Low probability of disease cure in advanced ovarian carcinomas before the PARP inhibitor era.

BACKGROUND: In ovarian carcinomas, the likelihood of disease cure following first-line medical-surgical treatment has been poorly addressed. The objective was to: (a) assess the likelihood of long-term disease-free (LDF) > 5 years; and (b) evaluate the impact of the tumour primary chemosensitivity (assessed with the modelled CA-125 KELIM) with respect to disease stage, and completeness of debulking surgery. METHODS: Three Phase III trial datasets (AGO-OVAR 9; AGO-OVAR 7; ICON-7) were retrospectively investigated in an "adjuvant dataset", whilst the Netherlands Cancer Registry was used in a "neoadjuvant dataset". The prognostic values of KELIM, disease stage and surgery outcomes regarding the likelihood of LDF were assessed using univariate/multivariate analyses. RESULTS: Of 2029 patients in the "adjuvant dataset", 82 (4.0%) experienced LDF (Stage I-II: 25.9%; III: 2.1%; IV: 0.5%). Multivariate analyses identified disease stage and KELIM (OR = 4.24) as independent prognostic factors. Among the 1452 patients from the "neoadjuvant dataset", 36 (2.4%) had LDF (Stage II-III: 3.3%; IV: 1.3%). Using multivariate tests, high-risk diseases (OR = 0.18) and KELIM (OR = 2.96) were significant. CONCLUSION: The probability of LDF > 5 years after first-line treatment in 3486 patients (<4%) was lower than thought. These data could represent a reference for future studies meant to assess progress related to PARP inhibitors.

Bevacizumab Combined with Platinum-Taxane Chemotherapy as First-Line Treatment for Advanced Ovarian Cancer: Results of the NOGGO Non-Interventional Study (OTILIA) in 824 Patients.

In the single-arm non-interventional OTILIA study, patients with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage IIIB-IV ovarian cancer received bevacizumab (15 mg/kg every 3 weeks for up to 15 months) and standard carboplatin-paclitaxel. The primary aim was to assess safety and progression-free survival (PFS). Subgroup analyses according to age were prespecified. The analysis population included 824 patients (453 aged <70 years, 371 aged ≥70 years). At data cutoff, the median bevacizumab duration was 13.8 months. Grade ≥3 adverse events (AEs), serious AEs, and AEs leading to bevacizumab discontinuation were more common in older than younger patients, whereas treatment-related AEs were less common. Median PFS was 19.4 months, with no clear difference according to age (20.0 vs. 19.3 months in patients <70 vs. ≥70 years, respectively). One-year OS rates were 92% and 90%, respectively. Mean change from baseline in global health status/quality of life showed a clinically meaningful increase over time. In German routine oncology practice, PFS and safety were similar to reported randomized phase 3 bevacizumab trials in more selected populations. There was no notable reduction in effectiveness and tolerability in patients aged ≥70 years; age alone should not preclude use of bevacizumab-containing therapy. ClinicalTrials.gov: NCT01697488.

First-line bevacizumab-containing therapy for HER2-negative locally advanced/metastatic breast cancer: Real-world experience from >2000 patients treated in the multicentre AVANTI study.

AIM: The multicentre non-interventional AVANTI study assessed safety, effectiveness and patient-reported outcomes with approved first-line bevacizumab-containing regimens for HER2-negative locally recurrent/metastatic breast cancer (LR/MBC) in German routine oncology practice. METHODS: Eligible patients had HER2-negative LR/MBC, no bevacizumab contraindications and no prior chemotherapy for LR/MBC. Chemotherapy schedule, diagnostics and follow-up were at physicians' discretion. Data were collected for 1 year after starting bevacizumab, then every 6 months for 1.5 years (maximum follow-up: 2.5 years). Patients and physicians rated treatment satisfaction. Subgroup analyses were prespecified in clinically relevant populations, including triple-negative breast cancer (TNBC). RESULTS: Between November 1, 2009 and April 30, 2016, 2065 eligible patients at 346 centres received bevacizumab with paclitaxel or capecitabine. Patients receiving bevacizumab-capecitabine were less likely to have de novo disease and more likely to have TNBC, age ≥60 years and prior anthracycline/taxane and/or endocrine therapy. Median PFS was 12.6 (95% CI 11.9-13.2) months (12.8 with bevacizumab-paclitaxel, 10.5 with bevacizumab-capecitabine); median OS was 23.9 (95% CI 22.2-25.1) months. Outcomes were worse in patients with TNBC, prior anthracycline/taxane or prior endocrine therapy. Grade ≥3 adverse events occurred in 27% of patients. Treatment was discontinued for adverse events in 15%. Treatment satisfaction was rated as good or better by 304/394 responding patients (77%) at week 54 and in 1393/2065 patients (67%) by physicians overall. CONCLUSIONS: In routine clinical practice, effectiveness and safety of first-line bevacizumab-containing therapy for LR/MBC were consistent with experience from phase III trials. Patient and physician treatment satisfaction showed high concordance.

A phase III, open label, randomized multicenter controlled trial of oral versus intravenous treosulfan in heavily pretreated recurrent ovarian cancer: a study of the North-Eastern German Society of Gynecological Oncology (NOGGO).

OBJECTIVE: In recurrent ovarian cancer (ROC), there is a high demand on effective therapies with a mild toxicity profile. Treosulfan is an alkylating agent approved as oral (p.o.) and intravenous (i.v.) formulation for the treatment of recurrent ovarian cancer. Data on safety and efficacy for either formulation are rare. For the first time we conducted a randomized phase III study comparing both formulations in women with ROC. METHODS: Patients having received at least two previous lines of chemotherapy were randomly assigned to one of two treatment arms: treosulfan i.v. 7000 mg/m2 d1 q4w or treosulfan p.o. 600 mg/m2 d1-28 q8w. Primary endpoint was safety regarding hematological and gastrointestinal toxicity grade III/IV, secondary endpoints were other toxicities, clinical benefit rate (CBR), time to progression (TTP), overall survival (OS) and quality of life. RESULTS: 250 patients were treated with treosulfan i.v. (128) or treosulfan p.o. (122). In general treosulfan therapy was well tolerated in both treatment arms. Leukopenia grade III/IV occurred significantly more frequently in the p.o. arm (3.9% i.v. arm, 14.8% p.o. arm, p = 0.002). Other toxicities were similar in both arms. CBR was comparable between arms (41.4% i.v. arm, 36.9% p.o. arm). No difference in TTP (3.7 months i.v. arm, 3.5 months p.o. arm) or OS (13.6 months i.v. arm, 10.4 months p.o. arm, p = 0.087) occurred. CONCLUSIONS: Given the safety and efficacy results treosulfan is an acceptable option for heavily pretreated OC patients. Regarding the toxicity profile the i.v. application was better tolerated with less grade III and IV toxicities.

Phase III study on efficacy of taxanes plus bevacizumab with or without capecitabine as first-line chemotherapy in metastatic breast cancer.

Taxanes (T) plus bevacizumab (B) and taxanes plus capecitabine (X) showed better progression-free survival (PFS) compared to taxanes alone. Since life-threatening or highly symptomatic situations require polychemotherapy in metastatic breast cancer (MBC), combination of taxanes, capecitabine plus bevacizumab appears reasonable. TABEA (NCT01200212), a prospectively randomized, open-label, phase III trial compares taxanes (paclitaxel 80 mg/m(2) i.v. d1,8,15 q22 or docetaxel 75 mg/m(2) i.v. d1 q22) plus bevacizumab (15 mg/kg i.v. d1 q22) with (TBX) or without capecitabine (TB, 1800 mg/m(2) daily d1-14 q22) as first-line therapy in MBC. Histologically confirmed HER2-negative, locally advanced or MBC patients with a chemotherapy indication and measurable or non-measurable target lesions (RECIST criteria) were included. Primary objective was PFS. Secondary objectives were response rate and duration, clinical benefit rate (complete response, partial response, stable disease ≥24 weeks), 3-year overall survival, PFS in patients ≥65 years, toxicity, and compliance. We assumed 10 and 13.3 months PFS for TB and TBX, respectively (HR = 0.75), requiring 432 patients and 386 events. Preplanned interim futility and safety analyses after 100 events in 202 patients showed no efficacy benefit and higher toxicity for TBX. Recruitment and therapy were stopped following advice from the IDMC. Final analysis revealed a HR 1.13 [95 %CI 0.806-1.59], P = 0.474, for PFS. Overall grade 3-4 adverse event (77.3 vs. 62.1 %, P = 0.014) and serious adverse event (40.0 vs. 30.2 %, P = 0.127) rates were higher for TBX after 26.1 months median follow-up, with six deaths for TBX versus 1 for TB. Adding capecitabine to TB cannot be recommended as first-line therapy in MBC.

Multicenter Phase II Study with Weekly Bendamustine and Paclitaxel as First- or Later-Line Therapy in Patients with Metastatic Breast Cancer: RiTa II Trial.

The combination of bendamustine (B) and paclitaxel (P) as anthracycline-free treatment option in patients with advanced breast cancer has been evaluated in the previous RiTa I trial. The regimen of weekly B 70 mg/m(2) and P 90 mg/m(2) with a pause every 4th week was established as an effective regimen with low toxicity. The aim of the present RiTa II study was to investigate the potential of BP as anthracycline-free combination therapy. The primary objective was to determine the progression-free survival (PFS); secondary endpoints were safety, tolerability, overall response rate (ORR) and overall survival (OS). 26 patients were available, 15 received BP as first-line, 11 as beyond first-line treatment. 27% patients had triple-negative breast cancer (TNBC). Median PFS and OS were 7.3 months (95% confidence interval (CI): 5.5-10.9) and 14.9 months (95% CI: 9.9-22.9), respectively. The 1-year PFS rate was 20.3% and the 1-year OS rate 71.2%. The ORR was 42.3%, including 4 complete and 7 partial remissions. TNBC patients reached an ORR of 71.4%. Anthracycline-pretreated patients showed an ORR of 43.8%, confirming bendamustine's lack of cross-resistance to anthracycline agents. BP represents a favorable option with moderate toxicity in pretreated metastatic breast cancer and offers a possibility for application in anthracycline-pretreated and TNBC patients.

[Is cardiotoxicity still an issue after breast-conserving surgery and could it be reduced by multifield IMRT?]. / Ist die Kardiotoxizität der Radiotherapie im Rahmen des Brusterhalts überhaupt noch relevant, und könnte sie durch Mehrfelder-IMRT gesenkt werden?

BACKGROUND: Postoperative radiotherapy after breast cancer surgery effectively reduces local relapses. A survival benefit after breast conservation, however, has only been proven recently which was in part due to excessive cardiac mortality of patients who had been treated with radiotherapy in the past. MATERIAL AND METHODS: The literature on postoperative radiotherapy for breast cancer was reviewed with regard to cardiac toxicity as the basis for hypothesis generation. RESULTS: From numerous publications on cardiac toxicity of breast cancer radiotherapy, the following pattern emerges: in series where a high radiation dose was applied to a significant percentage of the heart (postmastectomy and postlumpectomy series) cardiac toxicity/mortality was increased versus a nonexposed cohort or for left over right disease. If, however, a relevant exposure of cardiac muscle could be more or less excluded based on the technique used (mainly more recent postlumpectomy radiotherapy), no cardiac toxicity was observed. Series for which individual dose exposure varied or could not be clarified also came to varying conclusions. Also due to retrospectively unclear dose distributions, an exact quantification of tolerance doses/effects of different geographic dose distribution patterns could not be performed to date. A particularly difficult question to answer is the threshold volume for clinically relevant cardiotoxicity with tangential radiotherapy at prescription doses. As a consequence, this precludes an estimate in which situations multifield intensity-modulated radiotherapy (IMRT) with its characteristic dose distribution pattern of a larger volume exposed to intermediate doses and higher mean/median heart doses (as shown in Figure 1) might be preferable. CONCLUSION: This review updates the database on cardiac toxicity of breast cancer radiotherapy with special emphasis regarding the issues related to the clinical use of IMRT. Multifield IMRT may reduce the cardiac risk for a small subset of patients at excessive risk with conventional tangential radiotherapy due to unfavorable thoracic geometry, for whom partial-breast radiotherapy is not an option. Due to further concern about the effects of intermediate doses to larger heart volumes, potentially increased contralateral cancer risk and the long latency of clinically apparent toxicity, the introduction of breast IMRT should be closely followed. Accompanying functional studies may have the potential to detect cardiac toxicity at an earlier time.

Early initiation of external beam radiotherapy (EBRT) may increase the risk of long-term toxicity in patients undergoing intraoperative radiotherapy (IORT) as a boost for breast cancer.

BACKGROUND: Intraoperative radiotherapy (IORT) during breast-conserving surgery is increasingly used. We analyzed the influence of the interval between an IORT boost and external beam radiotherapy (EBRT) on late toxicity. METHODS: Forty-eight patients received 20 Gy IORT (50 kV X-rays (Intrabeam, Carl Zeiss, Oberkochen, Germany) followed by 46-50 Gy EBRT with a median interval of 36 days (14-197). Late toxicity was assessed with the modified LENT SOMA score after a median of 36 months. RESULTS: Twelve patients developed a higher grade fibrosis ( degrees II-III), three teleangiectases, one a breast edema grade degrees II, six retractions, four hyperpigmentations and five pain ( degrees II-III). The median interval between IORT and EBRT was significantly shorter in these patients (n=18) compared to the 30 patients without higher grade toxicity (29.5 days vs. 39.5 days, p=0.023, Mann-Whitney U-test). CONCLUSION: Starting EBRT about 5-6 weeks after IORT appears to be associated with a decreased risk of chronic late toxicity compared with a shorter interval. The impact on local recurrence of prolonged gaps between IORT and EBRT is not known.