 5-year survival rate for intermediate and high risk patients also appears to be improved. This is likely a result of advancement in adjuvant chemo-radiation and a younger patient population that presents with less advanced disease.     

The significance of thrombocytosis in patients with locally advanced cervical carcinoma: a Gynecologic Oncology Group study

OBJECTIVE: The aim of this study was to determine the incidence of thrombocytosis and its possible impact on survival probability among women with locally advanced cervical carcinoma. METHODS. The database of 294 patients with Stages IIB-IVA cervical carcinoma without periaortic node metastasis who were treated with standardized radiation therapy and concurrent hydroxyurea or misonidazole was analyzed. Pretreatment platelet counts were available for 291 patients who are the subject of this study. RESULTS. Thrombocytosis (platelet count >400 x 10(9)/liter) was present in 86 (29.6%) of the 291 patients. A multivariate Cox proportional hazards model showed that patients without extrapelvic disease and with thrombocytosis had a 55% greater chance of dying than those without thrombocytosis (relative risk = 1.55, 95% confidence interval 1.08-2.21). Patients with thrombocytosis had larger tumors and more frequently had bilateral parametrial involvement, tumor fixation to the sidewall, and positive pelvic lymph nodes than patients without thrombocytosis. Thrombocytosis was not found to be a prognostic factor in patients with positive pelvic nodes. However, in patients with negative pelvic nodes, the presence or absence of thrombocytosis was related to survival. CONCLUSION: Thrombocytosis is a frequent finding among patients with advanced cervical carcinoma and seems to be related to tumor burden. Among patients with locally advanced cervical carcinoma who had negative pelvic nodes, those with thrombocytosis had a poorer survival.     

Adjuvant therapy in stage III endometrial cancer confined to the pelvis

Objective

To review outcomes of patients with stage III endometrial cancer confined to the pelvis treated with adjuvant pelvic radiotherapy (RT) or sequential chemoradiotherapy (CRT).

Karyometry in atypical endometrial hyperplasia: a Gynecologic Oncology Group study

Objectives

Treatment for atypical endometrial hyperplasia (AEH) is based on pathologic diagnosis. About 40% of AEH is found to be carcinoma at surgery. This study's objective is to derive an objective characterization of nuclei from cases diagnosed as AEH or superficially invasive endometrial cancer (SIEC).

Methods

Cases from GOG study 167A were classified by a central pathology committee as AEH (n = 39) or SIEC (n = 39). High resolution digitized images of cell nuclei were recorded. Features of the nuclear chromatin pattern were computed. Classification rules were derived by discriminant analysis.

Results

Nuclei from cases of AEH and SIEC occupy the same range on a progression curve for endometrial lesions. Cases of AEH and SIEC both comprise nuclei of two phenotypes: hyperplastic characteristics and premalignant/neoplastic characteristics. The principal difference between AEH and SIEC is the percentage of premalignant/neoplastic nuclei. When this percentage approaches 50-60% superficial invasion is likely. SIEC may develop already from lesions at the low end of the progression curve.

Conclusions

AEH comprises cases which may constitute a low risk group involving < 40% of AEH cases. These cases hold a percentage of < 20% of nuclei of a preneoplastic phenotype. AEH cases from the central and high end of progression have > 40% of nuclei of preneoplastic phenotype. Nuclei of the preneoplastic phenotype in AEH lesions are almost indistinguishable from nuclei in SIEC, where this percentage exceeds 60%. The percentage of nuclei of the preneoplastic phenotype in AEH esions might serve as criterion for assessment of risk for the development of invasive disease.     

Measurement of vaginal length: reliability of the vaginal sound—a Gynecologic Oncology Group Study

A decrease in vaginal length associated with treatments for gynecological malignancies, particularly pelvic radiotherapy, negatively impacts sexuality. Research into this important problem has been hampered by a lack of instrumentation to measure vaginal length. The Gynecologic Oncology Group recently evaluated the reliability of an instrument, the "vaginal sound," designed to measure vaginal length. Eighty-eight physicians and nurses attended a training session in the use of the vaginal sound that included a clinical practicum with live models. Reliability was assessed at the time of the practicum. The instrument performed well, with vaginal lengths in models without cancer in the upper range of normal as documented by Masters and Johnson. The vaginal sound also appeared to be sensitive to hypothesized changes in vaginal length. Interrater reliability was high with intraclass correlation coefficients of 0.88 among instructors and 0.76 among trainees. In conclusion, the vaginal sound is a simple, yet reproducible measure and adds methodologic rigor to studies of vaginal length.