5562 Background: Experimental and clinical data (Gifford et al, Clin Cancer Res. 2004) indicate the potential importance of methylation in mediating resistance to carboplatin in ovarian cancer. A previous phase I trial (Appleton et al, J Clin Oncol. 2007) established the feasibility of combining carboplatin with the demethylating agent decitabine on a day 1 + 8 q4 weekly (w) schedule and PD data provided evidence of target cell demethylation. Methods: Patients (pt) with ovarian cancer relapsing 6–12 months following first line treatment were randomised to receive either 6 cycles of carboplatin AUC 6 q4 w (Arm A), or 90 mg/m 2 decitabine as a 6 hour infusion on day 1 and carboplatin AUC 6 on day 8 q4 w (Arm B). The primary endpoint was response rate. An interim analysis was planned after 11 patients were enrolled into Arm B. Results: 29 pt were enrolled. After the first 4 pt had been treated (at 90 mg/m 2 decitabine) the frequency of dose delays due to neutropenia was considered unacceptable, and therefore the starting dose of decitabine was reduced to 45 mg/m 2 for the subsequent 11 pt. 7 out of 14 pt in Arm A completed 6 cycles compared with 0 of 11 in Arm B (at 45 mg/m 2 decitabine). Grade 2/3 hypersensitivity reactions were more common in Arm B than Arm A (64% vs. 21%), as were prolonged treatment delays due to neutropenia (36% vs. 10%). At the interim analysis, in the 11 pt treated with 45mg/m 2 (Arm B), there were no RECIST responses, while 2 pt had short-lived CA125 responses (59 and 63 days). In contrast 6 of 14 patients in Arm A had RECIST responses consistent with the expected efficacy of carboplatin in this population. Conclusions: The lack of efficacy, as well as the difficulties in treatment delivery in Arm B, led the project team to conclude that the study should be closed. With this dose and schedule, decitabine is ineffective in reversing carboplatin resistance. Further investigations are ongoing to understand (a) the apparent increased incidence of hypersensitivity and (b) the trend towards reduced efficacy in Arm B. [Table: see text]
The aim of the study was to investigate the incidence of thyroid abnormalities in neck irradiated lymphoma patients. Of the 298 patients who had irradiation to the neck for lymphoma between 1966-1988, 174 were found to be alive and free of disease. These patients were invited to participate in the study. From the 174, 93 were able to participate (group 1). Two control groups were recruited; both were sex and aged matched. One group (group 2) consisted of lymphoma patients who were treated with chemotherapy (n=39) or irradiation to areas other than the neck (n=16). The other group (group 3) consisting of healthy volunteers (n=35) recruited from hospital staff and minor surgery attendees, had never had lymphoma or radiotherapy. All participants were required to complete a past medical history and thyroid symptom questionnaire, had blood taken for assays of thyroid stimulating hormone (TSH), thyroglobulin antibodies, thyroid peroxidase antibodies, sodium iodide symporter antibodies and TSH receptor antibodies and underwent ultrasound and clinical examination of the neck. A significant percentage of patients who had been irradiated in the neck had abnormalities on ultrasound, compared to groups 2 and 3 (77% vs 42% vs 24%). Abnormal TSH levels were found to be significantly more common in neck irradiated patients compared to the other groups (50% vs 9% vs 5%). There is a clear difference between neck irradiated patients and control groups. The importance of screening irradiated patients for thyroid abnormalities is re-emphasised.
Abstract Aims: Endometrial cancer is the commonest malignancy of the female genital tract. Surgery forms the cornerstone of treatment with adjuvant therapy proven to reduce local recurrence without demonstrating a clear survival benefit. The selection of adjuvant therapy is becoming increasingly more complex. The aim of this study was to investigate current adjuvant practices by reviewing outcomes of patients with endometrial cancer treated with intracavitary vaginal brachytherapy (VB). Materials & Methods: A retrospective analysis was carried out of all women with Stage II endometrial endometroid adenocarcinoma treated at Weston Park Hospital, Sheffield with adjuvant VB from 2003–2006. The data collected and analysed included histology, stage and grade of disease, radiotherapy treatment–related parameters, morbidity, recurrence rates and survival rates. Kaplan-Meier was used to analyse recurrence-free and overall survival rates. Wilson’s score was used to determine statistical significance of outcomes. Attention was focused on the method of treatment delivery, and this was compared with available literature. Results: In total, 33 patients were identified. All patients were treated with LDR 48 Gy prescribed to the surface of the applicator. Median follow-up was 36 months. Vaginal, pelvic and distant relapse rates were 9%, 15% and 18%, respectively. Recurrence-free and overall survival rates were 78.8% and 84.8%, respectively. Six of the seven patients (86%) who recurred developed distant metastases, not influenced by VB. No severe (Grade 3 or 4 toxicity) was recorded. When vaginal relapse rates were compared to published trials based on technique used, no statistically significant difference was demonstrated. Conclusion: Rates of vaginal relapses were comparable to the available literature suggesting current VB practice is an effective adjuvant local treatment. The study highlights the importance of surveillance and patient education regarding toxicity and its prevention with particular attention drawn to vaginal stenosis.
6674 Background: Optimising cytotoxic dose intensity is critical to achieving the best outcomes for patients with solid tumours. Chemotherapy dose intensification can be achieved by reducing cycle length or increasing doses of cytotoxic agents. In this study we explored the feasibility of delivering carboplatin/paclitaxel at a reduced cycle interval (10–11 days) supported by pegfilgrastim and autologous whole blood infusions. Methods: Patients with solid tumours received carboplatin AUC 6 (1 hour IV infusion) and paclitaxel 175mg/m2 (3 hour IV infusion) for a total of 6 cycles. Cycle 1 was 21 days, cycles 2–6 were administered every 10–11 days. Patients were randomised to receive pegfilgrastim 6mg, 12mg or 18mg on day 2 or filgrastim 5μg/kg from day 2 to an ANC ≥10x109/L. Prior to chemotherapy on day 1 of cycles 3–6, 750ml of whole blood was collected by venesection for re-infusion on day 2. The primary endpoint of the cycle 2–6 analysis was proportion of patients receiving cycles 2–6 at full dose (i.e. >75% of planned dose) and on schedule (i.e. every 11 days ± 3 days). Results: Fifty-three patients (37 [70%] with lung or ovarian cancer) started cycle 2 chemotherapy. A total of 39 (74%) patients completed 4 cycles of chemotherapy and 27 (51%) completed 6 cycles. Of 265 planned cycles of study chemotherapy, 201 (76%) were given on schedule. Only 8 (3%) were delayed due to slow ANC or platelet recovery. The most frequently reported serious adverse events (reported by 5 patients) were thrombocytopenia, abdominal pain and nausea. Other adverse events including bone pain were similar in incidence across the groups. Conclusions: It is feasible to administer full dose carboplatin/paclitaxel every 10–11 days with pegfilgrastim and whole blood support. There was no significant difference between filgrastim and pegfilgrastim 6, 12 and 18 mg with respect to enabling full dose on schedule and no increase in SAEs or bone pain at the higher doses. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Amgen Ltd. Amgen Amgen, Amgen Ltd. Amgen
5138 Background: Relapsed ovarian cancer has a poor prognosis but in recent years treatment has improved as new agents have been licensed. As the range of available agents becomes wider, the need increases to audit the outcomes achieved with each regimen in real clinical practice. Such audit is increasingly a requirement of UK national guidance on the appropriate use of these agents. However, it is difficult to obtain meaningful results in many centres, when the range of potential regimens is wide, and the number of patients treated for relapsed OC relatively small.Thus it was the aim of this audit to describe the patterns of chemotherapy usage and associated outcomes in patients with relapsed OC, pooling the data from 9 UK centres to provide robust results which could inform future management of the disease. Methods: Ovarian cancer patients in 9 UK hospitals who received treatment for recurrent disease between Aug 2001 and Feb 2004 were included in the analysis using a common data set. End points included response and toxicity to treatments and subsequent treatment-free interval. Results: 320 patient records were analysed. Platinum-based regimens were used in the treatment of 65% of first relapses, 32% of 2nd and 18% of 3rd relapses. Use of topotecan was 17–19% at each relapse, while use of liposomal doxorubicin (LD) increased from 2% at first relapse to 16% at 2nd and 3rd relapses. 5.8% lines of treatment were given as part of clinical trials. Response rates at any relapse were: carboplatin 47%, topotecan 21% and LD18%. Neutropenic sepsis was reported in 1.2% of carboplatin, 17% of topotecan and 3% of LD-treated patients. 27% of LD treated patients developed palmar-plantar erythema. Suspected allergic reactions were reported in 7.3% of carboplatin, 7.4% of topotecan and 3.2% of LD-treated patients. Treatment free intervals were highly variable at all lines of treatment, but the trend was for the mean interval to reduce with each relapse. Conclusions: Pooling data from several centres was a successful means of auditing relapsed OC management. Platinum-based regimens remain the mainstay of treatment, but where platinum resistance develops, topotecan and LD are worthwhile. The incidence of neutropenic sepsis with topotecan was not as high as previously reported. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, GlaxoSmithKline, Merck, Schering-Plough
5537 Background: In the absence of toxicity, carboplatin (the most widely used drug in ovarian cancer) is generally given at the same (flat) dose with each treatment cycle. However, retrospective data suggest a correlation between extent of myelosuppression and outcome, as has been observed in other diseases. Our hypothesis was therefore that intrapatient dose escalation, according to nadir blood counts, could lead to an improved outcome compared to conventional flat dosing. Methods: Patients with previously untreated stage IC to IV ovarian cancer were randomized to receive 6 cycles of carboplatin AUC 6 q3 w either with no dose modification except for toxicity (Arm A) or with dose escalations in cycles 2–6 based on nadir FBC (Arm B). The primary outcome measure was progression-free survival (PFS), and a target accrual of 1300 pts was envisaged, aimed at detecting a 20% increase in PFS with 80% power (5% 2-sided level of statistical significance). Results: From March 2004 to November 2008, 937 pts were recruited from 70 centres. Dose escalation occurred in 82% pts on Arm B. The median AUCs actually received were 6.0 (Arm A) and 6.84 (Arm B). As expected, more myelosuppression was seen in Arm B (p < 0.001 for all parameters). More grade 3/4 non-haematological toxicity was also seen in Arm B (31%, vs 22% in Arm A, p < 0.001) but there was no significant difference in global quality of life. To date, 477 PFS events have been observed out of a planned total of 950. The median PFS was 13.9m in Arm A, and 13.5m in Arm B, and the observed hazard ratio (Arm B/Arm A) is 1.04, with 95% C.I. of 0.87 to 1.24. This excludes the clinically relevant benefit of 0.83 used to design the study. A futility analysis also indicated that the probability of a statistically significant result in favour of Arm B at the planned study end was 0.12 at best. Conclusions: Following the Data Monitoring Committee recommendation, the trial has therefore been closed to recruitment, with no evidence of benefit for intra-patient dose escalation of carboplatin. A separate analysis of tissue samples, aimed at elucidating mechanisms of (single agent) carboplatin resistance is ongoing. No significant financial relationships to disclose.
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