George Bozas

Osteonecrosis of the Jaw in Cancer After Treatment With Bisphosphonates: Incidence and Risk Factors

PURPOSE Osteonecrosis of the jaw (ONJ) has been associated recently with the use of pamidronate and zoledronic acid. We studied the incidence, characteristics, and risk factors for the development of ONJ among patients treated with bisphosphonates for bone metastases. PATIENTS AND METHODS ONJ was assessed prospectively since July 2003. The first bisphosphonate treatment among patients with ONJ was administered in 1997. Two hundred fifty-two patients who received bisphosphonates since January 1997 were included in this analysis. RESULTS Seventeen patients (6.7%) developed ONJ: 11 of 111 (9.9%) with multiple myeloma, two of 70 (2.9%) with breast cancer, three of 46 (6.5%) with prostate cancer, and one of 25 (4%) with other neoplasms (P = .289). The median number of treatment cycles and time of exposure to bisphosphonates were 35 infusions and 39.3 months for patients with ONJ compared with 15 infusions (P < .001) and 19 months (P = .001), respectively, for patients with no ONJ. The incidence of ONJ increased with time to exposure from 1.5% among patients treated for 4 to 12 months to 7.7% for treatment of 37 to 48 months. The cumulative hazard was significantly higher with zoledronic acid compared with pamidronate alone or pamidronate and zoledronic acid sequentially (P < .001). All but two patients with ONJ had a history of dental procedures within the last year or use of dentures. CONCLUSION The use of bisphosphonates seems to be associated with the development of ONJ. Length of exposure seems to be the most important risk factor for this complication. The type of bisphosphonate may play a role and previous dental procedures may be a precipitating factor.

Endometrial Cancer: What Is New in Adjuvant and Molecularly Targeted Therapy?

Endometrial cancer is the most common gynaecological cancer in western countries. Radiotherapy remains the mainstay of postoperative management, but accumulating data show that adjuvant chemotherapy may display promising results after staging surgery. The prognosis of patients with metastatic disease remains disappointing with only one-year survival. Progestins represent an effective option, especially for those patients with low-grade estrogen and/or progesterone receptor positive disease. Chemotherapy using the combination of paclitaxel, doxorubicin, and cisplatin is beneficial for patients with advanced or metastatic disease after staging surgery and potentially for patients with early-stage disease and high-risk factors. Toxicity is a point in question; however, the combination of paclitaxel with carboplatin may diminish these concerns. In women with multiple medical comorbidities, single-agent chemotherapy may be better tolerated with acceptable results. Our increased knowledge of the molecular aspects of endometrial cancer biology has paved the way for clinical research to develop novel targeted antineoplastic agents (everolimus, temsirolimus, gefitinib, erlotinib, cetuximab, trastuzumab, bevacizumab, sorafenib) as more effective and less toxic options. Continued investigation into the molecular pathways of endometrial cancer development and progression will increase our knowledge of this disease leading to the discovery of novel, superior agents.

Young Age Is Associated with Favorable Characteristics but Is Not an Independent Prognostic Factor in Patients with Epithelial Ovarian Cancer: A Single Institution Experience

Background: Young age has been reported to be a favorable prognostic factor in ovarian cancer. The aim of the present study was to investigate the characteristics of ovarian cancer presenting in patients aged ≤40 and assess the prognostic significance of young age. Methods: Data from 591 consecutive ovarian cancer patients, including 37 subjects (6.3%) aged ≤40, who were treated postoperatively with platinum-based chemotherapy in our institution were retrospectively reviewed. Results: In our series, age ≤40 did not show an independent association with overall (p = 0.542) or progression-free survival (p = 0.334). Nonetheless, it was correlated with low tumor grade (p = 0.009) and small volume of residual disease after primary surgery (p = 0.020), while there was a nonsignificant trend for correlation with performance status 0 (p = 0.052). Stratified analysis showed that age ≤40 was associated with improved overall survival in the subgroups of serous histology and stage IIC–IV disease; however, multivariate analyses failed to identify age as an independent predictor of survival within either subgroup (p = 0.079 and p = 0.585, respectively). Conclusions: Age ≤40 was not an independent prognostic factor in our analysis. The survival advantage of young patients may be attributed to the association with low tumor grade, more complete surgical debulking and better performance status.

Developments in the systemic treatment of endometrial cancer

Systemic treatment represents the cornerstone of endometrial cancer management in advanced, relapsed and metastatic disease, which is still characterized by poor prognosis. Progestins remain an effective option for patients with low grade, estrogen and/or progesterone receptor positive disease, with some of them achieving prolonged survival. Platinum compounds, anthracyclines and more recently taxanes have been implemented in combination regimens achieving response rates more than 50% and resulting in overall survival above 1 year in randomized trials. Adjuvant chemotherapy with the same agents may be useful for patients with early stage disease and high-risk features, such as high grade or non-endometrioid histology. Combination of chemotherapeutic agents with radiotherapy remains investigational. Hematologic, cardiac toxicity and neurotoxicity represent the main concern of chemotherapy and increase the risk for treatment-related morbidity and death, especially in pretreated patients bearing substantial co-morbidities. The gradual elucidation of the molecular aspects of endometrial carcinogenesis has led to the development of novel, selective antineoplastic agents, targeting specific molecular pathways and mediators of signal transduction implemented in cell proliferation, survival and angiogenesis. In the current review, we report on the recent advances regarding systemic therapy of endometrial carcinoma with special emphasis on results of large, randomized phase III clinical trials. Biomarkers with potent prognostic significance or predictive value for response to treatment are presented and novel molecular agents showing promising results in early clinical trials are discussed.

Paclitaxel, epirubicin, and carboplatin in advanced or recurrent endometrial carcinoma: A Hellenic Co-operative Oncology Group (HeCOG) study

OBJECTIVE Taxanes, anthracyclines, and platinum compounds represent the chemotherapeutic agents with the greatest activity in metastatic endometrial carcinoma. We administered the combination of paclitaxel, epirubicin and carboplatin to patients with metastatic or recurrent carcinoma of the endometrium to evaluate its activity and to define its toxicity. METHODS Sixty-three consecutive patients were treated on an outpatient basis with epirubicin 50 mg/m(2), followed by paclitaxel 150 mg/m(2), administered intravenously over a 3-h period. Subsequently, the patients received carboplatin at AUC of 5. The chemotherapy was repeated every 3 weeks with granulocyte colony-stimulating factor (G-CSF) support for a maximum of six courses. RESULTS Response was assessed among 56 eligible patients. Thirty-six (63.2%) patients achieved objective clinical response (95% CI, 50.6-75.7%) including 14 (24.6%) complete and 22 (38.6%) partial responses. The median duration of response was 7.9 months, and the median times to progression and survival for all patients were 7.8 and 13.8 months, respectively. Grade 3 or 4 neutropenia occurred in 9 (15.5%) patients but only 3 episodes of neutropenic fever were encountered. Grade 2 or 3 neurotoxicity was observed in 19% of patients. Two patients died of sudden cardiac death 10 and 14 days after the administration of the first chemotherapy cycle, respectively, but these deaths were not clearly treatment related. CONCLUSIONS The combination of paclitaxel, epirubicin and carboplatin with G-CSF support appears active in patients with metastatic or recurrent carcinoma of the endometrium.

Systemic chemotherapy with pemetrexed and cisplatin for malignant peritoneal mesothelioma: a single institution experience

Background and aims Primary malignant peritoneal mesothelioma is a rare malignancy with an unfavorable prognosis. Pemetrexed has proven effective in the treatment of malignant mesothelioma, alone or in combination with platinum agents. In the present study, chemo-naïve patients were evaluated for the efficacy and safety of the pemetrexed-cisplatin combination. Methods Six patients with diffuse peritoneal mesothelioma were treated with 6 cycles of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2). Chemotherapy was administered on an outpatient basis every 3 weeks. Results Complete response was observed in 2 patients (33%) and partial response was observed in 3 patients (50%). The estimated median overall survival was 24 months and the estimated median time to disease progression was 9.5 months. The regimen was well tolerated. Conclusions Though our data reflect a small sample size, pemetrexed plus cisplatin accomplished a particularly high clinical benefit rate on chemo-naïve patients. Free full text available at www.tumorionline.it

Paclitaxel- and Platinum-Based Postoperative Chemotherapy for Primary Fallopian Tube Carcinoma: A Single Institution Experience

Background: Primary fallopian tube carcinoma (PFTC) is a rare gynecologic malignancy with very few data existing on the activity of the combination of paclitaxel with a platinum analogue as adjuvant chemotherapy. Methods: We retrospectively analyzed 41 consecutive patients with PFTC who were treated postoperatively with paclitaxel- and platinum-containing chemotherapy regimens. Results: We observed 12 (63.2%) complete and 6 (31.6%) partial responses among 19 patients with measurable disease. The median time to disease progression (TTP) for all patients was 68 months. The median overall survival (OS) for all patients has not been reached yet. The median TTP was 84 months for patients with stage I/II disease and 34 months for patients with advanced disease (p = 0.017). Median OS has not been reached yet for patients with stage I/II PFTC, while it was 63.8 months for patients with stage III/IV disease (p = 0.002). Furthermore, OS has not been reached yet for patients with optimally debulked tumors, while it was 34.1 months for patients with residual disease >2 cm (p < 0.0001). Conclusion: Adjuvant platinum- and paclitaxel-based chemotherapy should be regarded as the standard treatment in patients with PFTC. Early stage disease and optimal debulking are associated with improved TTP and OS.

Prechemotherapy serum levels of CD105, transforming growth factor beta2, and vascular endothelial growth factor are associated with prognosis in patients with advanced epithelial ovarian cancer treated with cytoreductive surgery and platinum-based chemotherapy.

Background: Serum CD105 has been associated with angiogenic activity in cancer, and low CD105 expression has been associated with improved prognosis. The present study evaluated the prognostic significance of serum levels of CD105 and related factors in patients with epithelial ovarian cancer (EOC) after cytoreductive surgery and chemotherapy. Patients and Methods: Eighty-six patients with stages IIC to IV EOC treated postoperatively with platinum-based chemotherapy were included. The enzyme-linked immunosorbent assay was used to measure prechemotherapy serum levels of CD105, transforming growth factor &bgr;1/2 (TGF-&bgr;1/2), angiopoietin 2, vascular endothelial growth factor, and tumor necrosis factor-&agr;. Results: High levels of TGF-&bgr;2 (>8908.86 pg/mL) and CD105 (>4.25 ng/mL) were independently associated with improved overall survival (not reached vs 39 months, P = 0.009 and 75 vs 39 months, P = 0.029, respectively), whereas a high level of TGF-&bgr;2 and a low level of vascular endothelial growth factor (<219.04 pg/mL) were independently associated with improved progression-free survival (49 vs 17 months, P = 0.022 and 57 vs 16 months, P = 0.023, respectively). Among patients with favorable (>4.25 ng/mL) CD105 levels, only patients with low TGF-&bgr;1 levels (<177.1 ng/mL) had superior survival than patients with low CD105 levels. Conclusions: Our study confirms the prognostic significance of angiogenesis in EOC and supports a biological interaction between CD105 and TGF-&bgr;1. High angiogenic activity may be associated by increased efficacy of postoperative chemotherapy.

Weekly Docetaxel with or without Gemcitabine as Second-Line Chemotherapy in Paclitaxel-Pretreated Patients with Metastatic Breast Cancer: A Randomized Phase II Study Conducted by the Hellenic Co-Operative Oncology Group

Objective: A randomized phase II trial was conducted to test whether the addition of gemcitabine to weekly docetaxel could improve the objective response rate and survival outcomes as second-line chemotherapy in patients with metastatic breast cancer who have failed a paclitaxel-containing regimen. Methods: Patients were randomized to receive either weekly docetaxel 40 mg/m2 (group A, n = 34) or the combination of weekly docetaxel 35 mg/m2 with gemcitabine 600 mg/m2 (group B, n = 41). Three consecutive weekly infusions followed by a 1-week rest period represented 1 chemotherapy cycle. Results: The objective response rate was 18% and 27.5% in group A and B, respectively (p = 0.413). No statistically significant differences were demonstrated in terms of median overall survival and time to disease progression. The rate and grade 3 and 4 neutropenia were higher in group B (23 vs. 3%). Conclusions: The weekly administration of docetaxel and gemcitabine did not result in superior clinical outcomes over weekly docetaxel.

Paclitaxel, topotecan, and carboplatin in metastatic endometrial cancinoma: A Hellenic Co-operative Oncology Group (HeCOG) study

OBJECTIVE Taxanes, and platinum compounds represent the chemotherapeutic agents with the greatest activity in metastatic endometrial carcinoma. We administered the combination of paclitaxel, topotecan and carboplatin to patients with metastatic or recurrent carcinoma of the endometrium to evaluate its activity and to define its toxicity. METHODS Thirty-nine consecutive patients were treated on an outpatient basis with paclitaxel 150 mg/m(2), administered intravenously over a 3-h period and followed by carboplatin at AUC of 5 on day 3, with both agents proceding topotecan that was given at 0.75 mg/m(2)/day on days 1 through 3. The chemotherapy was repeated every 3 weeks with granulocyte colony-stimulating factor (G-CSF) support for a maximum of six courses. RESULTS Twenty-one (60%) patients achieved objective clinical response (95% CI, 42.2-75.7%) including 4 (11.4%) complete and 17 (48.6%) partial responses. The median times to progression and survival for all patients were 8.9 and 17.7 months, respectively. Grade 3 or 4 thombocytopenia and neutropenia occurred in 5 (13%) and 4 (10%) patients, respectively, but only 2 episodes of neutropenic fever were encountered. Grade 2 or 3 neurotoxicity was observed in 23% of patients. CONCLUSIONS The combination of paclitaxel, topotecan and carboplatin with G-CSF support appears active with acceptable toxicity in patients with metastatic or recurrent carcinoma of the endometrium.