Evaluating the impact of dose reductions and delays on progression-free survival in women with ovarian cancer treated with either three-weekly or dose-dense carboplatin and paclitaxel regimens in the national prospective OPAL cohort study.

OBJECTIVES: To determine the impact of chemotherapy dose reductions and dose delays on progression-free survival (PFS) in women with ovarian cancer receiving first line chemotherapy in a real world prospective cohort study. METHODS: Patients with newly diagnosed epithelial ovarian (or peritoneal, fallopian tube) cancer enrolled in a national Australian prospective study, OPAL, who commenced three-weekly carboplatin (AUC 5 or 6) and paclitaxel 175 mg/m2 (CP) or carboplatin (AUC 5 or 6) and dose-dense weekly paclitaxel 80 mg/m2 (DD-CP) were eligible. Primary endpoint was PFS. RESULTS: 634 evaluable patients, 309 commenced CP and 325 DD-CP. Patient's age was similar in the two groups (median 62 years, range 21-79). All planned chemotherapy doses were completed by 66% vs 40% (p < 0.001) in the CP and DD-CP groups respectively. There was at least one treatment delay in 28% vs 58% (p < 0.001) in the CP and DD-CP groups, respectively, and 29% vs 49% (p < 0.001), respectively, required at least a 15% dose reduction for either carboplatin or paclitaxel. Median PFS was 29.2 [22.9, 43.8] and 21.5 [19.4, 23.1] months in the CP and DD-CP groups respectively. Adjusting for age, histology and FIGO stage PFS did not differ between treatment groups. Median PFS was similar in patients irrespective of dose reduction or dose delay. CONCLUSION: Patients receiving DD-CP required more dose reductions and delays due to haematological toxicities and lower completion rates than CP without significant difference in median PFS between CP and DD-CP. Median PFS was similar in patients irrespective of dose reduction or dose delay.

Obesity in total laparoscopic hysterectomy for early stage endometrial cancer: health gain and inpatient resource use.

OBJECTIVE: To explore relationships between BMI (morbid/severe obesity; BMI ≥ 35 kg/m2 vs. non morbid/severe obesity; BMI < 35 kg/m2), postoperative health gain and hospital resource use for women who receive a Total Laparoscopic Hysterectomy (TLH) for early stage endometrial cancer. DESIGN: Secondary analysis of RCT data (LACE Study; Total Abdominal Hysterectomy vs. TLH). SETTING: 20 tertiary gynaecological cancer centres in Australia, New Zealand and Hong Kong. POPULATION: About 404 women who received TLH to treat early stage endometrial cancer. METHODS: For women with BMI < 35 vs. BMI ≥ 35 kg/m2, we compared (i) postoperative health gain, using utility scores derived from responses to the EQ-5D-3L health-related quality of life instrument, and (ii) inpatient hospital resource use, using adverse events, surgery duration and postoperative length of stay as indicators, to 6 months post-surgery. MAIN OUTCOME MEASURES: Health gain, resource use. RESULTS: Mean postoperative health gain was 0.07 units, and did not vary by BMI. Women with a BMI ≥ 35 had an increased rate of severe postoperative AEs (BMI ≥ 35 RR = 1.95, P = 0.02), and the surgery took on average 9.6 min longer (BMI < 35 kg/m2 122.5 min 95% CI 117.4-127.8; BMI ≥ 35 kg/m2 132.1 min 95% CI 126.3-138.2; P = 0.02). CONCLUSION: While postoperative health gain for women with BMI ≥ 35 was similar to that of women with lower BMI, the gain was achieved at the expense of greater resource use. Further work could definitively quantify the excess cost of TLH for obese patients with endometrial cancer, and investigate the potential for non-surgical treatment options, at least for those women at high risk of postoperative AEs.

The association between diabetes, comorbidities, body mass index and all-cause and cause-specific mortality among women with endometrial cancer.

OBJECTIVE: Although endometrial cancer (EC) is associated with relatively good survival rates overall, women diagnosed with high-risk subtypes have poor outcomes. We examined the relationship between lifestyle factors and subsequent all-cause, cancer-specific and non-cancer related survival. METHODS: In a cohort of 1359 Australian women diagnosed with incident EC between 2005 and 2007 pre-diagnostic information was collected by interview at recruitment. Clinical and survival information was abstracted from women's medical records, supplemented by linkage to the Australian National Death Index. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific survival (EC death vs. non-EC death) associated with each exposure, overall and by risk group (low-grade endometrioid vs. high-grade endometrioid and non-endometrioid). RESULTS: After a median follow-up of 7.1 years, 179 (13%) women had died, with 123 (69%) deaths from EC. As expected, elevated body mass index (BMI), diabetes and the presence of other co-morbidities were associated with a significantly increased risk of all-cause and non-cancer related death. Women with diabetes had higher cancer-specific mortality rates (HR 2.09, 95% CI 1.31-3.35), particularly those who had were not obese (HR 4.13, 95% CI 2.20-7.76). The presence of ≥2 other co-morbidities (excluding diabetes) was also associated with increased risk of cancer-specific mortality (HR 3.09, 95% CI 1.21-7.89). The patterns were generally similar for women with low-grade and high-grade endometrioid/non-endometrioid EC. CONCLUSION: Our findings demonstrate the importance of diabetes, other co-morbidities and obesity as negative predictors of mortality among women with EC but that the risks differ for cancer-specific and non-cancer related mortality.

Consideration for safe and effective gynaecological laparoscopy in the obese patient.

BACKGROUND: The number of obese and morbidly obese patients within the developed world is dramatically increasing within the last 20 years. Apart from demographical changes, obese patients are especially prone to have oestrogen-dependent morbidities and neoplasias, of which laparoscopic treatment should be the standard of care. The increasing number of patients with BMI >40 is concerning, making it necessary to summarise considerations for safe and effective Gynaecological Laparoscopic Surgery. CONSIDERATIONS: The sequel to successful laparoscopic surgery in obese patients comprises an interdisciplinary appreciation of laparoscopy. Preoperatively, anaesthetics and medical review are suggested to optimise treatment of comorbidities (i.e. infections and blood sugar levels). Positioning of the patient should consider anti-slip options and pannus fixation to ease laparoscopic access and decrease pressure to the chest. There is no standard port placement in obese patients and landmarks have to be the bony structures of the pelvis and ribs. Retraction of the bowel is essential and mobilisation of the sigmoid with fan retractors or endoloops can accomplish adequate vision. 30° scopes can be considered for vision "around the obstacle". An experienced assistant with anticipation of surgical steps is favourable for successful surgery completion. Intra-operatively, good surgical techniques are essential. Vessel sealing systems reduce the need for instrument changes and may be helpful in following visualised tissue planes. A transvaginal vault closure may be advantageous compared to laparoscopic closure and Endostiches may be preferred to close the fascia of large trocar sites under vision.

Patterns of chemotherapy treatment for women with invasive epithelial ovarian cancer--a population-based study.

OBJECTIVE: Ovarian cancer five-year survival is poor at <40%. In the absence of effective screening or new treatments, ensuring all women receive optimal treatment is one avenue to improve survival. There is little population-based information regarding the primary chemotherapy treatment that women with epithelial ovarian cancer receive. This information is essential to identify potential gaps in care. METHODS: Cancer registries identified all women diagnosed with invasive epithelial ovarian cancer in Australia in 2005 (n=1192). Histopathology, chemotherapy and comorbidity information was abstracted from medical records. Multivariable logistic regression was used to identify factors associated with chemotherapy commencement, regimen, and completion. RESULTS: Women >70 years (p<0.0001), those with high-grade, stage IA/IB cancers (vs. stages IC-IV, p=0.003) and those with mucinous cancers (p=0.0002) were less likely to start chemotherapy. Most treated women received platinum-based drugs (97%), but only 68% received combination carboplatin-paclitaxel and only half completed six cycles without treatment modification/delay. Approximately 19% received single-agent carboplatin: mostly those aged >70 (p<0.0001) and/or with co-morbidities (p<0.0001). Age was the strongest predictor of completing six cycles of combination therapy. CONCLUSIONS: For specific patient groups, particularly older women, there is notable variation from standard treatment. Understanding how treatment variations affect survival and determining optimal regimens for these groups are research priorities.

Efficacy of oral or intrauterine device-delivered progestin in patients with complex endometrial hyperplasia with atypia or early endometrial adenocarcinoma: a meta-analysis and systematic review of the literature.

OBJECTIVES: To investigate the efficacy of progestin treatment to achieve pathological complete response (pCR) in patients with complex atypical endometrial hyperplasia (CAH) or early endometrial adenocarcinoma (EC). METHODS: A systematic search identified 3245 potentially relevant citations. Studies containing less than ten eligible CAH or EC patients in either oral or intrauterine treatment arm were excluded. Only information from patients receiving six or more months of treatment and not receiving other treatments was included. Weighted proportions of patients achieving pCR were calculated using R software. RESULTS: Twelve studies met the selection criteria. Eleven studies reported treatment of patients with oral (219 patients, 117 with CAH, 102 with grade 1 Stage I EC) and one reported treatment of patients with intrauterine progestin (11 patients with grade 1 Stage IEC). Overall, 74% (95% confidence interval [CI] 65-81%) of patients with CAH and 72% (95% CI 62-80%) of patients with grade 1 Stage I EC achieved a pCR to oral progestin. Disease progression whilst on oral treatment was reported for 6/219 (2.7%), and relapse after initial complete response for 32/159 (20.1%) patients. The weighted mean pCR rate of patients with grade 1 Stage I EC treated with intrauterine progestin from one prospective pilot study and an unpublished retrospective case series from the Queensland Centre of Gynaecologic Oncology (QCGC) was 68% (95% CI 45-86%). CONCLUSIONS: There is a lack of high quality evidence for the efficacy of progestin in CAH or EC. The available evidence however suggests that treatment with oral or intrauterine progestin is similarly effective. The risk of progression during treatment is small but longer follow-up is required. Evidence from prospective controlled clinical trials is warranted to establish how the efficacy of progestin for the treatment of CAH and EC can be improved further.

Challenges and controversies in the conservative management of uterine and ovarian cancer.

Uterine cancer is the fifth most common cancer in women worldwide with an estimated 320,000 annual diagnoses. Its most common form, endometrioid adenocarcinoma of the endometrium (endometrial adenocarcinoma [EAC]), is thought to develop through excessive proliferation of endometrial glands, and then increasing steadily in incidence. The current standard treatment for EAC is hysterectomy, which is often curative. However, it may be unacceptably expensive for women with severe medical comorbidities, those who are at risk of intra- and postoperative adverse events and those who desire fertility. Ovarian cancer is the most malignant of all gynaecological cancers, but patients with disease limited to one ovary and patients with non-epithelial tumours may expect a good prognosis. A selected group of young patients who desire fertility may be well treated with conservative surgery. This chapter reviews patient selection, diagnosis, pre-treatment evaluation, treatment options, surveillance and risk of relapse.

Elderly patients with stage III or IV ovarian cancer: should they receive standard care?

Due to the higher risk of morbidity and perioperative mortality compared to younger patients, elderly patients with advanced ovarian cancer are challenging to treat. A population-based analysis was performed to predict treatment outcomes and establish risk factors for early death of elderly patients with advanced ovarian cancer using a cohort of 3994 women diagnosed with stage III or IV ovarian cancer between 1992 and 1999, registered with the Surveillance, Epidemiology and End Results Cancer Registries. A multivariate accelerated failure time model allowed estimation of a risk factor model for overall survival. Patient's age, stage at presentation, presence of comorbidities, and oncology treatment facility were independently associated with overall survival at 12 months from diagnosis. Patients were assigned to low (0-7 points), moderate (8-14 points) or high (>/=15 points) risk groups according to accumulation of risk factors, which showed good ability to predict 12-month mortality (receiver-operator characteristics curve [ROC] derivation cohort = 0.763; ROC validation cohort = 0.756). Across all three risk groups, patients who received both surgery and chemotherapy showed significantly improved survival as compared to patients who received only surgery or chemotherapy. For patients 80 years and over who had upfront surgery, perioperative mortality was significantly greater in the high-risk group (21%; 95% CI = 16-26%) compared to patients within the moderate (8%; 95% CI = 5-12%) and low-risk groups (0%; 95% CI = 0-11%). The risk factor profile established could be helpful to plan future clinical trials to establish optimal treatment for elderly patients with advanced stage ovarian cancer.

Malnutrition among gynaecological cancer patients.

OBJECTIVE: To assess the nutritional status of patients with gynaecological cancer. DESIGN: A prospective study assessing the nutritional status of gynaecological patients with suspected or proven gynaecological cancer. SETTING: Queensland Centre for Gynaecological Cancer, Brisbane, Australia; a tertiary referral centre for gynaecological cancer. SUBJECTS: One hundred forty-five patients with suspected or proven gynaecological cancer aged 20-91 years. INTERVENTION: Scored patient-generated subjective global assessment (PG-SGA) and serum albumin before treatment. RESULTS: One hundred and sixteen (80%) patients were categorized as PG-SGA class A, 29 (20%) patients were PG-SGA B and none of the patients were PG-SGA C. Ovarian cancer patients had significantly lower serum albumin levels (P=0.003) and higher PG-SGA scores (P<0.001) than patients with other types of cancer and benign conditions. Sixty-seven per cent of patients with ovarian cancer were classified as PG-SGA B. After adjusting for patient's age, body mass index and albumin level, ovarian cancer patients were 19 times more likely to be categorized as PG-SGA class B compared to patients with benign conditions (95% confidence interval: 3.03-129.8; P=0.002). CONCLUSION: Malnutrition in gynaecological cancer patients is a significant problem, especially among those patients diagnosed with ovarian cancer.

Total laparoscopic versus open surgery for stage 1 endometrial cancer: the LACE randomized controlled trial.

PURPOSE: Endometrial cancer is the most common gynaecological malignancy in Australia and the US. Current standard treatment involves open surgery to remove the uterus, and both tubes and ovaries (TAH). The Laparoscopic Approach to Cancer of the Endometrium (LACE) trial was designed to assess equivalence of performing this in a total laparoscopic approach (TLH). METHODS: Patient recruitment was designed to proceed along two stages to accommodate for a potential increase in patient requests of laparoscopic surgery. During the first stage, patients are randomised in a 2:1 allocation to receive TLH or TAH, with the primary endpoint quality of life (QoL) at 6 month post-surgery, requiring 180 patients to be enrolled to have 80% power at alpha=0.05 to detect a clinically significant difference of 8 points on the Functional Assessment of Cancer General (FACT-G) QoL instrument. If additional recruitment of patients seems impossible after accrual of 180 patients, this cohort will be followed for 4 years, and disease free survival (DFS) of patients treated by TLH will be compared to DFS within the endometrial cancer population. During the second stage, recruitment will be extended to a total of 590 patients in a 1:1 TLH:TAH allocation, to assess the equivalence with respect to DFS with 80% power and alpha=0.05. Equivalence will be assumed if the difference in DFS does not exceed 7% at 4 years. Secondary outcomes include treatment related morbidity; costs and cost-effectiveness; patterns of recurrence; and overall survival. All data from this multicentre study will be entered using online electronic case report forms (e-CRF), allowing real time assessment of data completeness and patient follow-up. CONCLUSIONS: The LACE trial will establish the equivalence of a TLH approach for patients with stage 1 endometrial cancer following a two stage protocol to accommodate potential threats to patient recruitment through requests for laparoscopic surgery.

Correlation of vascular endothelial growth factor expression and microvessel density in cervical intraepithelial neoplasia.

BACKGROUND: Angiogenesis (the formation of new blood vessels) appears to be required for the growth of invasive tumors, but little information exists about its role in the development of preinvasive lesions. We examined microvessel density and expression of vascular endothelial growth factor in specimens of cervical intraepithelial neoplasia (CIN), a preinvasive lesion of the uterine cervix, to determine whether a connection could be established between these parameters of angiogenesis and the grade of dysplasia (i.e., tissue abnormality). METHODS: Sections of biopsy specimens from 83 patients with grades I-III CIN were examined retrospectively. Microvessels were localized by use of a polyclonal antibody directed against factor VIII-related antigen; vascular endothelial growth factor was detected by means of a monoclonal antibody. Reported P values are two-sided. RESULTS: Highest microvessel densities and highest expression of vascular endothelial growth factor were found in a narrow border region between CIN lesions and the underlying stroma. A significant correlation was observed between high vascular endothelial growth factor expression and high microvessel density (Kendall's tau = 0.27; 95% confidence interval [CI] = 0.03-0.50; P = .018). Mean microvessel density values +/- standard deviations for CIN I, CIN II, and CIN III lesions were 19.4 +/- 5.8, 21.9 +/- 7.0, and 34.1 +/- 14.8, respectively (Kendall's tau = 0.46; 95% CI = 0.30-0.61; P<.0001). Corresponding values for vascular endothelial growth factor expression were 8.3 +/- 3.5, 8.4 +/- 2.0, and 12.2 +/- 3.6, respectively (Kendall's tau = 0.41; 95% CI = 0.20-0.60; P<.0001). CONCLUSIONS: Our results are consistent with the idea that progression of cervical dysplasia is dependent on angiogenesis.

Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer.

Hypoxia-inducible factor 1alpha (HIF-1alpha) is a transcriptional factor that regulates genes involved in response to hypoxia and promotes neoangiogenesis, which are considered essential for tumor growth and progression. Using immunohistochemistry, we investigated the influence of HIF-1alpha expression on prognosis in 91 patients with cervical cancer stage pT1b. In univariate and multivariate analysis, patients with strong expression of HIF-1alpha had a significantly shorter overall survival time (P = 0.0307, log-rank test) and disease-free survival time (P < 0.0001, log-rank test) compared with those with moderate to absent HIF-1alpha expression. HIF-1alpha expression is a strong independent prognostic marker in early stage cervical cancer.

Overexpression of Id-1 protein is a marker for unfavorable prognosis in early-stage cervical cancer.

Inhibitor of differentiation/DNA binding (Id) proteins are transcription factors, involved in cell cycle regulation and neoangiogenesis. Using immunohistochemistry, we investigated the prognostic influence of Id-1, Id-2, and Id-3 expression in 89 patients with cervical cancer stage pT(1b). In univariate and multivariate analysis, patients with strong or moderate expression of Id-1 had a significant shorter overall survival time (P = 0.0144, log-rank test) and disease-free survival time (P = 0.0107, log-rank test) compared with those with low or absent Id-1 expression. Id-1 expression is an independent prognostic marker in early-stage cervical cancer.

Expression of hypoxia-inducible factor 1alpha in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy.

PURPOSE: To investigate the impact of expression of hypoxia-inducible factor (HIF)-1alpha on prognosis and on response to chemotherapy in epithelial ovarian tumors. EXPERIMENTAL DESIGN: Expression of HIF-1alpha protein was studied by immunohistochemistry in 102 specimens of epithelial ovarian cancers, in 50 borderline tumors, and in 20 cystadenomas. Results were correlated with p53, p21, and bcl-2 expression, microvessel density (MVD), apoptotic rate of tumor cells, and survival. RESULTS: In 68.6% of ovarian cancers and 88% of borderline tumors, expression of HIF-1alpha was observed. There was a significant correlation of HIF-1alpha protein expression and MVD (P < 0.001). HIF-1alpha overexpression alone and MVD showed no impact on survival of cancer patients. Furthermore, the response to platinum-based chemotherapy was independent from HIF-1alpha expression. Expression of HIF-1alpha correlated with apoptotic rate in the majority of cases, especially in low malignant potential tumors. In contrast, in cancer patients with strong expression of HIF-1alpha and p53 protein overexpression, not only a significantly increased MVD (P = 0.032, Mann-Whitney test) but also a significantly shorter overall survival was observed (P < 0.0001, Cox regression). The apoptotic rate was very low in these tumors. CONCLUSIONS: HIF-1alpha protein overexpression alone has no impact on the prognosis of ovarian cancer. The combination of HIF-1alpha protein overexpression with nonfunctional p53, however, indicates a dismal prognosis.

Selective immunohistochemical staining of blood and lymphatic vessels reveals independent prognostic influence of blood and lymphatic vessel invasion in early-stage cervical cancer.

Lymphovascular space invasion was shown to play a key role in the progression of cervical cancer. Because of the absence of a specific marker for lymphatic vessels, earlier studies could not reliably distinguish between blood and lymphatic vessel invasion. By immunostaining for podoplanin, a novel marker for lymphatic endothelium, and for factor VIII-related antigen, we determined lymphatic and blood vessel invasion in tissue samples of 98 patients with cervical cancer pT1b treated by radical hysterectomy. Eleven (11.2%) specimens showed invasion of blood vessels, 20 (20.4%) showed invasion of lymphatic vessels, and 15 (15.3%) showed invasion of blood and lymphatic vessels. There was a strong association of lymphatic vessel invasion and lymph node involvement (P < 0.001). In univariate analysis, both blood and lymphatic vessel invasion failed to reach a statistically significant influence on overall survival, but a significant influence on disease-free survival was found (P = 0.0002 and P < 0.0001, respectively). In multivariate analysis of disease-free survival, only blood vessel invasion remained statistically significant (P = 0.0457). Lymphatic vessel invasion reached significance when lymph node status was excluded from the model (P = 0.0025). Both lymphatic vessel and blood vessel invasion occur frequently in early-stage cervical cancer. Determination of the vessel status may be of clinical importance because it signifies the risk of recurrent disease.

Serum concentrations of vascular endothelial growth factor in vulvar cancer.

The aim of the present study was to evaluate serum concentrations of vascular endothelial growth factor (VEGF) in patients with vulvar cancer and healthy female controls with respect to correlation of VEGF with clinicopathological parameters and impact on the patients' prognosis. Serum concentrations of VEGF were measured using a commercially available ELISA. Results were correlated to clinical data. Median serum concentrations of VEGF in patients with vulvar cancer (n = 41) and healthy female controls (n = 130) were 260 (range, 33-1216) pg/ml and 216 (range, 0-777) pg/ml, respectively (Mann-Whitney U test, P = 0.048). Serum concentrations of VEGF significantly correlated with tumor stage (Mann-Whitney U test, P = 0.02) but not with histological grade (Mann-Whitney U test, P = 0.2). In a univariate analysis, elevated pretreatment serum concentrations of VEGF were significantly correlated with a shortened disease-free and overall survival (Wilcoxon test, P = 0.03; and Wilcoxon test, P = 0.04, respectively). A multivariate Cox regression model considering tumor stage and serum concentrations of VEGF revealed, however, that serum concentrations of VEGF did not confer additional prognostic information to that already obtained by the established prognosticator tumor stage (multivariate Cox regression model: P = 0.9 and P = 0.8, respectively). Our data indicate that angiogenesis, as reflected by serum concentrations of VEGF, plays a functional role in vulvar carcinogenesis. VEGF seems to be a mediator of vulvar tumor growth but not of tumor cell dedifferentiation. Although associated with impaired disease-free and overall survival, pretreatment serum concentrations of VEGF are not an independent predictor of outcome in patients with vulvar cancer.

Lack of impact of platinum dose intensity on the outcome of ovarian cancer patients. 10-year results of a prospective randomised phase III study comparing carboplatin-cisplatin with cyclophosphamide-cisplatin.

This prospective multicentre phase III trial was conducted to assess whether increased platinum dose intensity (DI) by combining carboplatin with cisplatin has an impact on overall survival (OS) and progression-free interval (PFI) compared with the standard combination of cyclophosphamide and cisplatin in patients with epithelial ovarian cancer. A total of 253 patients with epithelial ovarian cancer of stages International Federation of Gynecology and Obstetrics (FIGO) IC-IV were randomised to receive either cyclophosphamide (600 mg/m(2), intravenously (i.v.), day 1) and cisplatin (100 mg/m(2), i.v., day 2) (n=125) as the standard regimen or carboplatin (300 mg/m(2), i.v., day 1) and cisplatin (100 mg/m(2), i.v., day 2) (n=128), every 28 days for six courses. The median follow-up was 6.0 years. 124 patients randomised to the platinum dose-intensified arm and 123 patients randomised to the standard arm met all of the eligibility criteria. Patient characteristics were well balanced between the two treatment groups. All eligible patients randomised were included in the analysis of OS and PFI. The median OS of the standard and platinum dose-intensified arms were 41.2 (95% Confidence Interval (CI): 29.2-50.7) and 43.0 months (95% CI: 34.3-63.2), respectively (P=Non-significant (N.S.). The median PFI in the standard arm was 29.7 (95% CI: 17.4-41.7) versus 23.1 months (95% CI: 17.8-35.4) in the platinum dose-intensified arm, respectively (P=N.S.). Toxicity, comprising leucopenia, granulocytopenia, thrombocytopenia, anaemia, emesis and nausea, was statistically significantly higher in the platinum dose-intensified arm than in the standard arm. Unexpectedly, no statistically significant differences were found between the 2 arms' overall neuro- and ototoxicity. When converting carboplatin-platinum into cisplatin-platinum on the basis of an equivalence ratio of 4:1, patients in the platinum dose-intensified arm received a total platinum dose 1.58 times the platinum dose of the standard arm. With 35.0 mg/m(2)/week being administered, the total platinum DI of the dose-intensified arm was statistically significantly (P<0.0001) higher than that of the standard regimen (with 22.0 mg/m(2) being administered). Calculating the average administered relative dose intensities of the regimens yielded almost identical results with 0.56 and 0.58 for the standard and experimental arms, respectively. Thus, by conventional means, a 1.6-fold increase in the platinum DI could be reached by combining carboplatin and cisplatin without unacceptable morbidity. Nevertheless, this did not translate into any therapeutic benefit for the patient, even in the optimally debulked group of patients for whom dose-intensification would have been expected to be of benefit.

Peritoneal cytology: impact on disease-free survival in clinical stage I endometrioid adenocarcinoma of the uterus.

The prognostic significance of positive peritoneal cytology in endometrial carcinoma has led to the incorporation of peritoneal cytology into the current FIGO staging system. While cytology was shown to be prognostically relevant in patients with stage II and III disease, conflicting data exists about its significance in patients who would have been stage I but were classified as stage III solely and exclusively on the basis of positive peritoneal cytology (clinical stage I). Analysis was based on the data of 369 consecutive patients with clinical stage I endometrioid adenocarcinoma of the endometrium. Standard treatment consisted of an abdominal total hysterectomy, bilateral salpingo-oophorectomy with or without pelvic lymph node dissection. Peritoneal cytology was obtained at laparotomy by peritoneal washing of the pouch of Douglas and was considered positive if malignant cells could be detected regardless of the number of malignant cells present. Disease-free survival (DFS) was considered the primary statistical endpoint. In 13/369 (3.5%) patients, positive peritoneal cytology was found. The median follow-up was 29 months and 15 recurrences occurred. Peritoneal cytology was independent of the depth of myometrial invasion and the grade of tumour differentiation. Patients with negative washings had a DFS of 96% at 36 months compared with 67% for patients with positive washings (log-rank P<0.001). The presence of positive peritoneal cytology in patients with clinically stage I endometrioid adenocarcinoma of the endometrium is considered an adverse prognostic factor.