Nomograms Predicting Progression-Free Survival, Overall Survival, and Pelvic Recurrence in Locally Advanced Cervical Cancer Developed From an Analysis of Identifiable Prognostic Factors in Patients From NRG Oncology/Gynecologic Oncology Group Randomized Trials of Chemoradiotherapy.

PURPOSE: To evaluate the prognostic factors in locally advanced cervical cancer limited to the pelvis and develop nomograms for 2-year progression-free survival (PFS), 5-year overall survival (OS), and pelvic recurrence. PATIENTS AND METHODS: We retrospectively reviewed 2,042 patients with locally advanced cervical carcinoma enrolled onto Gynecologic Oncology Group clinical trials of concurrent cisplatin-based chemotherapy and radiotherapy. Nomograms for 2-year PFS, five-year OS, and pelvic recurrence were created as visualizations of Cox proportional hazards regression models. The models were validated by bootstrap-corrected, relatively unbiased estimates of discrimination and calibration. RESULTS: Multivariable analysis identified prognostic factors including histology, race/ethnicity, performance status, tumor size, International Federation of Gynecology and Obstetrics stage, tumor grade, pelvic node status, and treatment with concurrent cisplatin-based chemotherapy. PFS, OS, and pelvic recurrence nomograms had bootstrap-corrected concordance indices of 0.62, 0.64, and 0.73, respectively, and were well calibrated. CONCLUSION: Prognostic factors were used to develop nomograms for 2-year PFS, 5-year OS, and pelvic recurrence for locally advanced cervical cancer clinically limited to the pelvis treated with concurrent cisplatin-based chemotherapy and radiotherapy. These nomograms can be used to better estimate individual and collective outcomes.

Locally advanced adenocarcinoma and adenosquamous carcinomas of the cervix compared to squamous cell carcinomas of the cervix in gynecologic oncology group trials of cisplatin-based chemoradiation.

OBJECTIVE: Conflicting results have been reported for adeno- and adenosquamous carcinomas of the cervix with respect to their response to therapy and prognosis. The current study sought to evaluate impact of adeno- and adenosquamous histology in the randomized trials of primary cisplatin-based chemoradiation for locally advanced cervical cancer. METHODS: Patients with adeno- and adenosquamous cervical carcinomas were retrospectively studied and compared to squamous cell carcinomas in GOG trials of chemoradiation. RESULTS: Among 1671 enrolled in clinical trials of chemoradiation, 182 adeno- and adenosquamous carcinomas were identified (10.9%). A higher percentage of adeno- and adenosquamous carcinomas were stage IB2 (27.5% versus 20.0%) and fewer had stage IIIB (21.4% versus 28.6%). The mean tumor size was larger for squamous than adeno- and adenosquamous. Adeno- and adenosquamous carcinomas were more often poorly differentiated (46.2% versus 26.8%). When treated with radiation therapy alone, the 70 patients with adeno- and adenosquamous carcinoma of the cervix showed a statistically poorer overall survival (p=0.0499) compared to the 647 patients with squamous cell carcinoma of the cervix. However, when treated with radiation therapy with concurrent cisplatin-based chemotherapy, the 112 patients with adeno- and adenosquamous carcinomas had a similar overall survival (p=0.459) compared the 842 patients with squamous cell carcinoma. Adverse effects to treatment were similar across histologies. CONCLUSION: Adeno- and adenosquamous carcinomas of the cervix are associated with worse overall survival when treated with radiation alone but with similar progression-free and overall survival compared to squamous cell carcinomas of the cervix when treated with cisplatin based chemoradiation.

Cadherins, catenins and cell cycle regulators: impact on survival in a Gynecologic Oncology Group phase II endometrial cancer trial.

OBJECTIVE: We evaluated the clinical relevance of catenins, cadherins and cell cycle regulators in stage IV or recurrent endometrial carcinoma in a multi-center phase II trial (GOG protocol #119). METHODS: Tissue microarrays of metastatic or recurrent (n=42) tumor were developed and immunohistochemistry was performed. Average expression (percent staining x intensity) was assessed in tumor epithelium ((E)) and stroma ((S)) and categorized into tertiles (T1, T2, T3) for E-cadherin(E), N-cadherin(E), alpha-catenin(E), beta-catenin(E), gamma-catenin(E), p120-catenin(E) and Ki-67(E); as negative, below median or above median for p16(E), p27(E) and CD44(S); or as negative or positive for p53(E), Ki-67(S) and APC(S) (adenomatous polyposis coli). End points included response and survival. RESULTS: E-cadherin(E), p16(E), and p53(E) varied by race (p=0.003, p=0.024, p=0.002,) and N-cadherin(E), Ki-67(E), p16(E) and p27(E) by tumor type (p=0.015, p=0.011, p=0.005, p=0.021). Correlations were observed among E-cadherin(E) with p120(E) (r=0.66), p53(E) (r=-0.32), alpha-catenin(E) (r=0.52), beta-catenin(E) (r=0.58), and gamma-catenin(E) (r=0.58). High E-cadherin(E) (T2 or T3) versus low (T1) expression was associated with better survival in unadjusted (hazard ratio [HR]=0.14, 95% confidence interval [CI]=0.06-0.37 or HR=0.17, 95% CI=0.07-0.42) and adjusted models (HR=0.18, 95% CI=0.05-0.59 or HR=0.22, 95% CI=0.07-0.70). High p16(E) versus negative expression was associated with worse survival in unadjusted (HR=3.87, 95% CI=1.74-8.61) and adjusted (HR=4.18, 95% CI=1.28-13.6) models. Positive versus negative expression of p53(E) was associated with worse survival in unadjusted (HR=2.31, 95% CI=1.16-4.60) but not adjusted models. CONCLUSIONS: E-cadherin(E) and p16(E) appear to be clinically relevant, independent prognostic factors in stage IV or recurrent endometrial cancers treated with Tamoxifen and Medroxyprogesterone acetate, and merit further study.

Outcome of stage IVA cervical cancer patients with disease limited to the pelvis in the era of chemoradiation: a Gynecologic Oncology Group study.

OBJECTIVES: To evaluate the outcome of stage IVA cervical cancer treated with radiation and concurrent cisplatin-based chemotherapy. METHODS: We conducted a retrospective study of stage IVA cervical cancer patients from four trials (Gynecologic Oncology Group protocols 56, 85, 120, and 165) treated with radiotherapy with or without concurrent cisplatin-based chemotherapy. Patient records were reviewed for demographic and tumor features, treatment, and progression-free survival (PFS) and overall survival (OS). Stage IVA patients were compared to stage IIIB patients from these same studies. RESULTS: Among the 51 stage IVA patients studied, 92% were stage IVA on the basis of bladder involvement. The median PFS was 10.1 months (95% CI=6.3-14.5 months) and median OS was 21.2 months (95% CI=13.3-30.5 months). The 3 year survival was 32%. On univariate analysis, only advanced age was associated with OS (p=0.0115) but age had only marginal effect on PFS (p=0.083). Pathologic proven pelvic nodal metastasis was of marginal significance for both PFS and OS, p=0.059 and 0.064, respectively. Despite similar patient characteristics, the use of cisplatin-based chemotherapy had no impact on PFS or OS but was underpowered to address this question. When compared to stage IIIB patients, stage IVA patients had a poorer performance status (p=0.0231), larger tumor size (p=0.0302), and more frequent bilateral parametrial involvement (0.0063). CONCLUSION: Patients with stage IVA disease had poor median survival of only 21 months with only 32% 3 year survival. Stage IVA patients have larger tumor size, more bilateral parametrial involvement, and poorer survival when compared to stage IIIB patients.

Gynecologic Oncology Group quality assurance audits: analysis and initiatives for improvement.

BACKGROUND: The Gynecologic Oncology Group (GOG) is a multi-institution, multi-discipline Cooperative Group funded by the National Cancer Institute (NCI) to conduct clinical trials which investigate the treatment, prevention, control, quality of survivorship, and translational science of gynecologic malignancies. In 1982, the NCI initiated a program of on-site quality assurance audits of participating institutions. Each is required to be audited at least once every 3 years. In GOG, the audit mandate is the responsibility of the GOG Quality Assurance Audit Committee and it is centralized in the Statistical and Data Center (SDC). Each component (Regulatory, Investigational Drug Pharmacy, Patient Case Review) is classified as Acceptable, Acceptable, follow-up required, or Unacceptable. PURPOSE: To determine frequently occurring deviations and develop focused innovative solutions to address them. METHODS: A database was created to examine the deviations noted at the most recent audit conducted at 57 GOG parent institutions during 2004-2007. Cumulatively, this involved 687 patients and 306 protocols. RESULTS: The results documented commendable performance: Regulatory (39 Acceptable, 17 Acceptable, follow-up, 1 Unacceptable); Pharmacy (41 Acceptable, 3 Acceptable, follow-up, 1 Unacceptable, 12 N/A): Patient Case Review (31 Acceptable, 22 Acceptable, follow-up, 4 Unacceptable). The nature of major and lesser deviations was analyzed to create and enhance initiatives for improvement of the quality of clinical research. As a result, Group-wide proactive initiatives were undertaken, audit training sessions have emphasized recurring issues, and GOG Data Management Subcommittee agendas have provided targeted instruction and training. LIMITATIONS: The analysis was based upon parent institutions only; affiliate institutions and Community Clinical Oncology Program participants were not included, although it is assumed their areas of difficulty are similar. CONCLUSIONS: The coordination of the GOG Quality Assurance Audit program in the SDC has improved data quality by enhancing our ability to identify frequently occurring deviations and develop innovative solutions to avoid or minimize their occurrence in the future.

Impact of hydronephrosis on outcome of stage IIIB cervical cancer patients with disease limited to the pelvis, treated with radiation and concurrent chemotherapy: a Gynecologic Oncology Group study.

OBJECTIVES: To estimate the significance of hydronephrosis and impact of ureteral obstruction relief on outcome in patients with stage IIIB cervical cancer treated with radiation and concurrent chemotherapy. METHODS: We retrospectively studied stage IIIB cervical cancer patients treated on GOG trials 56, 85, 120 and 165 evaluating radiation and concurrent chemotherapy. Eligible patient records were reviewed to assess the presence of hydronephrosis and treatment of ureteral obstruction. Patients were classified into three groups; no hydronephrosis, hydronephrosis relieved from ureteral obstruction via stent or percutaneous nephrostomy and hydronephrosis without treatment of ureteral obstruction. RESULTS: 539 stage IIIB patients were studied. Hydronephrosis was present in 238 (44.2%). Patient age, race, and tumor characteristics (size, histology and grade) were not significantly different between patients with or without hydronephrosis. Patients with hydronephrosis received similar doses of radiation and cisplatin-based chemotherapy. Both overall and progression-free survival were worse with hydronephrosis (log-rank test p value=0.0189 and 0.0186, respectively). Univariable analysis identified five prognostic factors; pelvic nodal metastasis (p=0.0001), tumor diameter (p=0.0007), cisplatin-based concurrent chemoradiation (p=0.0031), hydronephrosis (p=0.0189), and performance status (p=0.0359). Hydronephrosis was associated with worse performance status (p<0.001). On multivariable analysis hydronephrosis was not a significant prognostic factor. Ureteral obstruction relief occurred for 88% of patients and was associated with improved survival. CONCLUSION: In patients with stage IIIB cervical cancer restricted to the pelvis, hydronephrosis at presentation is a significant but not independent prognostic factor associated with poor performance status and poorer survival. Relief of ureteral obstruction is correlated with improved outcome.

Surgical versus radiographic determination of para-aortic lymph node metastases before chemoradiation for locally advanced cervical carcinoma: a Gynecologic Oncology Group Study.

BACKGROUND: Patients with cervical cancer who had negative para-aortic lymph nodes (PALNs) identified by pretreatment surgical staging were compared with patients who had only radiographic exclusion of PALN metastases before they received treatment with pelvic radiation and brachytherapy (RT) plus cisplatin (C)-based chemotherapy. METHODS: Patients who participated in 1 of 3 Phase III Gynecologic Oncology Group (GOG) trials (GOG 85, GOG 120, and GOG 165) and who were assigned randomly to receive either RT plus C or RT plus C combined with 5-fluorouracil with or without hydroxyurea comprised this retrospective analysis. Patients who had negative PALN status determined by surgical sampling (mandatory in GOG 85 and GOG 120 and optional in GOG 165) were compared with patients who had negative PALN status determined radiographically (GOG 165). RESULTS: Five hundred fifty-five patients underwent surgical PALN sampling (the S group), and 130 patients underwent radiographic evaluation only (the R group). Age, race, histology, and tumor grade were similar. Patients in the R group had better performance status (P < .01), less advanced stage (P = .023), and smaller tumor size (P = .004) compared with patients in the S group, although patients with stage III and IV disease in the S group had better 4-year progression-free survival (48.9% vs 36.3%) and overall survival (54.3% vs 40%) compared with patients in the R group. In multivariate analysis, the R group was associated independently with a poorer prognosis compared with the S group (for disease progression: hazard ratio [HR], 1.35, 95% confidence interval [95% CI], 1.01-1.81; for death: HR, 1.46, 95% CI, 1.08-1.99). CONCLUSIONS: Surgical exclusion (compared with radiographic exclusion) of positive PALNs in patients with cervical cancer who received chemoradiation (RT plus C-based chemotherapy) had a significant prognostic impact.

Adjuvant ifosfamide and cisplatin in patients with completely resected stage I or II carcinosarcomas (mixed mesodermal tumors) of the uterus: a Gynecologic Oncology Group study.

OBJECTIVES: To determine progression-free survival (PFS) and overall survival (OS) in women with completely resected stage I or II carcinosarcoma of the uterus treated with adjuvant ifosfamide and cisplatin, and to assess the toxicity of this regimen. METHODS: Eligible patients had histologically confirmed carcinosarcoma (mixed mesodermal tumor) and no postoperative radiotherapy following complete resection for clinical stage I or II disease. They were to have adequate renal, hepatic, and hematologic functions and performance status of 2 or less. Study entry was to be within 8 weeks of hysterectomy. Patients with previous chemotherapy, or other noncutaneous malignancies, were ineligible. Ifosfamide was administered 1.5 g/m2 intravenously (IV) over 1 h and cisplatin was given 20 mg/m(2) over 15 min followed by mesna 120 mg/m2 IV bolus, then 1.5 g/m2/24 h as a continuous infusion. Initial doses (daily x 5 every 21 days x 3 cycles) were reduced by 20% (to 4 days) for myelotoxicity. RESULTS: Nine of seventy-six patients enrolled were deemed ineligible and another two who did not receive protocol treatment were inevaluable. Of the 65 evaluable patients, median age was 65 years; 50 patients (77%) were stage I and 15 (23%) were stage II. PFS and OS, respectively, were 69% and 82% at 24 months, and 54% and 52% at 84 months. Overall 5-year survival was 62%. Leukopenia was the most commonly reported, but manageable, toxicity. CONCLUSION: Adjuvant ifosfamide and cisplatin after primary surgery for stage I or II carcinosarcoma of the uterus is tolerable. In the absence of concurrent controls, the impact on PFS and OS is unclear. Pelvic relapse remains problematic.

Phase II study of medroxyprogesterone acetate plus tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study.

OBJECTIVES: The objectives of this study were to estimate the clinical response rate and toxicity of daily tamoxifen combined with intermittent weekly medroxyprogesterone acetate (MPA). METHODS: This study reports the results of 61 patients with measurable advanced or recurrent endometrial carcinoma enrolled on this study to be treated with tamoxifen 40 mg p.o. daily plus alternating weekly cycles of MPA 200 mg p.o. daily. RESULTS: One patient was excluded and two patients did not receive study treatment. The percent of patients responding (6 complete and 13 partial) was 33% (95% confidence interval [CI]: 21-46%) among 58 eligible patients who received therapy. Median progression-free survival (PFS) was 3 months and median overall survival (OS) was 13 months. CONCLUSION: The combination of daily tamoxifen and intermittent weekly medroxyprogesterone acetate is an active treatment for advanced or recurrent endometrial carcinoma. Further investigation of this combination is appropriate.