B. Richter

Addition of epirubicin as a third drug to carboplatin-paclitaxel in first-line treatment of advanced ovarian cancer: a prospectively randomized gynecologic cancer intergroup trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group and the Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens.

PURPOSE Despite the progress that has been achieved, long-term survival rates in patients with advanced ovarian cancer are still disappointing. One attempt to improve results could be the addition of non-cross-resistant drugs to platinum-paclitaxel combination regimens. Anthracyclines were among the candidates for incorporation as a third drug into first-line regimens. PATIENTS AND METHODS We performed a prospectively randomized phase III study comparing carboplatin-paclitaxel (TC; area under the curve 5/175 mg/m2, respectively) with epirubicin 60 mg/m2 added to the same combination (TEC) in previously untreated patients with advanced epithelial ovarian cancer. All drugs were administered intravenously on day 1 of a 3-week schedule for a planned minimum of six courses. RESULTS Between November 1997 and February 2000, 1,282 patients were randomly assigned to receive either TC (635 patients) or TEC (647 patients), respectively. Grade 3/4 hematologic and some nonhematologic toxicities (nausea/emesis, mucositis, and infections) occurred significantly more frequently in the TEC arm. Accordingly, quality-of-life analysis showed inferiority of TEC versus TC. Median progression-free survival time was 18.4 months for the TEC arm and 17.9 months for the TC arm (hazard ratio [HR], 0.95; 95% CI, 0.83 to 1.07; P = .3342). Median overall survival time was 45.8 months for the TEC arm and 41.0 months for the TC arm (HR, 0.93; 95% CI, 0.81 to 1.08; P = .3652). Similar nonsignificant differences were observed when strata were analyzed separately. CONCLUSION Addition of epirubicin to TC did not improve survival or time to treatment failure in patients with advanced epithelial ovarian cancer; therefore, it cannot be recommended for clinical use in this population.

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.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.

Topotecan versus treosulfan, an alkylating agent, in patients with epithelial ovarian cancer and relapse within 12 months following 1st-line platinum/paclitaxel chemotherapy. A prospectively randomized phase III trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group (AGO-OVAR).

OBJECTIVE Effective therapies with a low rate of side effects are warranted in the 2nd-line setting in ovarian cancer. Both topotecan and the alkylating agent treosulfan have demonstrated efficacy in this patient group and are broadly used in Germany. Therefore, we started a prospectively randomized phase III trial comparing these two drugs in early recurrent ovarian cancer. METHODS Patients having relapsed after platinum-taxane therapy were randomized to receive either topotecan or treosulfan. Stratification depended on platinum sensitivity (stratum 1: up to 6 months after primary chemotherapy, stratum 2: 6 to 12 months). RESULTS A total of 274 patients were treated either with topotecan (136 patients) or treosulfan (138). Hematologic toxicity was significantly more frequent with topotecan but without severe clinical consequences. Non hematologic toxicity was similar in both study arms. Overall survival was significantly longer with topotecan (p=0.0023), with a median of 55.0 weeks versus 41.0 weeks as well as progression-free survival (p=0.0020) with a median of 23.1 weeks versus 12.7 weeks. Similar results were found for stratum 2 subgroup. Overall response rate was 27.5% for topotecan and 16.0% for treosulfan (p=0.0307). In stratum 1 progression-free survival was 18.1 weeks for topotecan and 9.4 weeks for treosulfan (p=0.0476), but there was no difference in overall survival in this prognostic poor subgroup. CONCLUSIONS This randomized phase III trial could detect superiority of topotecan versus treosulfan in patients with recurrent disease after platinum-paclitaxel combination therapy. Our experience indicates that optimization of systemic treatment could improve outcome even in this poor prognostic subgroup of patients with relapsed ovarian cancer.

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.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.

Randomized phase II trial of carboplatin and paclitaxel with or without lonafarnib in first-line treatment of epithelial ovarian cancer stage IIB-IV

OBJECTIVES This study evaluates whether a molecular targeted therapy with the farnesyltransferase inhibitor lonafarnib added to standard chemotherapy in first-line treatment of advanced ovarian cancer (OC) could improve progression-free (PFS) and overall survival (OS). PATIENTS AND METHODS We performed a prospective randomized phase II study to compare standard therapy carboplatin (C; AUC 5) and paclitaxel (T; 175 mg/m(2)) in primary advanced OC with or without lonafarnib (L). Lonafarnib was given in a dose of 100mg orally twice a day during chemotherapy and was increased afterwards to 200mg up to six months as a maintenance therapy. RESULTS 105 patients were recruited (53 patients were randomized to receive LTC, 52 to TC). Hematologic toxicity was similar in both arms. Grade 3 and 4 non-hematological toxicity, occurred significantly more often with LTC (23% versus 4%, p=0.005) and was associated with a higher dropout rate. PFS and OS were not significantly different among both arms. The LTC arm showed inferiority in the stratum with residual tumor of more than 1cm: median PFS was 11.5 months (95% CI: 7.4-14.2) compared with 16.4 (95% CI: 10.3-40.4) for TC (p=0.0141; HR=0.36 (95% CI: 0.15-0.84)) with median OS 20.6 months (95% CI: 13.1-31.0) and 43.4 months (95% CI: 15.7-) for the TC arm (p=0.012; HR=0.32 (95% CI: 0.13-0.8)). CONCLUSION The addition of lonafarnib did not improve PFS or OS. Patients with a residual tumor of more than 1cm had significantly shorter PFS and OS. Incorporation of lonafarnib into future studies for primary therapy of OC is not recommended.

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.

Factors Influencing Decision-Making for or against Adjuvant and Neoadjuvant Chemotherapy in Postmenopausal Hormone Receptor-Positive Breast Cancer Patients in the EvAluate-TM Study

Background: Decision-making for or against neoadjuvant or adjuvant chemotherapy in postmenopausal patients with hormone receptor-positive breast cancer does not follow any clear guidelines, and some patients may unnecessarily undergo chemotherapy and be exposed to the associated toxicity. The aim of this study was to identify the patient population for whom this issue may bear relevance. Methods: Patients being treated with letrozole in the prospective multicenter noninterventional EvAluate-TM study were recruited. The percentage of patients receiving chemotherapy and factors associated with chemotherapy administration were identified. Results: In all, 3,924 (37.4%) patients received chemotherapy before treatment with letrozole. Of these, 293 (20%) underwent neoadjuvant therapy. Younger age was predictive for both adjuvant and neoadjuvant therapy. Overall, decisions in favor of administering chemotherapy are more likely to be made in patients with a higher body mass index (BMI), and neoadjuvant chemotherapy is administered at a higher rate in women with a lower BMI. Concomitant medication influenced the overall decision-making regarding chemotherapy, irrespective of whether it was given on a neoadjuvant or adjuvant basis. Conclusion: There is an ongoing debate as to whether all of the many patients who receive chemotherapy actually benefit from it. Neoadjuvant chemotherapy is frequently administered in this patient population, and this should encourage further research to resolve current clinical and research issues.

Prognose nach isoliertem Lokalrezidiv beim Vulvakarzinom – eine Subgruppenanalyse der AGO-CaRE-1 Studie

Hintergund/Zielsetzung: Abhangig vom Lymphknotenstatus entwickeln 15 – 40% der Patientinnen mit Vulvakarzinom ein Lokalrezidiv. Ein isoliertes Rezidiv im Bereich der Vulva gilt dabei als wenig relevant fur die weitere Prognose. Methoden: Die AGO-CaRE-1 Studie ist eine retrospektive Datensammlung zu Behandlungsstrategien und Prognosefaktoren des Vulvakarzinoms. Insgesamt wurden 1618 Patientinnen mit vulvarem Plattenepithelkarzinom FIGO Stadium ≥1B, behandelt an 29 deutschen Zentren 1998 – 2008, erfasst. Diese Subgruppenanalyse untersucht Patientinnen, die im Krankheitsverlauf ein isoliertes Lokalrezidiv entwickelten. Ergebnisse: 1249/1618 (77,2%) Patientinnen erhielten ein operatives Staging der Leiste und hatten einen bekannten Nodalstatus. Die meisten zeigten lokal begrenzte Primartumore [1124/1249 (90,0%) pT1b/pT2], die R0 reseziert wurden [1022/1249 (81,8%)]. 447/1249 (35,8%) Patientinnen waren nodalpositiv. Bei 324 (25,9%) wurde eine adjuvante Therapie durchgefuhrt. Das mediane Follow-up betrug 39,4 Monate. 360 Patientinnen (28,8%) entwickelten ein Rezidiv; davon 193 (53,6%) isoliert im Bereich der Vulva nach medianen 17,1 Monaten. Initial erhielten 38 (19,7%) dieser Patientinnen eine Radiotherapie der Vulva. Die Therapie des Lokalrezidives umfasste die alleinige Operation in 104 (53,9%), eine Operation und Radiotherapie in 40 (20,7%) und eine Radio(chemo)therapie in 14 (7,3%) Fallen [19 (9,8%) erhielten keine Rezidivtherapie und bei 16 (8,3%) war die Therapie unbekannt]. 58 (30,1%) entwickelten ein zweites Rezidiv in den folgenden Lokalisationen: 40 (20,7%) Vulva, 15 (7,8%) Leiste, 7 (3,6%) Becken, 12 (6,2%) Fernmetastasen, 2 (1,0%) unbekannt (multiple Nennung moglich). Die 1-Jahres-Rezidivfreie-Uberlebensrate nach Lokalrezidiv lag bei 58,5%. Das 3- und 5-Jahres-Gesamtuberleben betrug 76,7% bzw. 66,9% verglichen mit 85,9% und 80,6% bei Patientinnen ohne Lokalrezidiv. Zusammenfassung: Entgegen der allgemeinen Annahme zeigen AGO-CaRE-1 Patientinnen mit Lokalrezidiv eine beeintrachtigte Prognose. Ein wesentlicher Anteil der Betroffenen entwickelt ein Zweitrezidiv nach initial isoliertem Lokalrezidiv.

Entwicklung der Therapie des Ovarialkarzinoms

Die Kombination von Cisplatin und Paclitaxel erwies sich in zwei randomisierten Pha- se-III-Studien gegenuber dem alteren Standard (Platin plus einem Alkylans) uberlegen [1,2] und wurde deshalb als neuer Standard in der Primartherapie des fortgeschrittenen Ovarialkarzinoms akzeptiert. Die besseren Resultate wurden mit mehr Toxizitat, speziell Neurotoxizitat, erkauft. Die Substitution von Cisplatin durch Carboplatin sollte den Effektivitatsvorteil dieser neuen Kombination mit einem gunstigeren Toxizitatsprofil verbinden. 7 Phase-I/II-Studien entwickelten eine Kombination von Carboplatin-Paclitaxel [3,4, 5,6,7,8,9]; die Erfahrungen dieser Studien fuhrten zur Initiierung von 3 Pha- se-III-Studien zum Vergleich der Cisplatin-Paclitaxel-Standardtherapie mit einer Carbo- platin-Paclitaxel-Kombination. Die Interimsanalyse der AGO-Studie OVAR-3 [10] wird hier vorgestellt. Zwischen 10/95 und 11/97 wurden 798 Patientinnen in diese prospektiv randomisierte Studie eingeschlossen. Die Therapiearme bestanden aus Carboplatin dosiert nach AUC 6 [11] plus Paclitaxel 185 mg/m2 (Arm A) und Cisplatin 75 mg/m2 plus Paclitaxel 185 mg/m2 (Arm B). Paclitaxel wurde als 3-Stunden-Infusion verabreicht, die Pramedikation bestand aus einer Einmaldosis von Dexamethason, einem 5-HT3-, einem H1 und einem H2-Antagonisten. In beiden Armen wurden 6 Zyklen alle 3 Wochen verabreicht. 790 der 798 rekrutierten Patientinnen erfullten die Einschluskriterien mit einem Ovarialkarzinom FIGO IIB-IV und einem Intervall ≤ 6 Wochen zur Primaroperation.