Surgical staging and prognosis in serous borderline ovarian tumours (BOT): a subanalysis of the AGO ROBOT study.

BACKGROUND: Incomplete surgical staging is a negative prognostic factor for patients with borderline ovarian tumours (BOT). However, little is known about the prognostic impact of each individual staging procedure. METHODS: Clinical parameters of 950 patients with BOT (confirmed by central reference pathology) treated between 1998 and 2008 at 24 German AGO centres were analysed. In 559 patients with serous BOT and adequate ovarian surgery, further recommended staging procedures (omentectomy, peritoneal biopsies, cytology) were evaluated applying Cox regression models with respect to progression-free survival (PFS). RESULTS: For patients with one missing staging procedure, the hazard ratio (HR) for recurrence was 1.25 (95%-CI 0.66-2.39; P=0.497). This risk increased with each additional procedure skipped reaching statistical significance in case of two (HR 1.95; 95%-CI 1.06-3.58; P=0.031) and three missing steps (HR 2.37; 95%-CI 1.22-4.64; P=0.011). The most crucial procedure was omentectomy which retained a statistically significant impact on PFS in multiple analysis (HR 1.91; 95%-CI 1.15-3.19; P=0.013) adjusting for previously established prognostic factors as FIGO stage, tumour residuals, and fertility preservation. CONCLUSION: Individual surgical staging procedures contribute to the prognosis for patients with serous BOT. In this analysis, recurrence risk increased with each skipped surgical step. This should be considered when re-staging procedures following incomplete primary surgery are discussed.

Age-dependent differences in borderline ovarian tumours (BOT) regarding clinical characteristics and outcome: results from a sub-analysis of the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) ROBOT study.

BACKGROUND: Approximately one-third of all borderline ovarian tumours (BOT) are diagnosed in patients with child-bearing potential. Detailed information regarding their specific characteristics and prognostic factors is limited. METHODS: Clinical parameters of BOT patients treated between 1998 and 2008 in 24 German centres were retrospectively investigated. Central pathology review and prospective follow-up were carried out. Patients <40 versus ≥40 years were analysed separately and then compared regarding clinico-pathological variables and prognosis. RESULTS: A total of 950 BOT patients with a median age of 49.1 (14.1-91.5) years were analysed [280 patients <40 years (29.5%), 670 patients ≥40 years (70.5%)]. Fertility-preserving surgery was carried out in 53.2% (149 of 280) of patients <40 years with preservation of the primarily affected ovary in 32 of these 149 cases (21.5%). Recurrence was significantly more frequent in patients <40 years (19.0% versus 10.1% 5-year recurrence rate, P < 0.001), usually in ovarian tissue, whereas disease-specific overall survival did not differ between the subgroups. In case of recurrent disease, malignant transformation was less frequent in younger than in older patients (12.0% versus 66.7%, P < 0.001), mostly presenting as invasive peritoneal carcinomatosis. Multivariate analysis for patients <40 years identified advanced International Federation of Gynecology and Obstetrics (FIGO) stage and fertility-sparing approach as independent prognostic factors negatively affecting progression-free survival (PFS) while, for patients ≥40 years, higher FIGO stage and incomplete staging was associated with impaired PFS. CONCLUSIONS: Despite favourable survival, young BOT patients with child-bearing potential are at higher risk for disease recurrence. However, relapses usually remain BOT in the preserved ovaries as opposed to older patients being at higher risk for malignant transformation in peritoneal or distant localisation. Therefore, fertility-sparing approach can be justified for younger patients after thorough consultation.

A phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: a randomized multicenter trial with sunitinib (SU11248) to evaluate dosage, schedule, tolerability, toxicity and effectiveness of a multitargeted receptor tyrosine kinase inhibitor monotherapy.

BACKGROUND: Recurrent platinum-resistant ovarian cancer usually has a poor outcome with conventional chemotherapeutic therapy and new treatment modalities are warranted. This phase II study was conducted to evaluate sunitinib, an oral antiangiogenic multitargeted tyrosin kinase inhibitor, in this setting. MATERIAL AND METHODS: The primary end point of this randomized phase II trial was the objective response rate according to RECIST criteria and/or Gynecologic Cancer InterGroup CA125 response criteria to sunitinib in patients with recurrent platinum-resistant ovarian cancer who were pretreated with up to three chemotherapies. A selection design was employed to compare two schedules of sunitinib (arm 1: 50 mg sunitinib daily orally for 28 days followed by 14 days off drug; and arm 2: 37.5 mg sunitinib administered daily continuously). RESULTS: Of 73 patients enrolled, 36 patients were randomly allocated to the noncontinuous treatment arm (arm 1) and 37 patients were randomly allocated to the continuous treatment arm (arm 2). The mean age was 58.8 and 58.5 years, respectively. We observed six responders (complete response + partial response) in arm 1 (16.7%) and 2 responders in arm 2 (5.4%). The median progression-free survival (arm 1: 4.8 [2.9-8.1] months; arm 2: 2.9 [2.9-5.1] months) and the median overall survival (arm 1: 13.6 [7.0-23.2] months; arm 2: 13.7 [8.4-25.6] months) revealed no significant difference. Adverse events included fatigue as well as cardiovascular, gastrointestinal and abdominal symptoms, hematologic and hepatic laboratory abnormalities. Pattern and frequency of adverse events revealed no substantial differences between both treatment groups. CONCLUSIONS: Sunitinib treatment is feasible and moderately active in relapsed platinum-resistant ovarian cancer. The noncontinuous treatment schedule should be chosen for further studies in ovarian cancer.

Predictors of survival in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery based on the pooled analysis of an international collaborative cohort.

BACKGROUND: This study aims to identify prognostic factors and to develop a risk model predicting survival in patients undergoing secondary cytoreductive surgery (SCR) for recurrent epithelial ovarian cancer. METHODS: Individual data of 1100 patients with recurrent ovarian cancer of a progression-free interval at least 6 months who underwent SCR were pooled analysed. A simplified scoring system for each independent prognostic factor was developed according to its coefficient. Internal validation was performed to assess the discrimination of the model. RESULTS: Complete SCR was strongly associated with the improvement of survival, with a median survival of 57.7 months, when compared with 27.0 months in those with residual disease of 0.1-1 cm and 15.6 months in those with residual disease of >1 cm, respectively (P<0.0001). Progression-free interval (≤23.1 months vs >23.1 months, hazard ratio (HR): 1.72; score: 2), ascites at recurrence (present vs absent, HR: 1.27; score: 1), extent of recurrence (multiple vs localised disease, HR: 1.38; score: 1) as well as residual disease after SCR (R1 vs R0, HR: 1.90, score: 2; R2 vs R0, HR: 3.0, score: 4) entered into the risk model. CONCLUSION: This prognostic model may provide evidence to predict survival benefit from secondary cytoreduction in patients with recurrent ovarian cancer.

The anti-idiotypic antibody abagovomab in patients with recurrent ovarian cancer. A phase I trial of the AGO-OVAR.

BACKGROUND: Abagovomab is a murine anti-idiotypic antibody against the antigen CA-125 which has been shown to elicit humoral and cellular immune responses against ovarian cancer (oc). PATIENTS AND METHODS: This phase I trial included 36 patients with recurrent oc comparing two subcutaneous (s.c.) vaccination schedules: nine (group L) versus six injections (group S), 18 patients in each group. Four injections of 2.0 mg abagovomab were administered every 2 weeks and then two or five additional doses monthly. Primary endpoint was drop-out rate due to toxicity, and the secondary endpoint was analysis of immunological response. RESULTS: Treatment was completed in eight (44%) and 16 (89%) patients in groups L and S, respectively. Premature termination occurred due to patient withdrawal or disease progression. No treatment-limiting toxicities occurred in either group. The most common toxicity related to the vaccine was grade 1/2 local injection site reaction. Induction of Ab3 was observed in all evaluable patients. There were no differences between the groups with regard to induction of human anti-mouse antibody (P = 0.1006). IFNgamma-expressing CA125-specific CD8+ T-cells were significantly more frequent in group L, while there was no significant difference between CD4+ T-cells in the two groups. CONCLUSIONS: Abagovomab s.c. vaccination is safe and well tolerated. The long vaccination schedule tended to be more effective with regard to AB3-induction and cellular cytotoxicity.

Non-enrolment of ovarian cancer patients in clinical trials: reasons and background.

BACKGROUND: Some retrospective analyses have suggested that participation in clinical trials is associated with better outcome. However, it is not clear to what extent selection bias contributes to this observation. PATIENTS AND METHODS: We evaluated the reasons for non-enrolment of ovarian cancer patients in clinical trials. All patients with ovarian cancer not enrolled in clinical studies and treated in 2001 in the participating centres were documented retrospectively and compared with patients enrolled in clinical trials at the same institutions during the same time period. RESULTS: Two hundred and seventy-four patients with advanced ovarian cancer (FIGO stage IIB-IV) were included, of whom 139 (51%) and 135 (49%) patients were enrolled in this study and in prospective clinical trials, respectively. Ninety-four of 274 patients (34%) did not meet the inclusion criteria for clinical trials. Of 180 eligible patients, 28 (16%) refused participation and a further 17 patients (9%) were not recruited although they met the inclusion criteria. The non-study patients were older (66.7 versus 57.2 years; P <0.0001), underwent less radical surgery (hysterectomy, oophorectomy and omentectomy performed: 61.2% versus 80.7%; P = 0.001; rate of lymphadenectomy 30.9% versus 45.2%; P = 0.015) and more frequently had bulky residual disease (residual disease >2 cm: 36.2% versus 20%; P = 0.016). However, 62% of the non-study patients were treated with the same chemotherapy as in the standard arm of the respective clinical studies. CONCLUSIONS: Study patients differ substantially from non-study patients, thus hampering generalisation of study results. Our results suggest that at least some inclusion criteria for clinical trials should be modified to increase study participation without compromising safety.

Acute problems during low-dose-rate intracavitary brachytherapy for cervical carcinoma.

OBJECTIVE: To estimate the incidence and severity of problems arising during the hospitalization of cervical carcinoma patients undergoing low-dose-rate intracavitary brachytherapy (ICB). METHODS: One hundred seventy ICB implants in 128 cervical carcinoma patients undergoing curative radiation therapy were reviewed. All events during the hospitalization requiring physician evaluation and/or intervention were scored as a "problem" and divided into 10 categories (fever/infection, pain, gastrointestinal, renal, pulmonary, cardiac, dermatologic, gynecologic, endocrinologic, psychiatric). Problems were scored as mild (no significant morbidity, therapy not discontinued), moderate (therapy discontinued but no significant morbidity), or severe (significant morbidity or mortality). Patient and treatment factors were correlated with acute problems. RESULTS: Forty-two implants (24.7%) were associated with acute problems (95% minor, 5% moderate, 0% severe). The most common types were fever/infection (14.1%) and gastrointestinal problems (5. 9%). Other problem types occurred in <3% of implants. No patient or treatment factor including age, comorbid disease, weight, implant duration, or anesthesia type was significantly correlated with acute problems. Patients who developed acute problems had a survival (P = 0.21) and risk of late sequelae (P = 0.74) similar to those of patients without acute problems. CONCLUSION: Problems occur during the hospitalization in approximately one-quarter of cervical carcinoma patients undergoing low-dose-rate ICB. However, most are minor and do not result in morbidity, require discontinuation of therapy, or adversely impact on outcome.