Association of location of BRCA1 and BRCA2 mutations with benefit from olaparib and bevacizumab maintenance in high-grade ovarian cancer: phase III PAOLA-1/ENGOT-ov25 trial subgroup exploratory analysis.

BACKGROUND: In the phase III PAOLA-1 study, the addition of maintenance olaparib to bevacizumab in patients with newly diagnosed high-grade ovarian cancer (HGOC) resulted in prolonged progression-free survival (PFS), particularly for homologous recombination deficiency-positive tumors, including those with a BRCA mutation (BRCAm). The magnitude of benefit from olaparib and bevacizumab according to the location of mutation in BRCA1/BRCA2 remains to be explored. PATIENTS AND METHODS: Patients with advanced-stage HGOC responding after platinum-based chemotherapy + bevacizumab received maintenance therapy bevacizumab (15 mg/kg q3w for 15 months) + either olaparib (300 mg b.i.d. for 24 months) or placebo. PFS was analyzed in the subgroup of patients with BRCA1m/BRCA2m according to mutation location in the functional domains of BRCA1 [Really Interesting Gene (RING), DNA-binding domain (DBD), or C-terminal domain of BRCA1 (BRCT)] and BRCA2 [RAD51-binding domain (RAD51-BD); DBD]. RESULTS: From 806 randomized patients, 159 harbored BRCA1m (19.7%) and 74 BRCA2m (9.2%). BRCA1m in RING, DBD, and BRCT domains was detected in 18, 40, and 33 patients, and BRCA2m in RAD51-BD and DBD in 36 and 13 patients, respectively. After a median follow-up of 25.5 months, benefit from maintenance olaparib + bevacizumab was observed irrespective of location of BRCAm. The benefit was particularly high for those with BRCA1m located in the DBD, with 24-month PFS estimated to be 89% and 15% [olaparib + bevacizumab versus placebo + bevacizumab hazard ratio = 0.08 (95% confidence interval 0.02-0.28); interaction P = 0.03]. In BRCA2m patients, 24-month PFS rates for those with mutations located in the DBD were 90% and 100% (olaparib + bevacizumab versus placebo + bevacizumab), respectively. CONCLUSIONS: Advanced-stage BRCA-mutated HGOC patients reported PFS benefit from maintenance olaparib and bevacizumab regardless of mutation location. The benefit is particularly high for patients with mutations located in the DBD of BRCA1. Mutations located in the DBD of BRCA2 are also associated with excellent outcome.

Long-term significance of urinary neopterin in ovarian cancer: a study by the Austrian Association for Gynecologic Oncology (AGO).

BACKGROUND: Neopterin is produced by activated macrophages upon stimulation with interferon-γ (IFN-γ) and thus, elevated neopterin concentrations in patients indicate cellular inate immune response. Most studies in patients with malignant diseases found an association between higher neopterin concentrations and reduced survival and impaired prognosis. Nevertheless, neopterin is not a classical tumor marker since it is not produced by the cancer cells themselves. PATIENTS AND METHODS: In a study conducted by the Austrian Gynecologic Oncology Group (AGO) in 114 patients with ovarian cystadenomas and 223 patients with invasive ovarian cancer, patients' urinary neopterin was determined before and after primary therapy. The relevance of neopterin in long-term median follow-up was assessed. RESULTS: Elevated levels (cut-off 250 µmol/mol creatinine) were found less frequently in women with benign ovarian cystadenomas (24%) than in patients with malignant disease (58%). After 10 years, only 57% of ovarian cancer patients with elevated urinary neopterin levels survived without disease progression following primary therapy when compared with 86% of women with normal levels (P < 0.001). Along with residual tumor, FIGO stage, age and histological type, neopterin was significantly associated with overall survival (OS) and progression-free survival (PFS). The median PFS was 52 and 12 months and the median OS was 81 and 24 months for patients with normal and elevated neopterin, respectively, P < 0.001. In a multivariate Cox regression analysis, only residual tumor, neopterin and age were independently associated with OS, while only residual tumor was predictive for PFS. Thirty patients with early-stage invasive ovarian cancer (FIGO I and II) were analyzed separately. Of 3 patients with elevated neopterin, 2 died of disease in contrast to 2 out of 27 patients with normal neopterin (P = 0.004). CONCLUSION: In ovarian cancer, the negative impact of elevated urinary neopterin levels indicates a detrimental effect of cancer-associated inflammatory reaction.

Does long-term application of granulocyte colony-stimulating factor adversely influence overall survival in patients with ovarian cancer? A clinical study.

The purpose of this study was to investigate the effect of long-term administration of G-CSF with regard to its impact on overall survival of patients with ovarian cancer. We report the results of a non-randomized trial on 64 patients with advanced ovarian cancer treated with 6 cycles of conventional chemotherapy. Chemotherapy comprised carboplatin 400 mg/m2 and epirubicin 70 mg/m2 on day 1 of each cycle and prednimustine 100 mg/m2 on days 3 to 7, every 28 days. Thirty-three patients received CEP chemotherapy with G-CSF support whereas 31 women received CEP chemotherapy alone. The schedule of G-CSF was 5 mg/kg/day subcutanously on days 8 to 21 of each cycle. The severity of reduction in white cells and neutrophil count was significantly different in the two treatment groups (p<0.05), with more toxicity in the non- G-CSF group. G-CSF users had a non significant 0.88-fold lower risk of dying from ovarian cancer (95% CI, 0.48-1.60, p=0.678). In a survival analysis using a Cox proportional hazards model, residual tumor remained as an independent prognostic factor. The increasing amount of residual tumor resulted in a 1.767-fold higher risk (95% CI, 1.23-2.53, p=0.002) of death secondary to the underlying disease. In conclusion, this trial has failed to demonstrate any negative impact on patients' overall survival for the additional use of G-CSF with platinum-based chemotherapy; our results were consistent with the beneficial effects of G-CSF treatment on cytotoxic chemotherapy-induced myelosuppression.

Impact of hysteroscopy on disease-free survival in clinically stage I endometrial cancer patients.

Recent data strongly suggest tumor cell dissemination of endometrial carcinoma cells in the course of fluid hysteroscopy. In patients who had endometrial cancer which was (except for peritoneal cytology) confined to the uterus, the disease-free survival (DFS) of 135 patients who underwent hysteroscopy prior to staging laparotomy was compared with the DFS of 127 patients without hysteroscopy. After a median follow-up of 23 months, 10 patients experienced tumor recurrence. Although there was a trend towards a higher incidence of positive peritoneal cytology at laparotomy in patients who underwent hysteroscopy, this difference did not achieve statistical significance (P = 0.47). For 5 years, the DFS was 92.4% in patients with hysteroscopy and 84.7% in patients without hysteroscopy before laparotomy (log-rank, P = 0.782). Our data therefore suggest a similar short-term DFS in endometrial cancer patients with and without hysteroscopy prior to laparotomy.

Endometrial cancer: accuracy of the finding of a well differentiated tumor at dilatation and curettage compared to the findings at subsequent hysterectomy.

The objective of this study was to examine the accuracy of the finding of a histologically well differentiated endometrial carcinoma at dilatation and curettage (D & C) prior to hysterectomy. A retrospective multicentric chart review of 137 endometrial cancer patients was conducted, including all patients in whom a well differentiated endometrial carcinoma had been diagnosed by D & C. Histopathologic grading as determined by D & C was compared with the grading established at the final histologic examination after hysterectomy. Seventy-eight percent of all cases in which a well differentiated tumor was diagnosed with D & C were confirmed as well differentiated endometrial carcinomas, whereas 20.4% had to be upgraded as moderately differentiated tumors after evaluation of the hysterectomy specimen. In one case in which a uterine adenocarcinoma was diagnosed by D & C, a well differentiated adenocarcinoma was found to be combined with a carcinosarcoma in the hysterectomy specimen. In order to avoid false findings of a well differentiated tumor, the histologic grade should be confirmed by intraoperative frozen section examination. This is especially important in cases in which surgical staging was not planned initially.

[The value of surgical staging in the early stages of ovarian carcinoma]. / Die Bedeutung der Staging-Operation bei den Frühstadien des Ovarialkarzinoms.

The value of surgery in early ovarian cancer was assessed in a retrospective analysis of prognostic factors in all 222 patients with primary stage I epithelial ovarian carcinoma treated in this department between 1975 and 1987. Only cellular differentiation grade (p less than 0.03) and surgical procedure - total abdominal hysterectomy, bilateral salpingo-oophorectomy +/- omentectomy vs. unilateral salpingo-oophorectomy - (p less than 0.02) were of significant influence on estimated survival (Cox model). All other factors (age, FIGO stage, integrity of the capsule, uni-vs. bilaterality, histology) were of no prognostic importance. Unilateral salpingo-oophorectomy without any additional staging reduces the 5-year survival probability (62% vs. 84%). Future prospective studies on adjuvant therapy must be based on exact staging during surgical management before randomisation. Determination of cellular differentiation is also essential.

[The value of cytoreductive second-look surgery in advanced epithelial ovarian carcinoma]. / Die Wertigkeit der zytoreduktiven Second-look-Operation beim forgeschrittenen epithelialen Ovarialkarzinom.

40 patients with advanced epithelial ovarian carcinoma were investigated to evaluate the influence of further cytoreduction during second-look surgery on survival after termination of first-line polychemotherapy containing cisplatinum. Radical tumorectomy with no macroscopic residual tumor mass was achieved in 27.5% of cases; in 52.5% the residual tumour mass was less than 2 cm and in 20% it was more than 2 cm in diameter after cytoreductive second-look surgery. Median survival time after second-look within these three groups of patients was 15.2 months, 16.9 months and 15.3 months, respectively (Mantel test, p = 0.74). In contrast to the situation at the diagnostic operation, further cytoreduction during second-look surgery has no positive influence on survival. We therefore abandoned this operation in clinically tumour-positive patients.

[Influence of adjuvant hormonal therapy on the whole female organism: benefit versus potential injury]. / Einfluss einer adjuvanten Hormontherapie aud den Gesamtorganismus der Frau: Nutzen versus potentieller Schaden.

Not only do patients suffering from hormone receptor-positive tumors of the mammary gland show an increased survival rate, but patients with endometrial as well as ovarian cancer also benefit from hormone replacement therapy. On the one hand, hormonal treatment as well as any other medical treatment influences the tumor, and on the other hand it influences the whole body, which sometimes leads to unfavorable events (increased rate of endometrial cancers during tamoxifen therapy vs. increase of bone density in postmenopausal women). Therefore, hormonal cancer treatment is often suspect. As unfavorable events are rare, and since the benefit is convincing, doctors have to inform women about all the pros and cons of this treatment option, which leads to well-informed and cooperative patients.

[The value of adjuvant irradiation in patients with cervical carcinoma in histopathological stage Ib and negative lymph nodes]. / Zum Wert der adjuvanten Bestrahlung bei Patientinnen mit einem Zervixkarzinom im histopathologischen Stadium Ib und negativen Lymphknoten.

The present retrospective study attempts to evaluate the significance of adjuvant radiotherapy as a prognostic factor for stage Ib cervical carcinoma without lymph node metastases in addition to factors such as age, histological type, histological grading and tumor size. Between 1975 and 1987 224 patients were operated at our department or referred to postoperative radiotherapy and fulfilled the inclusion criteria: histopathological stage Ib, radical hysterectomy with pelvic lymphadenectomy and negative pelvic lymph nodes. The multivariate analysis confirmed that tumor size (tumor infiltration of the cervix greater than 2/3 vs less than 2/3: RR = 4.48) and histological grading (G3 vs G1 + G2: RR = 3.12) are significant prognostic parameters for survival. Postoperative adjuvant irradiation is a marginal significant factor for survival in stage Ib cervical carcinoma and negative nodes (RR = 3.22; p = 0.057). For women with negative nodes but high-risk prognostic factors in the cervix, a prospective randomized trial proving the value of postoperative irradiation would be of therapeutic interest.

Is CA-125 monitoring useful in patients with epithelial ovarian carcinoma and preoperative negative CA-125 serum levels?

Between December 1983 and December 1988 we examined the postoperative tumor marker development and correlated this to the clinical course of the disease in 56 patients suffering from primary epithelial ovarian carcinoma of International Federation of Gynecology and Obstetrics stages I-III and with a preoperative CA-125 serum level less than or equal to 65 U/ml. In 54% of all cases there was a reduction of more than 50% of the CA-125 serum level within the first 3 months after surgery. Nine out of thirteen patients with progressive disease (69%) showed an increasing CA-125 serum level with a median lead time of 6 months (0-11 months) prior to clinical diagnosis. These preliminary results indicate that the monitoring of cancer patients with CA-125 tumor marker seems to be a useful method of early diagnosis of progressive disease even in patients with preoperative serum levels lower than 65 U/ml.

Prognostic factors related to recurrent endometrial carcinoma following initial surgery.

Site of recurrence and histological type are significant prognostic factors for survival in recurrent endometrial carcinoma. The aim of this retrospective analysis of 56 patients suffering from recurrences of endometrial carcinoma following initial surgery was to establish the prognostic relevance that the following factors had on the survival rate: age, primary tumor stage, histological assessment (papillary vs non-papillary), postoperative adjuvant radiation therapy, recurrence free interval (< 24 months, > 24 months) and localisation of recurrence. The univariate analysis showed a significantly longer median survival time after recurrence for the following parameters: local recurrence vs extra vaginal recurrence (77.5 months vs 15.7 months, p = 0.02), non-papillary vs papillary carcinoma (36.1 months vs 7.7 months, p = 0.02), no adjuvant irradiation vs adjuvant irradiation (82.0 months vs 8.8 months, p = 0.007). Patients after adjuvant radiation treatment and patients suffering from papillary carcinomas have a significantly higher proportion of patients with distant metastasis (patients with adjuvant radiation treatment: Chi-square test: p = 0.001; patients suffering from papillary carcinomas: p = 0.033). In the case of local recurrences, a three year survival rate of 54% can be achieved with radiation treatment. Recurrences of papillary endometrial carcinomas and patients suffering from distant metastasis on the other hand, show very low survival rates if they are treated with radiation therapy (papillary carcinomas: three-year survival rate of 18%, patients suffering from distant metastasis: 19%). These patients should be included in randomised studies with a view to examining the therapeutic effects of either additional or exclusive treatment with chemotherapy.

Oestrogen and progesterone receptor content as a prognostic factor in advanced epithelial ovarian carcinoma.

Levels of oestrogen receptor (ER) and progesterone receptor (PgR) in ovarian cancer tissue were examined with regard to their prognostic importance for survival in 179 patients with primary epithelial ovarian cancer stage III or IV in relation to: FIGO-stage, histological type, histological grade, age, ascites, and postoperative residual tumour. Hormone receptor content was determined with the DCC-method, receptor values higher than 9 fmol/mg protein were considered positive. Response to postoperative chemotherapy was significantly correlated with PgR content (80% responders in the group with PgR positive tumours and only 61% responders in the group with PgR negative tumours). A Cox proportional hazards regression model identified histological grade, residual tumour, age and PgR content as independent prognostic factors for survival in advanced epithelial ovarian carcinoma. PgR content had particularly significant prognostic relevance for patients with postoperative residual tumour mass less than or equal to 2 cm in diameter. Within this group of patients, those who are PgR positive have a 2-years survival probability of 83% compared with only 51% in the PgR-negative group.

Lunar phases and survival of breast cancer patients--a statistical analysis of 3,757 cases.

The potential influence of lunar phases on human life has been widely discussed by the lay press. The purpose of this study was to find out whether the timing of surgery during particular lunar phases influences the survival of breast cancer patients. It has been postulated that breast cancer surgery performed during the waxing moon, or particularly at full moon, is associated with a poorer outcome. We tested this hypothesis by evaluating the overall survival for 3,757 consecutive patients with invasive breast cancer. All patients underwent either modified radical mastectomy or breast conserving surgery plus radiotherapy, followed by adjuvant cytotoxic or hormonal therapy. The date of definitive surgery was allocated to the lunar phases. 1,904 (50.7%) patients were operated on during the waxing moon and 1,853 (47.3%) during the waning moon. The median follow-up was 74 months (range 1-372 months). The mean age at primary surgery did not differ significantly in the two groups 58.39 (SD 13.14) versus 58.34 (12.75) (p >0.05, t-test). Breast cancer stages at initial diagnosis were evenly distributed according to the lunar phases (p = 0.325; chi-square). Survival curves were plotted according to the method of Kaplan-Meier. No significant differences were observed when timing of surgery was allocated to the lunar phases (p = 0.4841, log-rank). Subgroup analysis of premenopausal patients revealed similar results (p = 0.2950, log-rank; n = 1072). Using multivariate Cox modelling, we found a significant association between the patient's age, stage of disease and survival, whereas no association with survival was observed for the timing of surgery (RR= 1.062; 95% CI, 0.970-1.163; p = 0.1937). No significant differences in overall survival of breast cancer patients were observed when timing of breast cancer surgery during the lunar cycle was considered. Although this was not a prospective randomized trial, the statistical magnitude of the results do not support any recommendations for scheduling patients for surgery at any particular day of the lunar phase.

Does hysteroscopy facilitate tumor cell dissemination? Incidence of peritoneal cytology from patients with early stage endometrial carcinoma following dilatation and curettage (D & C) versus hysteroscopy and D & C.

BACKGROUND: In several case reports, distension and irrigation of the uterine cavity during fluid hysteroscopy was suspected to cause tumor cell dissemination into the abdominal cavity in patients with endometrial carcinoma. It was the aim of this study to compare the incidence of positive peritoneal cytology in patients who underwent dilatation and curettage (D & C) with or without previous hysteroscopy. METHODS: The authors conducted a multicentric, retrospective cohort analysis. One hundred thirteen consecutive patients with endometrial carcinoma treated between 1996 and 1997 were included. Endometrial carcinoma had to be limited to the inner half or less than the inner half of the myometrium (pathologic Stage IA,B). Positive peritoneal cytology was obtained during staging laparotomy. Patients underwent D & C either with or without prior diagnostic fluid hysteroscopy. No selection or randomization was applied to the two groups. Positive peritoneal cytology, defined as malignant or suspicious, was considered the primary statistical endpoint. RESULTS: Peritoneal cytology was suspicious or positive in 10 of 113 patients (9%). The presence of suspicious or positive peritoneal cytology was associated with a history of hysteroscopy (P = 0.04) but not with myometrial invasion (P = 0.57), histologic subtype (P = 1.00) or grade (r = 0.16, P = 0.10), or the time between D & C and staging laparotomy (r = 0.04, P = 0.66). CONCLUSIONS: Based on the limited extent of endometrial carcinoma in the current analysis, our data strongly suggest dissemination of endometrial carcinoma cells after fluid hysteroscopy. Determining whether a positive peritoneal cytology affects the prognoses of patients without further evidence of extrauterine disease will require longer follow-up.

Interferon-gamma in the first-line therapy of ovarian cancer: a randomized phase III trial.

Intraperitoneal treatment with interferon-gamma (IFN-gamma) has been shown to achieve surgically documented responses in the second-line therapy of ovarian cancer. To assess its efficacy in the first-line therapy, we conducted a randomized controlled trial with 148 patients who had undergone primary surgery for FIGO stage Ic-Illc ovarian cancer. In the control arm women received 100 mg/m(-2) cisplatin and 600 mg/m(-2) cyclophosphamide, the experimental arm included the above regimen with IFN-gamma 0.1 mg subcutaneously on days 1, 3, 5, 15, 17 and 19 of each 28-day cycle. Progression-free survival at 3 years was improved from 38% in controls to 51% in the treatment group corresponding to median times to progression of 17 and 48 months (P= 0.031, relative risk of progression 0.48, confidence interval 0.28-0.82). Three-year overall survival was 58% and 74% accordingly (n.s., median not yet reached). Complete clinical responses were observed in 68% with IFN-gamma versus 56% in controls (n.s.). Toxicity was comparable in both groups except for a mild flu-like syndrome, experienced by most patients after administration of IFN-gamma. Thus, with acceptable toxicity, the inclusion of IFN-gamm in the first-line chemotherapy of ovarian cancer yielded a benefit in prolonging progression-free survival.