Quality of life in patients with advanced epithelial ovarian cancer (EOC) randomized to maintenance pazopanib or placebo after first-line chemotherapy in the AGO-OVAR 16 trial. Measuring what matters-patient-centered end points in trials of maintenance therapy.

Background: Health-related quality of life (HRQoL) was a secondary end point in AGO-OVAR 16, which randomized 940 patients with EOC after first-line chemotherapy to maintenance pazopanib (PZ) or placebo (P). Additional post hoc analyses were carried out to investigate additional patient-centered end points. Patients and methods: HRQoL was measured with EORTC-QLQ-C30, QLQ-OV28 and EQ-5D-3L. Pre-specified end points included mean differences in HRQoL between treatment arms. Exploratory analyses included quality-adjusted progression-free survival (QAPFS), impact of specific symptoms and progressive disease (PD) on HRQoL and time to second-line chemotherapy. The objective was to provide clinical perspective to the significant median PFS gain of 5.6 months with PZ. Results: There were statistically significant differences between PZ and P in QLQ-C30 global health status [5.5 points; 95% confidence interval (CI), 0.7-10.4, P = 0.024] from baseline to 25 months, but not EQ-5D-3L (0.018 points; 95% CI - 0.033 to 0.069, P = 0.485). The impact of diarrhea was captured in QLQ-OV28 Abdominal/GI-Symptoms scale (8.1 points; 95% CI 3.6-12.5, P = 0.001). QAPFS was 386 days (95% CI 366-404 days) with PZ versus 359 days (95% CI 338-379 days) with placebo (P = 0.052). PD was associated with a decline in HRQoL (P < 0.0001). Median time to second-line chemotherapy was 19.7 months with PZ and 15.0 months with P [hazard ratio (HR) 0.72, 95% CI 0.69-0.86, P = 0.0001]. Conclusions: There were small to no significant mean score differences in global HRQoL and EQ5D-3L between PZ and placebo, respectively, despite the increased toxicity of PZ. Exploratory end points including QAPFS, impact of specific symptoms on HRQoL during treatment and at PD help place the PFS gain with PZ in context and interpret the results. Additional patient-centered end points should be considered in trials of maintenance therapy in EOC beyond mean differences in HRQoL scores alone, to support the benefit to patients of prolongation of PFS. Clinical Trials Registration Number: NCT00866697.

Topotecan plus carboplatin versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabine plus carboplatin (GC) or pegylated liposomal doxorubicin plus carboplatin (PLDC): a randomized phase III trial of the NOGGO-AGO-Study Group-AGO Austria and GEICO-ENGOT-GCIG intergroup study (HECTOR).

BACKGROUND: Randomized, phase III trial to evaluate safety and efficacy of topotecan and carboplatin (TC) compared with standard platinum-based combinations in platinum-sensitive recurrent ovarian cancer (ROC). PATIENTS AND METHODS: Patients were randomly assigned in a 1:1 ratio to the experimental TC arm (topotecan 0.75 mg/m2/ days 1-3 and carboplatin AUC 5 on day 3 every 3 weeks) or to one of the standard regimes [(PC) paclitaxel plus carboplatin; (GC) gemcitabine plus carboplatin; (PLDC) pegylated liposomal doxorubicin and carboplatin] which could be chosen by individual preference but before randomization. The primary end point was progression-free survival (PFS) after 12 months. Overall survival (OS), response rate, toxicity, quality of life and treatment preference regarding standard treatment were defined as secondary end points. RESULTS: A total of 550 patients were recruited. The PFS rate after 12 months was 37.0% for TC compared with 40.2% in the standard combinations (P = 0.470). The overall response rate was 73.1% for TC versus 75.1% for standard combinations (P = 0.149). After a median follow-up of 20 months, the median PFS was 10 months [95% confidence interval (CI) 9.4-10.6] and did not differ between both arms (P = 0.414). The median OS was 25 months in the TC arm versus 31 months in the standard arm (95% CI: 22.4-27.6 resp. 26.0-36.0; P = 0.163). Severe hematologic toxicities (grade 3/4) were rare in the experimental arm (P < 0.001), with 17.4% leucopenia, 27.8% neutropenia and 15.9% thrombopenia. CONCLUSION: The combination of carboplatin and topotecan was well tolerated with significant lower rates of severe hematological toxicities but did not improve PFS or OS in platinum-sensitive relapsed ovarian cancer compared with established standard regimens.

[Peripartum aortic dissection]. / Peripartale Aortendissektion.

A 29-year-old primagravida developed severe chest pains during labor. An emergency caesarean section was performed as the symptoms persisted. Imaging diagnosis immediately after delivery revealed an acute proximal (type A) aortic dissection. The patient was transferred to the nearest cardiothoracic surgery centre and successful emergency surgical aortic repair was performed. The perioperative course of a type A aortic dissection during pregnancy and labor is complicated by time pressure, diagnostic restrictions until delivery and potentially fatal uterine bleeding during cardiopulmonary bypass and hypothermic cardiac arrest. This case report describes the diagnosis and the surgical, anesthesiological and gynecological management of this life-threatening peripartum complication.

Carboplatin-paclitaxel-induced leukopenia and neuropathy predict progression-free survival in recurrent ovarian cancer.

BACKGROUND: We assess the prognostic value of chemotherapy-induced leukopenia and sensory neuropathy in the CALYPSO trial patients treated with carboplatin-paclitaxel (CP) or carboplatin-liposomal doxorubicin (CPLD). METHODS: We performed a landmark analysis at first month after randomisation to correlate leukopenia (nadir white blood cell <4.0 × 10(9) per litre or severe infection) during cycle 1 of chemotherapy with progression-free survival (PFS). Using time-dependent proportional-hazards models, we also investigated the association between neuropathy and PFS. RESULTS: Of 608 patients with nadir blood and did not receive growth factors, 72% (CP=70%, CPLD=73%) had leukopenia. Leukopenia was prognostic for PFS in those receiving CP (adjusted hazard ratio (aHR) 0.66, P=0.01). Carboplatin-liposomal doxorubicin was more effective than CP in patients without leukopenia (aHR 0.51, P=0.001), but not those experiencing leukopenia (aHR 0.93, P=0.54; interaction P=0.008).Of 949 patients, 32% (CP=62%, CPLD=28%) reported neuropathy during landmark. Neuropathy was prognostic for PFS in the CP group only (aHR 0.77, P=0.02). Carboplatin-liposomal doxorubicin appeared to be more effective than CP among patients without neuropathy (aHR 0.70, P<0.0001), but not those with neuropathy (aHR 0.96, P=0.81; interaction P=0.15). CONCLUSION: First-cycle leukopenia and neuropathy were prognostic for patients treated with CP. Efficacy of CP treatment was similar to CPLD in patients who developed leukopenia. These findings support further research to understand the mechanisms of treatment-related toxicity.

Ovarian cancer in elderly patients: carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in late relapse: a Gynecologic Cancer Intergroup (GCIG) CALYPSO sub-study.

BACKGROUND: CALYPSO (CAeLYx in Platinum Sensitive Ovarian) patients compared carboplatin-pegylated liposomal doxorubicin (C-PLD) with carboplatin-paclitaxel (C-P) in patients with late-relapsing recurrent ovarian cancer (ROC). We analyzed outcomes in patients ≥70 years. PATIENTS AND METHODS: Nine hundred and seventy-six patients with taxane-pretreated ROC relapsing >6 months after first- or second-line platinum-based therapy were randomly assigned to 4-weekly C area under the curve (AUC) 5 plus PLD 30 mg/m(2) or 3-weekly C AUC 5 plus P 175 mg/m(2) for six or more cycles. RESULTS: One hundred and fifty-seven (16%) patients ≥70 years (median: 74 years, C-PLD; 73 years, C-P; range 70-82 years) were included (n = 71, C-PLD; n = 86, C-P). In comparing elderly and younger, elderly patients experienced fewer grade ≥2 allergic reactions (P = 0.005) but more grade ≥2 sensory neuropathy (P = 0.007). Myelosuppression did not differ with age. Elderly patients completed planned treatment as frequently as younger (79%, C-PLD; 82%, C-P). In comparing arms within elderly patients, C-P was associated with more grade ≥2 alopecia, sensory neuropathy, arthralgia/myalgia (P < 0.001 for all), severe leukopenia plus febrile neutropenia; C-PLD was associated with more grade ≥2 hand-foot syndrome (P = 0.005). Median progression-free survival was 11.6 months (C-PLD) and 10.3 months (C-P; P = 0.44). CONCLUSIONS: Patients ≥70 years experienced more neuropathy, with a higher incidence in the C-P arm. Similar to all study patients, C-PLD provided a better therapeutic index with less toxicity than C-P in elderly women with platinum-sensitive ROC.

Can routine gynecologic examination contribute to the diagnosis of cervical involvement by primary endometrial cancer?

OBJECTIVE: There are few data in the literature as to whether findings at routine preoperative gynecologic examination of patients with primary endometrial cancer including cervical cytology, colposcopy and rectovaginal bimanual pelvic exam could predict cervical extension of the disease. METHODS AND MATERIALS: The present retrospective study was undertaken to preoperatively identify potential clinical parameters associated with the histological diagnosis of cervical involvement by primary endometrial cancer in the hysterectomy specimen. We reviewed the records of 104 patients with Stage II endometrial cancer treated at our institution between 1985 and 2005 by simple or radical abdominal hysterectomy with special emphasis on cervical Pap smear, colposcopy, cervical palpation as well as rectal parametrial assessment. Patients with Stage I disease operated on before and after each study patient were selected as controls (n = 208). Patients with more advanced disease were excluded. RESULTS: Overall, 312 records of patients with primary endometrial cancer were reviewed. Patients with Stage II disease had a significantly lower prevalence (p < 0.0001) of endometrioid carcinomas and a significantly higher (p < 0.01) prevalence of G3 tumors compared to the control patients. Pap smears and colposcopic findings were abnormal in 39% of patients with Stage II and in 9% and 10% of patients with Stage I disease (p < 0.0001). Of patients with Stage II disease, 42% had a suspicious cervical palpation compared to only 4% of patients with Stage I disease (p < 0.0005). Parametrial assessment was suspicious in 16% of patients with Stage II disease and in no patient with Stage I disease (p < 0.001). CONCLUSION: The four routine clinical parameters Pap smear, colposcopy, cervical palpation and rectal parametrial examination are significantly more often pathologic in patients with Stage II than in Stage I disease. The majority of patients with Stage II disease had at least one of these tests positive. Thus they may be useful to preoperatively detect cervical involvement by primary endometrial cancer.

Prevalence of pre-malignant and malignant lesions in prophylactic mastectomy specimens of BRCA1 mutation carriers: comparison with a control group.

PURPOSE: BRCA1 mutation carriers are at high risk for breast cancer (BC). The risk management strategy may include radiological investigations for early detection or prophylactic mastectomy (PM). For a mutation carrier, PM may be more significant than surveillance alone when pre-malignant and malignant changes occur increasingly in mastectomy specimens, given normal findings on radiological investigations. In the present study we retrospectively investigated the differences between histological findings in PM specimens of BRCA1 carriers and those of a control group. METHODS: Twenty-four healthy and 28 affected carriers in the presence of normal preoperative radiological findings were included in the study. To compare the frequency of pre-malignant and malignant lesions in PM specimens, a control group matched for age and disease status was included. T-tests for independent samples and Wilcoxon's signed-rank test were used for comparison of groups. RESULTS: The entire study group differed significantly from the control group (42.3 vs. 5.8%; P < 0.001) in terms of the occurrence of pre-malignant and malignant lesions. Both, the sub-group comparison of healthy mutation carriers as well as diseased carriers with their controls, showed a significant difference in terms of the occurrence of pre-malignant and malignant changes (45.8 vs. 0%; P = 0.002; 39.3 vs. 10.7%; P = 0.03). In PM specimens of mutation carriers, carcinomas were identified in 5.8% (3/52) and pre-malignant changes in 36.5% (19/52). CONCLUSIONS: BRCA1 mutation carriers should be informed of the fact that pre-malignant and even malignant changes are frequently found in PM specimens despite normal radiological findings.

Interferon-gamma in combination with carboplatin and paclitaxel as a safe and effective first-line treatment option for advanced ovarian cancer: results of a phase I/II study.

We have previously shown that interferon-gamma 1b (IFN-gamma) in combination with cyclophosphamide and cisplatin significantly prolongs progression-free survival in ovarian cancer. In this phase I/II study, we examined if administration of IFN-gamma is also safe in combination with the current standard treatment, paclitaxel and carboplatin. Thirty-four patients with newly diagnosed advanced epithelial ovarian cancer, FIGO stage III/IV, were treated for six to nine cycles with paclitaxel (175 mg/m(2)) and carboplatin (area under the curve [AUC] 5) every 3 weeks. IFN-gamma was administered in an escalating dose from 6 days/cycle with 0.025 mg sc up to 9 days/cycle with 0.1 mg sc. As expected, administration of IFN-gamma was associated with flu-like symptoms. Grade 3/4 neutropenia was observed in 74% (25 out of 34) of patients. Other side effects, in particular peripheral neuropathies, were within the previously observed ranges for the paclitaxel plus carboplatin combination. Overall response rate (complete or partial response) in patients who received either six or nine doses (0.1 mg) of IFN-gamma/cycle (n = 28) was 71%. IFN-gamma is safe in combination with carboplatin and paclitaxel for first-line treatment of patients with advanced ovarian cancer. This combination should be further evaluated as an immunotherapeutic treatment option for ovarian cancer.

Long-term control of bone marrow carcinosis and severe thrombocytopenia with standard-dose chemotherapy in a breast cancer patient: a case report.

BACKGROUND: Primary metastatic breast cancer with bone marrow involvement and pronounced thrombocytopenia is rare. The myelosuppressive effect of most cytotoxic drugs limits chemotherapy in patients with cytopenia due to marrow involvement. CASE REPORT: A 62-year-old patient, who presented with locally and systemically advanced breast cancer, is reported. The initial work-up revealed bone marrow carcinosis with thrombocytopenia of less than 20,000/mm3 lung and osseous metastases without signs of suppressed erythropoiesis and leucopoiesis. The patient was stabilized with 6 different standard-dose chemotherapy regimens, antihormonal therapy, and trastuzumab before dying 57 months after first diagnosis. The patient received only platelet transfusions on 2 instances with platelets of 2,000/mm3. CONCLUSION: This case illustrates that aggressive standard chemotherapy may be feasible in selected patients with bone marrow carcinosis-associated thrombocytopenia without major bleeding episodes.

Combined PEG liposomal doxorubicin and gemcitabine are active and have acceptable toxicity in patients with platinum-refractory and -resistant ovarian cancer after previous platinum-taxane therapy: a phase II Austrian AGO study.

OBJECTIVES: Platinum resistance is a significant problem in patients with ovarian cancer. The aim of this phase II study was to define the response rates, the progression-free survival and the toxicity profile of the combination of PEG liposomal doxorubicin (L-DXR) and gemcitabine (GEM). MATERIAL AND METHODS: Thirty one patients with histologically confirmed platinum-refractory or -resistant epithelial ovarian cancer were scheduled to receive 6 cycles of L-DXR 30 mg/m(2) on day 1 as well as GEM 650 mg/m(2) on days 1 and 8 every 28 days. RESULTS: The median number of chemotherapy cycles given was 4. The mean dose intensity for L-DXR and GEM on day 1 was 96% and 97%, respectively. The mean dose intensity for GEM on day 8 was 93%. The overall response rate was 33% (10 of 30 evaluable patients; 20% complete responses). The median progression-free survival was 3.8 months, and the median overall survival was 15.8 months, respectively. Toxicity was acceptable. One quarter of patients developed grade 3 or 4 neutropenia, but none developed febrile neutropenia. Palmoplantar erythrodysesthesia (PPE) grades 2 and 3 occurred in 13% and 3% only, respectively, and no grade 4 PPE was observed. Grades 1 to 3 stomatitis was found in 58% of patients (10% grade 3). CONCLUSION: The combination of L-DXR and GEM is an active and acceptably tolerated option in the treatment of patients with platinum-resistant and -refractory ovarian cancer. Dose reductions seem advisable in the case of > or =grade 2 stomatitis and/or PPE > or =grade 2.

[Wound rupture after Misgav-Ladach cesarean section: a case report]. / Platzbauch nach Misgav-Ladach-Sektio Ein Fallbericht.

INTRODUCTION: We describe a patient with wound rupture and burst abdomen after cesarean section with the Misgav-Ladach technique. CASE REPORT: A 33-year-old woman underwent primary cesarean section at 36 + 5 weeks gestation for a fetal indication. The procedure was done according to the Misgav-Ladach technique, i.e. the uterus was closed with a one-layer continuous locking stitch and the visceral and parietal peritoneal layers were left open. The rectus sheath was stitched with a continuous nonlocking stitch, the skin was closed with a continuous intracutaneous suture. On the seventh postoperative day, omentum was seen extruding from the skin incision. Reexploration showed that the suture of the rectus sheath had ruptured. The further postoperative course was uneventful. CONCLUSION: Although no general recommendations can be deduced from a single case, further reports on any complications of this technique will show whether it is as safe as believed until now.

Palliative cytostatic treatment of cervical carcinoma.

UNLABELLED: PURPOSE OF THE ARTICLE: In patients recurring after primary therapy for cervical cancer, treatment remains palliative. In the present article we focus on treatment results with single cytostatic drugs or combinations in randomized trials in squamous cell cervical cancer. RESULTS: In one randomized trial, monotherapy with platinum analogues lead to overall remission rates between 11% and 15% only. The median overall survival ranged between 5.6 and 6.5 months. Various combinations lead to overall remission rates between 21% and 31% and the median overall survival ranged between 7.3 and 14.3 months. The most active combinations were cisplatin/bleomycin/mitomycin C/vindesine, cisplatin/paclitaxel, and cisplatin/irinotecan. There are several smaller studies with cystostatic therapy in cervical adenocarcinoma. However, using 5-fluoruracil, ifosfamide, paclitaxel, or cisplatinum, only response rates between 15 and 30% can be achieved. Predictors of a favorable chemotherapy response include a higher performance status, higher age, extrapelvic recurrence sites (especially lung metastases), a recurrence-free interval > 1 year, and no previous radiotherapy and chemotherapy. CONCLUSION: In conclusion, palliative cytostatic therapy with single agents has moderate activity. Combinations are more active but also more toxic. In general, chemotherapy needs to be used earlier in the course of disease when tissue vascularization is preserved.

Can bowel endoscopy predict colorectal surgery in patients with an adnexal mass?

The objective of this retrospective study was to identify the ability of preoperative endoscopy of the lower gastrointestinal tract and other tests to predict large bowel resection in patients with an adnexal mass. We reviewed 573 patients with a suspected adnexal mass admitted for surgery between 1987 and 1997. Two hundred fifty four patients (44%) had preoperative sigmoidoscopy (n = 97) or colonoscopy (n = 157). We identified patients who underwent a colorectal operation as part of their surgery and correlated surgical findings with the results of preoperative endoscopy, preexisting clinical symptoms, preoperative pelvic exam and ultrasonography, and the CA125 level. The sensitivity and positive predictive value of bowel endoscopy for predicting large bowel surgery were 18% and 59%, respectively. Multivariate analysis showed preexisting bowel-related symptoms, a pelvic exam suggestive of malignancy, a CA125 value >1000 U/ml, and infiltration of the colorectal wall at bowel endoscopy to be independently associated with subsequent colorectal surgery. We conclude that preoperative bowel endoscopy cannot accurately predict colon resection in patients with a suspected adnexal mass. Preexisting bowel-related symptoms, a pelvic exam suggestive of malignancy and a CA125 value >1000 U/ml are associated with subsequent colorectal surgery.

Long-term disease-free survival after breast cancer metastatic to the ovary.

The prognosis of patients with breast cancer symptomatically metastatic to the ovary is almost uniformly poor. In this case report, we present a 33-year-old para-4 with a symptomatic metastasis to the ovary. Previously, a modified radical mastectomy with adjuvant radiotherapy had been performed for invasive ductal carcinoma of the left breast. Laparotomy showed a 13-cm tumor of the left ovary; frozen section histology showed malignancy consistent with the previous breast cancer. The patient received adjuvant combination chemotherapy. About 5 years later, a carcinoma of the right breast was treated with conservative surgery and adjuvant radiation and chemotherapy. After a further 4 years, a recurrence at the left chest wall was treated with radiation. At the last follow-up, more than 13 years after the first breast cancer and 12 years after the ovarian metastasis, the patient was alive and well without evidence of disease. Bilateral oophorectomy is a therapeutic option in premenopausal patients with localized or advanced breast cancer. Our patient experienced long-term disease-free survival following an isolated metastasis to one ovary. This represents the first report of long-term survival of such a patient in the literature.

Prognostic parameters in carcinosarcomas of the uterus: a clinico-pathologic study.

BACKGROUND: Carcinosarcomas of the uterus are highly aggressive malignant neoplasms with early lymphatic and hematogenous spread. The most important prognostic factor in carcinosarcoma is the extent of the tumor at the time of diagnosis. The prognostic impact of other factors such as myometrial invasion, menopausal age, age, parity and adjuvant therapy is still being discussed controversially. MATERIALS AND METHODS: Nineteen patients with histologically proven carcinosarcoma were included in the analysis. The patients were staged according to a modification of the International Federation of Gynecology and Obstetrics (FIGO) staging system for endometrial cancer. For each patient, the histological material was reviewed by an experienced pathologist. Carcinosarcoma was defined histologically as any tumor of uterine origin composed of carcinomatous and sarcomatous components. RESULTS: The median follow-up time was 91 months (25% quartile, 47 months; 75% quartile, 145 months). The median overall survival of the 19 patients was 59 months, resulting in a 5-year overall survival rate of 43%. Three out of the nineteen (16%) patients demonstrated progressive disease while 6 out of 10 (32%) patients developed recurrent disease with a median disease free survival of 16 months (range 8-54). Eleven out of nineteen (58%) patients died of the disease. A univariate model revealed that early tumor stage (stage 1) (p<0.023), low myometrial invasion (p<0.017) and late onset of the menopause (p<0.050) were significantly associated with a lengthened overall survival in patients with carcinosarcoma. Age (p=0.34), parity (p=0.16) and adjuvant radiotherapy (p=0.45) did not influence overall survival of patients with carcinosarcoma. CONCLUSION: Early tumor stage, low myometrial invasion and late onset of the menopause are associated with a lengthened overall survival in patients with carcinosarcoma.