Domenica Lorusso

Phase III Trial of Gemcitabine Compared With Pegylated Liposomal Doxorubicin in Progressive or Recurrent Ovarian Cancer

PURPOSE We aimed at investigating the efficacy, tolerability, and quality of life (QOL) of gemcitabine (GEM) compared with pegylated liposomal doxorubicin (PLD) in the salvage treatment of recurrent ovarian cancer. PATIENTS AND METHODS A phase III randomized multicenter trial was planned to compare GEM (1,000 mg/m(2) on days 1, 8, and 15 every 28 days) with PLD (40 mg/m(2) every 28 days) in ovarian cancer patients who experienced treatment failure with only one platinum/paclitaxel regimen and who experienced recurrence or progression within 12 months after completion of primary treatment. RESULTS One hundred fifty-three patients were randomly assigned to PLD (n = 76) or GEM (n = 77). Treatment arms were well balanced for clinicopathologic characteristics. Grade 3 or 4 neutropenia was more frequent in GEM-treated patients versus PLD-treated patients (P = .007). Grade 3 or 4 palmar-plantar erythrodysesthesia was documented in a higher proportion of PLD patients (6%) versus GEM patients (0%; P = .061). The overall response rate was 16% in the PLD arm compared with 29% in the GEM arm (P = .056). No statistically significant difference in time to progression (TTP) curves according to treatment allocation was documented (P = .411). However, a trend for more favorable overall survival was documented in the PLD arm compared with the GEM arm, although the P value was of borderline statistical significance (P = .048). Statistically significantly higher global QOL scores were found in PLD-treated patients at the first and second postbaseline QOL assessments. CONCLUSION GEM does not provide an advantage compared with PLD in terms of TTP in ovarian cancer patients who experience recurrence within 12 months after primary treatment but should be considered in the spectrum of drugs to be possibly used in the salvage setting.

A Laparoscopy-Based Score To Predict Surgical Outcome in Patients With Advanced Ovarian Carcinoma: A Pilot Study

BackgroundOur objective was to set up a more objective quantitative laparoscopy-based model in predicting the chances of optimal cytoreductive surgery in advanced ovarian cancer patients.MethodsSixty-four advanced ovarian cancer patients were submitted to both laparoscopy and standard longitudinal laparotomy sequentially, to define the chances of optimal debulking surgery (residual disease ≤1 cm). Three patients could not be evaluated by laparoscopy because of the presence of multiple and tenacious adherences. Sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy were calculated for each laparoscopic parameter. On the basis of the statistical probability of each factor to predict surgical outcome, seven laparoscopic features were selected for inclusion in the final model. Each parameter was assigned a numerical score based on the strength of statistical association, and a total predictive index value was tabulated for each patient. Receiver operating characteristic curve analysis was used to assess the ability of the model to predict surgical outcome.ResultsAfter debulking surgery, 41 (67.2%) of 61 patients were left with optimal residual disease. The presence of omental cake, peritoneal carcinosis, diaphragmatic carcinosis, mesenteric retraction, bowel and/or stomach infiltration, and liver metastases satisfied the basic inclusion criteria and were assigned a final predictive index value of 2. In the final model, a predictive index score ≥8 identified patients undergoing suboptimal surgery with a specificity of 100%. The positive predictive value was 100%, and the negative predictive value was 70%.ConclusionsThe reliability of laparoscopy in assessing the chance of optimal cytoreduction can be improved by using a simple scoring system.

Prospective validation study of a predictive score for operability of recurrent ovarian cancer: The multicenter intergroup study DESKTOP II. A project of the AGO kommission OVAR, AGO study group, NOGGO, AGO-Austria, and MITO

Purpose: The DESKTOP I trial proposed a score for the prediction of complete cytoreduction in recurrent ovarian cancer. Resectability was assumed if 3 factors were present: (1) complete resection at first surgery, (2) good performance status, and (3) absence of ascites. The DESKTOP II trial was planned to verify this hypothesis prospectively in a multicenter setting. Methods: Participating centers prospectively enrolled all consecutive patients with platinum-sensitive first or second relapse. The score was applied to all patients, but centers were free to decide on therapy. All further therapies were documented, and the outcome of patients was analyzed. A 75% complete resection rate in 110 prospectively classified patients had to be achieved to confirm a positive predictive value of 2 or higher of 3 with 95% probability. Results: A total of 516 patients were screened within 19 months; of these, 261 patients (51%) were classified as score positive, and 129 patients with a positive score and first relapse were operated on. The rate of complete resection was 76%, thus confirming the validity of this score regarding positive prediction of complete resectability in 2 or more of 3 patients. Complication rates were moderate including second operations in 11% and perioperative mortality in 0.8%. Conclusions: This score is the first prospectively validated instrument to positively predict surgical outcome in recurrent ovarian cancer. It can aid in the selection of patients who might benefit from secondary cytoreductive surgery and will be enrolled in the recently started randomized prospective DESKTOP III trial investigating the role of surgery in recurrent platinum-sensitive ovarian cancer.

Carboplatin Plus Paclitaxel Versus Carboplatin Plus Pegylated Liposomal Doxorubicin As First-Line Treatment for Patients With Ovarian Cancer: The MITO-2 Randomized Phase III Trial

PURPOSE Carboplatin/paclitaxel is the standard first-line chemotherapy for patients with advanced ovarian cancer. Multicentre Italian Trials in Ovarian Cancer-2 (MITO-2), an academic multicenter phase III trial, tested whether carboplatin/pegylated liposomal doxorubicin (PLD) was more effective than standard chemotherapy. PATIENTS AND METHODS Chemotherapy-naive patients with stage IC to IV ovarian cancer (age ≤ 75 years; Eastern Cooperative Oncology Group performance status ≤ 2) were randomly assigned to carboplatin area under the curve (AUC) 5 plus paclitaxel 175 mg/m(2) or to carboplatin AUC 5 plus PLD 30 mg/m(2), every 3 weeks for six cycles. Primary end point was progression-free survival (PFS). With 632 events in 820 enrolled patients, the study would have 80% power to detect a 0.80 hazard ratio (HR) of PFS. RESULTS Eight hundred twenty patients were randomly assigned. Disease stages III and IV were prevalent. Occurrence of PFS events substantially slowed before obtaining the planned number. Therefore, in concert with the Independent Data Monitoring Committee, final analysis was performed with 556 events, after a median follow-up of 40 months. Median PFS times were 19.0 and 16.8 months with carboplatin/PLD and carboplatin/paclitaxel, respectively (HR, 0.95; 95% CI, 0.81 to 1.13; P = .58). Median overall survival times were 61.6 and 53.2 months with carboplatin/PLD and carboplatin/paclitaxel, respectively (HR, 0.89; 95% CI, 0.72 to 1.12; P = .32). Carboplatin/PLD produced a similar response rate but different toxicity (less neurotoxicity and alopecia but more hematologic adverse effects). There was no relevant difference in global quality of life after three and six cycles. CONCLUSION Carboplatin/PLD was not superior to carboplatin/paclitaxel, which remains the standard first-line chemotherapy for advanced ovarian cancer. However, given the observed CIs and the different toxicity, carboplatin/PLD could be considered an alternative to standard therapy.

Pegylated liposomal doxorubicin-associated hand–foot syndrome: Recommendations of an international panel of experts

BACKGROUND Hand-foot syndrome (HFS) is dose-limiting and the most common cumulative toxicity associated with pegylated liposomal doxorubicin (PLD). It can cause considerable discomfort and lead to therapy interruption. Numerous approaches to HFS management have been reported, but there is no consensus. METHODS Published literature (identified via Medline and internet search) and expert experience regarding HFS and its pathogenesis, incidence, risk factors, prevention and treatment in patients undergoing treatment with PLD were collected and reviewed by a panel of experts. A consensus technique was used to develop recommendations. FINDINGS The pathogenesis of PLD-associated HFS has been recently elucidated. Systems used to grade, prevent and treat HFS in individuals treated with PLD vary widely. A randomised clinical study demonstrated that PLD dose intensity reduction can prevent HFS. While there is limited literature support, patient education and supportive measures were endorsed by the expert panel as effective strategies for HFS prevention and treatment. An easy to use HFS grading and management algorithm was developed, early signs and symptoms of HFS outlined and specific recommendations for supportive care developed. INTERPRETATION The paucity of data on the management of PLD-associated HFS led the expert panel to develop consensus-based recommendations. Patient education and supportive measures are important elements in the management of HFS and dose intensity reduction has documented efficacy in prevention. At a PLD dose intensity not exceeding 10mg/m(2) weekly, HFS can be easily managed. Phase III research to support the efficacy other interventions is lacking.

A systematic review comparing cisplatin and carboplatin plus paclitaxel-based chemotherapy for recurrent or metastatic cervical cancer.

INTRODUCTION The prognosis of advanced/recurrent cervical cancer patients is generally poor with 1-year survival ranging between 15 and 20%. Cisplatin (CDDP) based treatments are considered the most effective regimens; unfortunately toxicity is an issue in a population in which the treatment remains palliative in the finality. Carboplatin (CBDCA), with its more favorable non toxicity profile and the convenience of outpatient administration, may be a suitable alternative to CDDP in combination regimens. MATERIALS AND METHODS We performed a systematic review of the literature comparing CDDP and CBDCA based chemotherapy for advanced cervical cancer (recurrent, persistent or metastatic disease). Only studies that met the following criteria were considered for the present review: 1) patients treated with CDDP/paclitaxel or CBDCA/paclitaxel combinations as first line chemotherapy for metastatic disease; 2) one or more of the following data available: overall response rate (RR), progression free survival (PFS) or time to progression (TTP), overall survival (OS); 3) single-arm retrospective or prospective study; and 4) at least 20 patients enrolled. RESULTS 17 eligible studies comprehensive of 1181 patients were included in the final analysis. The objective RR was 48.5% for CBDCA and 49.3% for CDDP-based chemotherapy. Median PFS for CDDP and CBDCA-based treatments was 6.9months and 5months respectively (p=0.03); the corresponding figures for median OS were 12.87 and 10months respectively (p=0.17). DISCUSSION Our study indicates that CBDCA may represent an attractive and valid alternative to the more toxic and equally effective CDDP in the treatment of advanced or recurrent cervical cancer.

Quality of life and emotional distress in early stage and locally advanced cervical cancer patients: a prospective, longitudinal study

OBJECTIVES This prospective, longitudinal study investigates QoL issues and emotional distress in early stage cervical cancer (ECC) patients undergoing radical surgery (RS) and in locally advanced cervical cancer (LACC) patients triaged to chemoradiation (CT/RT) followed by RS. METHODS The Global Health Status scale of EORTC QLQ-C30 (GHS), the EORTC QLQ-CX24 (CX24) and the Hospital Anxiety and Depression Scale (HADS) questionnaire were administered at baseline, and after 3, 6, and 12 months from surgery. For LACC patients QoL assessment was also performed after CT/RT. Statistical analysis was performed by the ANOVA for repeated measures and the Between Subject test. RESULTS In ECC and LACC patients, the GHS scores improved over time (5.5% difference in mean scores compared to baseline in ECC, and 7.0% difference in mean score compared to baseline in LACC patients). An early worsening of lymphedema scores was documented in ECC cases (14.6% difference in mean values compared to baseline, p value=0.001), and in LACC patients (difference up to 28.3% of mean values, value=0.0001). Menopausal symptoms persistently worsened over time reaching >15% difference of mean values compared to baseline in both groups. Sexual activity scores markedly improved both in ECC and LACC patients (difference of mean score values compared to baseline was 16.5% in ECC, and 6.7% in LACC patients). Both ECC and LACC patients experienced an improvement of anxiety scores. CONCLUSIONS Lymphedema and menopausal symptoms were the most disabling treatment-related sequelae; the amount of QoL issues and their multifaceted aspects require the cooperation of multidisciplinary teams.

A treatment selection protocol for recurrent ovarian cancer patients: the role of FDG-PET/CT and staging laparoscopy.

Objective: To investigate the best diagnostic and staging strategy for recurrent ovarian cancer. Methods: The negative predictive value, specificity, positive predictive value, sensitivity, and accuracy rates of the fluorine-18-fluorodeoxyglucose positive emission tomography computed tomography (FDG-PET/CT) and staging laparoscopy in identifying surgically treatable/untreatable patients are assessed in a consecutive series of 70 recurrent ovarian cancer cases. Moreover, the diagnostic performance of each staging procedure in the evaluation of the number of nodules is analyzed. Results: The negative predictive value of the FDG-PET/CT was 83.3%, whereas the positive predictive value was 76.9%. Specificity was 55.6%, whereas sensitivity was 93.0%. Accuracy rate was 78.6%. Negative predictive value, specificity, positive predictive value, sensitivity, and accuracy rate of staging laparoscopy were 88.9, 64.0, 80.8, 95.0 and 83.1%, respectively. Combined radiological and laparoscopic evaluation showed a negative predictive value of 88.9%, a specificity of 59.3%, a positive predictive value of 78.8%, a sensitivity of 95.3%, and an accuracy rate of 81.4%. The number of nodules identified by FDG-PET/CT corresponded in only 23 patients (40.3%) at laparotomy, whereas 15 of 30 patients were correctly diagnosed (50.0%) by staging laparoscopy. Conclusions: The combination of FDG-PET/CT and staging laparoscopy has a significant effect on the multimodal approach to the population of patients with recurrent ovarian cancer. Such techniques should be considered complementary, because of the potential of each one to identify a different setting of the disease.

Phase II study of liposomal doxorubicin and gemcitabine in the salvage treatment of ovarian cancer

In total, 70 patients were enrolled into this phase II study, to evaluate the activity of the pegylated liposomal doxorubicin (PLD) and gemcitabine (GEM) combination in recurrent ovarian cancer patients. PLD, 30 mg m−2, was administered on day 1 by 60′ i.v. infusion, followed by GEM, 1000 mg m−2, given by 30′ i.v. on days 1 and 8; cycles were repeated every 21 days. In all, 67 patients are so far evaluable for response. Seven complete responses (10.4%, 95% CI: 3.1–17.7), 16 partial responses (23.9%, 95% CI: 13.7–34.1), 26 disease stabilisations (38.8%, 95% CI: 27.1–50.5) and 18 progressions (26.9%, 95% CI: 16.3–37.5) have been registered. Within the resistant population (n=36), the response rate was 25% (95% CI: 10.9–39.1). Within the group of platinum-sensitive patients (n=31), the response rate was 45.2% (95% CI: 27.7–62.7). A total of 443 courses are evaluable for toxicity. Grade 3–4 hematological toxicity was registered in 30 patients (42.8%), mainly represented by neutropenia (35.6%); palmar-plantar erythrodysesthesia affected 24 patients (34.2%), but it was of grade 3 in only seven of them (10%).

Pazopanib plus weekly paclitaxel versus weekly paclitaxel alone for platinum-resistant or platinum-refractory advanced ovarian cancer (MITO 11): a randomised, open-label, phase 2 trial

BACKGROUND Inhibition of angiogenesis is a valuable treatment strategy for ovarian cancer. Pazopanib is an anti-angiogenic drug active in ovarian cancer. We assessed the effect of adding pazopanib to paclitaxel for patients with platinum-resistant or platinum-refractory advanced ovarian cancer. METHODS We did this open-label, randomised phase 2 trial at 11 hospitals in Italy. We included patients with platinum-resistant or platinum-refractory ovarian cancer previously treated with a maximum of two lines of chemotherapy, Eastern Cooperative Oncology Group performance status 0-1, and no residual peripheral neurotoxicity. Patients were randomly assigned (1:1) to receive weekly paclitaxel 80 mg/m(2) with or without pazopanib 800 mg daily, and stratified by centre, number of previous lines of chemotherapy, and platinum-free interval status. The primary endpoint was progression-free survival, assessed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01644825. This report is the final analysis; the trial is completed. FINDINGS Between Dec 15, 2010, and Feb 8, 2013, we enrolled 74 patients: 37 were randomly assigned to receive paclitaxel and pazopanib and 37 were randomly assigned to receive paclitaxel only. One patient, in the paclitaxel only group, withdrew from the study and was excluded from analyses. Median follow-up was 16·1 months (IQR 12·5-20·8). Progression-free survival was significantly longer in the pazopanib plus paclitaxel group than in the paclitaxel only group (median 6·35 months [95% CI 5·36-11·02] vs 3·49 months [2·01-5·66]; hazard ratio 0·42 [95% CI 0·25-0·69]; p=0·0002). We recorded no unexpected toxic effects or deaths from toxic effects. Adverse events were more common in the pazopanib and paclitaxel group than in the paclitaxel only group. The most common grade 3-4 adverse events were neutropenia (11 [30%] in the pazopanib group vs one [3%] in the paclitaxel group), fatigue (four [11%] vs two [6%]), leucopenia (four [11%] vs one [3%]), hypertension (three [8%] vs none [0%]), raised aspartate aminotransferase or alanine aminotransferase (three [8%] vs none), and anaemia (two [5%] vs five [14%]). One patient in the pazopanib group had ileal perforation. INTERPRETATION Our findings suggest that a phase 3 study of the combination of weekly paclitaxel plus pazopanib for patients with platinum-resistant or platinum-refractory advanced ovarian cancer is warranted. FUNDING National Cancer Institute of Napoli and GlaxoSmithKline.