Christian Schauer

Impact of secondary cytoreductive surgery on survival in patients with platinum sensitive recurrent ovarian cancer: Analysis of the CALYPSO trial

OBJECTIVE The role of secondary cytoreductive surgery (SCR) in platinum-sensitive recurrent ovarian cancer (ROC) remains controversial. The overall survival (OS) benefits for surgery reported in observational studies may be due to the selection of patients with better prognosis. METHODS Using data from the CALYPSO trial, OS of patients who had SCR was compared to those treated with chemotherapy alone. Multivariate analyses were performed to adjust for prognostic factors. We also tested for an interaction between baseline prognostic groupings and the benefit of surgery. RESULTS Of the 975 patients randomised in CALYPSO, 19% had SCR and 80% had chemotherapy alone. OS was longer for the SCR group than for chemotherapy alone (median, 49.9 vs. 29.7 months; adjusted hazard ratio (HR), 0.68; P = 0.004). For patients with SCR, the 3-year OS was 72% for those with no measurable disease, and 28% if residual tumour was larger than 5 cm. Patients with good prognostic features benefited the most from SCR (HR 0.43; P < 0.001). The benefit of SCR was less in patients with poorer prognostic features (test of trend P < 0.001). CONCLUSION SCR was associated with improved OS in platinum-sensitive ROC, particularly in patients with favourable prognostic characteristics. However, these findings may be due to selection bias, and hence randomised trials are still essential.

A prognostic nomogram to predict overall survival in patients with platinum-sensitive recurrent ovarian cancer

BACKGROUND Patients with platinum-sensitive recurrent ovarian cancer have variable prognosis and survival. We extend previous work on prediction of progression-free survival by developing a nomogram to predict overall survival (OS) in these patients treated with platinum-based chemotherapy. PATIENTS AND METHODS The nomogram was developed using data from the CAELYX in Platinum-Sensitive Ovarian Patients (CALYPSO) trial. Multivariate proportional hazards models were generated based on pre-treatment characteristics to develop a nomogram that classifies patient prognosis based on OS outcome. We also developed two simpler models with fewer variables and conducted model validations in independent datasets from AGO-OVAR Study 2.5 and ICON 4. We compare the performance of the nomogram with the simpler models by examining the differences in the C-statistics and net reclassification index (NRI). RESULTS The nomogram included six significant predictors: interval from last platinum chemotherapy, performance status, size of the largest tumour, CA-125, haemoglobin and the number of organ sites of metastasis (C-statistic 0.67; 95% confidence interval 0.65-0.69). Among the CALPYSO patients, the median OS for good, intermediate and poor prognosis groups was 56.2, 31.0 and 20.8 months, respectively. When CA-125 was not included in the model, the C-statistics were 0.65 (CALYPSO) and 0.64 (AGO-OVAR 2.5). A simpler model (interval from last platinum chemotherapy, performance status and CA-125) produced a significant decrease of the C-statistic (0.63) and NRI (26.4%, P < 0.0001). CONCLUSIONS This nomogram with six pre-treatment characteristics improves OS prediction in patients with platinum-sensitive ovarian cancer and is superior to models with fewer prognostic factors or platinum chemotherapy free interval alone. With independent validation, this nomogram could potentially be useful for improved stratification of patients in clinical trials and also for counselling patients.

AGO Austria recommendations for genetic testing of patients with ovarian cancer.

SummaryIn Austria, 700 women are diagnosed every year with ovarian carcinoma. Approximately 15 % of the patients with epithelial ovarian cancer have a germline mutation in the BRCA1 or BRCA2 genes. The increased incidence of breast and/or ovarian cancer in genetically related family members has given rise to the term “hereditary breast and ovarian cancer syndrome” (HBOC). Some 25–55 % of these in-family diseases are attributed to germline mutations of BRCA1 or BRCA2, and approximately 5–10 % to other known tumor predisposition syndromes. The remaining persons may carry mutations in as yet unidentified genes. HBOC caused by BRCA1 and BRCA2 mutations is an autosomal dominant disorder with high penetrance. BRCA1 and BRCA2 encode for so-called tumor suppressor proteins. Inherited functional mutations of these genes cause loss of function of the respective allele. Loss of function of the second allele causes complete loss of the corresponding protein and facilitates the development of a malignancy.The Association of Gynecologic Oncology recommends that testing for a germline mutation in BRCA1 or BRCA2 should be offered to all patients with epithelial ovarian cancer. When mutations in BRCA1, BRCA2, or other cancer-susceptibility genes have been identified, patients with ovarian carcinoma can be treated with new, innovative therapies. This recommendation is intended as a standard guideline for genetic testing of patients with an ovarian carcinoma.ZusammenfassungIn Österreich erkranken jedes Jahr etwa 700 Frauen an einem Ovarialkarzinom. Etwa 15 % der Patientinnen mit epithelialem Ovarialkarzinom sind Träger einer Keimbahnmutation im BRCA1- oder BRCA2-Gen. Aufgrund des häufig gemeinsamen Vorkommens von Mamma- und Ovarialkarzinomen spricht man vom „hereditären Mamma- und Ovarialkarzinomsyndrom“ (HBOC). Etwa 25–55 % dieser familiären Erkrankungen werden Keimbahnmutationen des BRCA1- oder BRCA2-Gens zugeschrieben, etwa 5–10 % anderen bekannten Tumordispositionssyndromen. Die verbleibenden Erkrankungen werden durch bisher nicht bekannte Gene erklärt. BRCA1- und BRCA2-Mutationen werden autosomal-dominant mit hoher Penetranz vererbt. Physiologischerweise kodieren BRCA1 bzw. BRCA2 für sogenannte Tumorsuppressorproteine. Funktionelle Mutationen dieser Gene führen zum Ausfall des Allels. Ein Ausfall auch des zweiten Allels führt zum Verlust der entsprechenden Proteine und erleichtert die maligne Transformation.Eine genetische Testung und Bestimmung einer Keimbahnmutation in BRCA1 oder BRCA2 soll allen Patientinnen mit epithelialem Ovarialkarzinom angeboten werden. Durch den Nachweis von Mutationen im Bereich sogenannter Krebssuszeptibilitätsgene (wie BRCA1 und BRCA2) können bei Patientinnen mit manifestem Ovarialkarzinom neue, innovative Therapien eingesetzt werden. Durch die vorliegende Empfehlung soll die genetische Testung von Patientinnen mit Ovarialkarzinom einheitlich definiert werden.

Carboplatin and nonpegylated liposomal doxorubicin in primary advanced or recurrent endometrial cancer: a phase 2 trial conducted by AGO Austria.

Objective Recurrent/advanced endometrial carcinoma carries a poor prognosis. Chemotherapy usually consists of cisplatin/doxorubicin and paclitaxel or the doublet of carboplatin and paclitaxel. We report on final results of the Austrian phase 2 AGO trial of nonpegylated doxorubicin citrate and carboplatin in 39 patients with primary advanced or relapsed endometrial cancer. The main primary end point is response rate, and the main secondary end point is feasibility. Methods Thirty-nine patients received 60 mg/m2 nonpegylated doxorubicin citrate and carboplatin (area under the curve, 5) every 3 weeks for 6 to 9 cycles or until progression. Best response during therapy, progression-free survival, and the toxicity profile were recorded. Results Thirteen patients (33%) had primary advanced disease, and 26 patients (67%) had recurrent disease. Seventy-five percent of the tumors were adenocarcinomas, 15% were serous carcinomas, and 5% were clear cell and mixed müllerian carcinomas. We observed 1 complete response (3%) and 16 partial responses (41%) in the intention-to-treat population. The median progression-free survival was 7.2 months, and the median overall survival was 14.7 months. Overall, 177 cycles were administered; the mean number of cycles per patient was 4.5. Ten percent of patients received 9 cycles of chemotherapy, and 44% of patients received 6 cycles of chemotherapy. Grade 3/4 neutropenia occurred in 17%, grade 3/4 anemia in 5%, and grade 3/4 thrombopenia in 12% of the cycles. In 6% of the cycles, febrile neutropenia was noticed. Grade 3/4 nausea was seen in 5% of cycles. One patient (3%) experienced cardiac toxicity and had a reduction in the left ventricular ejection fraction to below 50%. Conclusions The reported combination demonstrates considerable activity and should be evaluated further.

The european network for gynaecological oncological trial groups charta for privileged partnership

Christian Marth, ENGOT Chair, AGO-Austria, Andreas du Bois, ENGOT Vice-Chair, AGO Germany, Christian Schauer (AGO-Austria), Andreas du Bois (AGO-Germany), Antonio Casado (EORTC GCG), Ignace Vergote (BGOG), Jose Maria del Campo (GEICO), Athina Goudopoulou (HECOG), Eric Pujade-Lauraine (GINECO), Ilan Bruchim (ISGO), Nicoletta Colombo (ManGO), Sandro Pignata (MITO), Jonathan Ledermann (NCRI/MCR), Radoslav Chekerov (NOGGO), Mansoor Raza Mirza (NSGO), Anneke Westermann (DGOG), Ros Glasspool (SGTCG), Cagatay Taskiran (TSGO), Mathias Fehr (SAKK), and David Cibula (CEEGOG)

Clinical consequences of the Calypso trial showing superiority of PEG-liposomal doxorubicin and carboplatin over paclitaxel and carboplatin in recurrent ovarian cancer: Results of an Austrian gynecologic oncologists' expert meeting

ZusammenfassungDie Calypso Studie hat eine signifikante Verbesserung des progressionsfreien Überlebens mit PEG-liposomalem Doxorubicin (PLD) and carboplatin (P) im Vergleich zum Standardschema Paclitaxel (PCLTX) und P in der Zweit- oder Drittlinientherapie des Platin-sensitiven epithelialen Ovarialkarzinom ergeben [1]. Eine österreichische Expertengruppe der Gynäkologischen Onkologie hat versucht, die klinischen Konsequenzen der Daten der Calypso-Studie für die klinische Routine zu definieren. PLD + P wies eine signifikant niedrigere Rate an Alopezie und Neuropathie als das Taxan-Schema auf, Toxizitäten, die die Lebensqualität deutlich beeinträchtigen. Wegen möglicher signifikanter Thrombozytopenien sollten wöchentliche Blutbildkontrollen bei Patientinnen unter PLD + P vorgenommen werden. PLD + P ist mit einem höheren Risiko für Übelkeit und Erbrechen assoziiert. Die palmoplantare Erythrodysästhesie stellt eine signifikante Toxizität unter PLD + P dar, meist nach dem 3. oder 4. Zyklus. Prophylaxe durch das Vermeiden von Druck auf Hände und Füße scheint besonders wichtig zu sein. Ähnlich ist eine Prophylaxe der Mucositis durch die Vermeidung des Konsums heißer, scharfer oder salziger Speisen und Getränke von Bedeutung. Trockenheit der Mundschleimhaut sollte vermieden werden. Die Prämedikation mit Antiemetika und Dexamethason sollte in 5% Glucose gelöst werden, um mögliche Überempfindlichkeitsreaktionen zu vermeiden. Zusammenfassend ist der therapeutische Index für PLD + P günstiger als für PCTX + P.SummaryThe Calypso trial showed an improved progression-free survival with PEG-liposomal doxorubicin (PLD) and carboplatin (P) as compared with the standard regimen paclitaxel (PCLTX) and P in the second- or third-line treatment of platinum-sensitive epithelial ovarian cancer [1]. A panel of Austrian gynecologic oncologists discussed the clinical consequences of the data from the Calypso study for the routine practice. PLD + P had a significantly lower rate of alopecia and neuropathy than the taxane regimen, both toxicities which compromise the quality of life. Due to possible significant thrombocytopenia, the blood counts of patients undergoing PLD + P therapy should be monitored weekly. Patients receiving PLD/P are at higher risk of nausea and vomiting. Palmoplantar erythrodysesthesia (hand-foot syndrome) is a significant toxicity of PLD + P most prevalent after the third or fourth cycle. Prophylaxis consists of avoiding pressure on feet and hands and other parts of the body. Similarly, prophylaxis of mucositis seems important and includes avoiding consumption of hot, spicy and salty foods and drinks. Mouth dryness should be avoided. Premedication with antiemetics and dexamethasone dissolved in 5% glucose is done to prevent hypersensitivity to PLD. In conclusion, the therapeutic index is more favorable for PLD + P than for PCTX + P.