Neoadjuvant chemotherapy for epithelial ovarian cancer—role of apoptosis

Background Ovarian cancer is one of the most frequently fatal gynecological cancers because most cases are diagnosed at an advanced stage. Loss of growth control and a marked resistance to apoptosis are considered major mechanisms driving tumor progression. Little is known about the effect of various treatment regimens on the distribution of molecular markers of apoptosis in epithelial ovarian cancer. The objective of this study was to compare the expression levels of both proapoptotic and antiapoptotic proteins p53, p73, Bcl-2, Bcl-XL and survivin in the ascitic cells and tumor samples of patients undergoing treatment with two different regimens.Methods A total of 24 patients with untreated epithelial ovarian cancer were randomized into two groups of 12 each. Group 1 patients received three cycles of chemotherapy prior to surgery and three cycles after surgery and group 2 patients received six cycles of chemotherapy prior to surgery. The expression of apoptosis-related proteins was analyzed in ascitic fluid and tumor samples by Western blotting and immunohistochemistry. The apoptotic index was also determined in these samples by the TUNEL assay.Results Significant decreases in antiapoptotic bcl-2 and survivin were seen, accompanied by increases in apoptotic index in tumors that had undergone chemotherapy as compared to the baseline ascites samples. No significant change in bcl-XL was observed. A significant decrease in proapoptotic p53 was also seen. No expression of p73 was observed in tumors or ascites. The findings were similar in groups 1 and 2 patients and were not statistically significantly different, perhaps due to the small sample size (n=12) of each group.Conclusions The above findings indicate that chemotherapy in ovarian carcinoma leads to an increase in apoptosis by a p53-independent pathway, which involves the downregulation of antiapoptotic Bcl-2 and survivin but not Bcl-XL. Furthermore, administering neoadjuvant chemotherapy (six cycles) as an alternative form of therapy for advanced epithelial ovarian cancer is more effective in inducing apoptosis than three cycles. However, the findings of this study need to be corroborated using a larger sample.     

Paclitaxel/carboplatin versus topotecan/paclitaxel/carboplatin in patients with FIGO suboptimally resected stage III–IV epithelial ovarian cancer a multicenter,randomized study

ObjectiveThe objective of this prospective randomized phase III trial was to compare paclitaxel plus carboplatin (PC) versus topotecan plus carboplatin and paclitaxel (TPC) in women with suboptimal stage III (residual tumour >1 cm) or stage IV ovarian cancer to evaluate the survival rate and toxicities.MethodsEligible for the study were patients aged at least 18 years old with histological/cytological diagnosis of FIGO stages III (residual tumour ?1 cm after primary surgery) – IV epithelial ovarian cancer. Patients were randomized to iv PC on day 1, every 21 days or iv topotecan daily for three days and PC on day 3, every 21 days.ResultsThe intention to treat population was made of 326 patients in total, 170 in the PC group and 156 in the TPC group. The life table estimates of survival probabilities at one, three and five years were, respectively, 0.94 (95% CI: 0.88–0.97), 0.53 (95% CI: 0.44–0.62) and 0.32 (95%CI: 0.23–0.42) in the PC group, and 0.92 (95% CI: 0.86–0.95), 0.52 (95% CI: 0.42–0.61), and 0.32(95%CI: 0.22–0.43) in the TPC group (log-rank test at 5 years: ns). The results of the survival analysis based on Cox regression model showed no statistically significant differences between groups (p-value: ns). The number of subjects with at least one event with possible relationship to study medication was 151 (88.8%) in the PC group and 139 (89.1%) in the TPC group (p = ns).In the PC group, 79 patients (23.6%) experienced at least one Adverse Event (AE) graded as severe and 16 patients (4.8%) at least one life-threatening AE, whilst in the TPC group, the number of patients who presented at least one severe or life-threatening AE was 86 (24%) and 37 (10.3%), respectively.ConclusionThe results of the present study show that the addition of topotecan to a standard paclitaxel/carboplatin regimen in the treatment of advanced epithelial ovarian cancer did not result in significant advantages in terms of survival rate. A slightly worse toxicity profile for TPC was observed.     

A feasibility study of sequential doublet chemotherapy comprising carboplatin–doxorubicin and carboplatin–paclitaxel for advanced endometrial adenocarcinoma and carcinosarcoma

BackgroundPlatinum compounds, taxanes and anthracyclines provide the major effective drug classes in the treatment of advanced and recurrent endometrial cancer and carcinosarcoma.Patients and methodsA total of 52 women with advanced or recurrent endometrial cancer and carcinosarcoma were treated with four cycles of carboplatin area under the curve (AUC) 5 and doxorubicin (50 mg/m²) for four cycles before or after four cycles of carboplatin AUC5 and paclitaxel (175 mg/m²) with each cycle administered at 21-day intervals.ResultsThirty-seven patients (71.2%) completed all planned treatment. Excluding six patients who did not complete treatment for non-drug-related causes, 80.4% completed all planned treatment. Three hundred and seventy-one treatment cycles were administered and 303 (81.7%) occurred on time. Common Toxicity Criteria grade 3/4 haematological toxic effects, particularly neutropenia and thrombocytopenia, were the predominant cause of treatment delays and dose reductions. A low incidence of grade 3 neurotoxicity and no cardiac toxicity were observed. The overall response rates for patients with evaluable disease were 82.1% and 66.7% for endometrial and carcinosarcoma, respectively. At a median follow-up of 21 months, the median progression-free survival for the endometrial adenocarcinoma and carcinosarcoma cohorts were 15.3 and 12.0 months, respectively.ConclusionThis regimen is generally well tolerated with encouraging efficacy.     

First-line therapy for ovarian cancer with carboplatin followed by paclitaxel–gemcitabine (SCOTROC5): A feasibility study and comparative analysis of the SCOTROC series

BackgroundWe have conducted a series of four feasibility studies in stage Ic–IV ovarian cancer exploring six sequential first-line schedules with the same entry criteria in a total of 339 patients. Here we present the results of the sixth study, and an analysis of the overall series.MethodsIn this trial patients received 4 cycles of carboplatin AUC 7 every 3 weeks, followed by 4 cycles of concurrent paclitaxel 175 mg/m² (day 1) and gemcitabine 1000 mg/m² (days 1 and 8) every 3 weeks. The primary end-point of the trial was feasibility of administering all cycles of planned chemotherapy to >60% of patients.ResultsFifty-four patients were recruited to the trial between June 05 and June 06. A total of 40 (74.1%) patients received all 8 cycles of treatment. Reasons for early discontinuation included toxicity (n = 8) and disease progression (n = 4). The overall response rate was 73.7%, and the median progression free survival (PFS) was 14.2 months with a median follow-up of 24 months. A comparative analysis of all six regimens from the SCOTROC series suggests that the sequential schedule in which paclitaxel was given weekly (median PFS 19.5 m) is most effective.¹ConclusionThe sequential schedule explored in this trial is feasible, but comparative efficacy analysis suggests that trials involving weekly paclitaxel should be prioritised for further study.     

Quality-of-life outcomes from a randomized phase III trial of dose-dense weekly paclitaxel and carboplatin compared with conventional paclitaxel and carboplatin as a first-line treatment for stage II–IV ovarian cancer: Japanese Gynecologic Oncology Group Trial (JGOG3016)

BackgroundDose-dense weekly paclitaxel (Taxol) and carboplatin (dd-TC) improved survival compared with conventional tri-weekly paclitaxel and carboplatin (c-TC) as a first-line chemotherapy for newly diagnosed stage II–IV ovarian cancer in the Japanese Gynecologic Oncology Group 3016 trial. We report the quality-of-life (QoL) results from this trial.Patients and methodsA total of 637 patients were randomly assigned to receive c-TC or dd-TC (c-TC, n = 319; dd-TC, n = 312) and were asked to complete a QoL assessment at baseline, just after the third and sixth chemotherapy cycles, and at 12 months after randomization. QoL was assessed using Functional Assessment of Cancer Therapy (FACT)-general (FACT-G), FACT-taxane subscale (FACT-T), and FACT-ovary subscale (FACT-Ov). The overall QoL and that according to each subscale were analyzed using mixed-effects models adjusted for treatment and time.ResultsBaseline QoL assessment was completed by 204 out of 319 (63.9%) and 200 out of 312 (64.1%) patients in the c-TC and dd-TC groups, respectively. In these groups, the compliance rates with regard to QoL assessment were 74.5% and 73.0%, respectively, after three chemotherapy cycles; 86.8% and 86.9%, respectively, after six chemotherapy cycles; and 74.2% and 71.6%, respectively, at 12 months after randomization. The overall QoL did not differ significantly between the two treatment groups up to 12 months after randomization (P = 0.46). However, QoL according to the FACT-T subscale was significantly lower in the dd-TC group than in the c-TC group (P = 0.02).Conclusiondd-TC does not decrease overall QoL compared with c-TC.Clinical trial informationNCT00226915.     

Pharmacodynamic stimulation of thrombogenesis by angiotensin (1–7) in recurrent ovarian cancer patients receiving gemcitabine and platinum-based chemotherapy

Purpose

This randomized, double-blind, placebo-controlled Phase 2 study evaluated safety and efficacy of A(1–7) for reduction in Grade 3–4 thrombocytopenia in patients receiving myelosuppressive chemotherapy. Pharmacodynamic activity of A(1–7) in platelet production and retention of scheduled dose intensity were also determined.

Methods

Thirty-four patients with ovarian, Fallopian tube, or peritoneal carcinoma receiving gemcitabine and carboplatin or cisplatin were evaluated. Patients were randomized to receive study drug subcutaneously at 100 mcg/kg (n = 11), 300 mcg/kg (n = 13), or placebo (n = 10) following chemotherapy for up to six cycles. Hematologic variables were obtained throughout each treatment cycle.

Results

There were no drug-related safety issues. There were no instances of Grade 4 thrombocytopenia in patients who received 100 mcg/kg treatment compared to 6 % of chemotherapy cycles for patients receiving placebo (p = 0.07). The maximal percentage increase in platelet concentration from baseline was higher for patients who received 100 mcg/kg A(1–7) compared to placebo (p = 0.02). This increase was accompanied by a reduction in the nadir absolute neutrophil count (p = 0.04). Relative dose intensity for the combination chemotherapy was higher for patients who received 100 mcg/kg A(1–7) compared to placebo (p = 0.04). There were no differences in outcomes for patients receiving 300 mcg/kg dose compared to placebo.

Conclusions

A 100 mcg/kg dose of A(1–7) was shown to produce pharmacodynamic effects on peripheral blood platelet counts, preserve planned dose intensity, and reduce Grade 3–4 thrombocytopenia following gemcitabine and platinum chemotherapy. These findings are consistent with A(1–7)-induced stimulation of thrombogenesis in the bone marrow following marrow-toxic chemotherapy.     

Accuracy of self-reported family history of cancer in a large case–control study of ovarian cancer

OBJECTIVE: To evaluate the reliability of self-reported family history of cancer in first-degree female relatives and to examine possible determinants of accurate reporting. METHODS: Women with ovarian cancer and controls were recruited between 1995 and 1999 and interviewed. The study comprised 579 cases and 1,564 controls with 6,265 first-degree female relatives. Self-reported familial cancer diagnoses were validated from registry data. Sensitivity, specificity, and kappa were calculated, and possible determinants were examined by logistic regression. RESULTS: The sensitivity of self-reporting ranged from 0.78 to 0.90 for all cancers but was lower for self-reporting of most site-specific cancers, ranging from 0.29 to 0.94. The specificity of self-reporting ranged from 0.91 to 0.99 for cancer in general and from 0.99 to 1.00 for site-specific cancers. Type of relative, age at interview, and length of education influenced the sensitivity and specificity significantly. The odds ratio for ovarian cancer was higher when based on registry data than on self-reported data and was significant (OR = 2.58 vs. 1.56). CONCLUSIONS: Cancer diagnoses in first-degree relatives are not always accurately reported by patients with ovarian cancer or by controls. The results indicate that studies of associations with family cancer history should validate self-reported family cancer diagnoses as carefully as possible.     

Body size and ovarian cancer: case–control study and systematic review (Australia)

Objective: Although increased body mass is an established risk factor for a variety of cancers, its relation with cancer of the ovary is unclear. We therefore investigated the association between measures of body mass index (BMI) and ovarian cancer risk. Methods: Data from an Australian case–control study of 775 ovarian cancer cases and 846 controls were used to examine the association with BMI. We have also summarized the results from a number of other studies that have examined this association. Results: There was a significant increased risk of ovarian cancer with increasing BMI, with women in the top 15% of the BMI range having an odds ratio (OR) of 1.9 (95% confidence interval (CI), 1.3–2.6) compared with those in the middle 30%. Stratifying by physical activity showed a stronger effect among inactive women (OR = 3.0, 95% CI 1.3–6.9). The overall effect was consistent with the findings of most prior population-based case–control studies, while cohort studies reported positive effects closer to the null. Hospital-based studies gave variable results. Conclusions: Taken together, the evidence is in favor of a small to moderate positive relation between high BMI and occurrence of ovarian cancer.     

Weekly administration of topotecan–paclitaxel as second-line treatment in ovarian cancer

Purpose To investigate the weekly administration of topotecan combined with paclitaxel in pretreated advanced ovarian cancer patients; our objectives were to determine efficacy, toxicity and survival Methods The chemotherapy agents, topotecan and paclitaxel were administered on a weekly basis for 3 consecutive weeks, every 28 days. The plan was to give three courses (each course included three once-weekly infusions). The dose of topotecan was 1.75 mg/m² and of paclitaxel 70 mg/m². Results From January 2004 until January 2006, 45 patients were enrolled in this multicenter trial; 44 patients were evaluable for response and toxicity. The median age was 60 years old (range 39–82 years) and performance status was 0–2. Thirty-nine patients were in stage III and 5 in stage IV. All patients had been pretreated with carboplatin or cisplatin in combination with paclitaxel. Complete and partial responses were seen in 39% of the patients, stable disease in 43% and progressive disease in 18%; median survival time was 9 months, range 2–24+ months, (95% CI: 7.9–10.2). There was a notable absence of grade 3 toxicity except for neutropenia in 11% of the patients. Conclusion The combination of topotecan and paclitaxel administered on a weekly basis is a well-tolerated chemotherapy schedule. The response rate of 39% is quite high for patients with pretreated ovarian cancer.     

Statin use and risk for ovarian cancer: a Danish nationwide case–control study

Background:

Limited data suggest that statin use reduces the risk for ovarian cancer.

Methods:

Using Danish nationwide registries, we identified 4103 cases of epithelial ovarian cancer during 2000–2011 and age-matched them to 58 706 risk-set sampled controls. Conditional logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for epithelial ovarian cancer overall, and for histological types, associated with statin use.

Results:

We observed a neutral association between ever use of statins and epithelial ovarian cancer risk (OR=0.98, 95% CI=0.87–1.10), and no apparent risk variation according to duration, intensity or type of statin use. Decreased ORs associated with statin use were seen for mucinous ovarian cancer (ever statin use: OR=0.63, 95% CI=0.39–1.00).

Conclusions:

Statin use was not associated with overall risk for epithelial ovarian cancer. The inverse association between statin use and mucinous tumours merits further investigation.     

A population-based case–control study of carotenoid and vitamin A intake and ovarian cancer (United States)

Objective: To evaluate the association between dietary intake of carotenoids and vitamin A and the incidence of ovarian cancer. Methods: We conducted a population-based case–control study of ovarian cancer in Massachusetts and Wisconsin. Incident cases diagnosed between 1991 and 1994 were identified through statewide tumor registries. We selected community controls at random from lists of licensed drivers and Medicare recipients; 327 cases and 3129 controls were included in the analysis. Data were collected by telephone interview, which included an abbreviated food and supplement list to quantify typical consumption of carotenoids (lutein/zeaxanthin, alpha-carotene, beta-carotene), retinol and total vitamin A at 5 years prior to diagnosis in cases, or to a comparable reference date in controls. Results were adjusted for age, state, and other risk factors. Results: Participants with the highest dietary intake of lutein/zeaxanthin (24,000 g/week) experienced a 40% lower risk of ovarian cancer (95% CI = 0.36–0.99) compared to those with the lowest intake. Intake of alpha-carotene, beta-carotene, retinol and total vitamin A was unrelated to risk. Among foods, we observed non-significantly lower risks with high consumption of spinach, carrots, skim/lowfat milk and liver. Conclusion: These results support previous findings suggesting an inverse relationship between carotenoid intake and ovarian cancer risk.     

First-line chemotherapy with epirubicin, paclitaxel, and carboplatin for advanced ovarian cancer: a phase I/II study of the Arbeitsgemeinschaft Gyn?kologische Onkologie Ovarian Cancer Study Group.

PURPOSE: Despite the progress that has been achieved over the years, survival rates in patients with advanced ovarian cancer are still disappointing. New methods to improve the efficiency of first-line chemotherapy are warranted. One method to improve results is to add more non-cross-resistant drugs to platinum-paclitaxel combination regimens. Anthracyclines are among the candidates for incorporation as the "third drug" into first-line regimens for advanced ovarian cancer. PATIENTS AND METHODS: We performed a phase I/II trial with escalating doses of epirubicin (60, 75, and 90 mg/m2) combined with fixed doses of paclitaxel and carboplatin in 27 previously untreated patients with advanced gynecologic malignancies. RESULTS: Dose-limiting toxicity occurred at dose level 2 (75 mg/m2 epirubicin) and consisted of myelosuppression (neutropenia, thrombocytopenia). No dose-limiting, nonhematologic toxicities were observed. The maximum tolerable dose was epirubicin 60 mg/m2 (E) combined with a 3-hour infusion of paclitaxel 175 mg/m2 (T) and carboplatin AUC 5 (Carbo). Preliminary analysis indicated promising activity against ovarian cancer. CONCLUSION: The three-drug combination ET-Carbo, given according to the outlined dose and schedule, should be considered for further phase III evaluation. A randomized German-French intergroup trial comparing ET-Carbo with carboplatin-paclitaxel has already been initiated.     

Leukocyte telomere length in a population-based case–control study of ovarian cancer: a pilot study

Objectives

Telomeres are structures at chromosome ends that contribute to maintaining genomic integrity. Telomere shortening with repeated cell divisions may lead to genomic instability and carcinogenesis. Studies suggest that shorter telomeres in constitutional DNA are associated with bladder, breast, lung, and renal cancer. Ovarian cancer tissues also have shortened telomeres and increased telomerase activity, suggesting that telomere abnormalities may be related to ovarian cancer.

Methods

We investigated leukocyte telomere length in 99 women with serous ovarian adenocarcinoma and 100 age-matched cancer-free controls enrolled in a population-based case–control study.

Results

Cases tended to have shorter telomeres than controls (P _wilcoxon = 0.002). Compared to subjects with telomere lengths in the longest tertile, those in the middle and shortest tertiles showed respective age-adjusted odds ratios (95% confidence intervals) of 2.69 (1.23–5.88) and 3.39 (1.54–7.46) (P _trend = 0.002). Strongest associations were found for subjects with poorly differentiated carcinomas (OR = 4.89, 95% CI 1.93–12.34).

Conclusions

This study shows that short leukocyte telomeres are associated with serous ovarian adenocarcinoma. These findings should be confirmed in large, prospective studies.     

Intraoperative hyperthermic versus postoperative normothermic intraperitoneal chemotherapy for colonic peritoneal carcinomatosis: a case–control study

BackgroundCytoreductive surgery and intraperitoneal chemotherapy has improved prognosis in patients with peritoneal carcinomatosis. The main modes of intraperitoneal chemotherapy treatment are peroperative hyperthermic intraperitoneal chemotherapy (HIPEC) and normothermic sequential postoperative intraperitoneal chemotherapy (SPIC). The aim of this study was to compare HIPEC and SPIC with respect to overall survival, disease-free survival, morbidity, and mortality in patients with peritoneal carcinomatosis from colon cancer.Patients and methodsA matched case–control study was conducted in patients with surgical macroscopic complete removal of carcinomatosis; matching was according to the peritoneal cancer index score. Thirty-two patients were included, 16 in each group (HIPEC and SPIC). Overall survival, disease-free survival, morbidity, mortality, and clinicopathological parameters were compared.ResultsMedian overall survival was 36.5 months in the HIPEC group and 23.9 months in the SPIC group (P = 0.01). Median disease-free survival for these groups was 22.8 (HIPEC) and 13.0 months (SPIC; P = 0.02). Morbidity was not statistically different, 19% in SPIC and 37% in HIPEC. Postoperative mortality was observed in one patient in each group.ConclusionHIPEC was associated with improved overall survival and disease-free survival compared with SPIC at similar morbidity and mortality, suggesting that HIPEC is the treatment of choice in colonic peritoneal carcinomatosis.     

Comparison of survival and hospitalization rates between Medicare patients with advanced NSCLC treated with bevacizumab–carboplatin–paclitaxel and carboplatin–paclitaxel: A retrospective cohort study

ObjectiveThe use of bevacizumab in advanced non-squamous non-small cell lung cancer (NSCLC) is controversial among elderly patients. This study aimed to compare overall survival for Medicare patients diagnosed with NSCLC and treated with either first-line bevacizumab–carboplatin–paclitaxel (BCP) or carboplatin–paclitaxel (CP).MethodsPatients ≥65 years old, first diagnosed with non-squamous NSCLC stage IIIB/IV between 2006 and 2009, and treated with either first-line BCP or CP, were selected from the SEER-Medicare database that links cancer registry and US Medicare claims data. Kaplan–Meier estimates were used to evaluate survival. Multivariable Cox proportional hazards models were used to compare the effect of BCP versus CP on the hazard of death. Age-stratified analyses were conducted for patients aged 65–74 and ≥75 years.ResultsOf 1706 patients in the study sample, 592 (34.7%) received BCP and 1114 (65.3%) received CP; 692 (40.6%) were ≥75 years. Adjusted median survival time in the BCP versus CP cohorts was 10.5 versus 8.5 months (p = 0.008). The difference in median survival favoring the BCP cohort was statistically significant for both patients aged ≥75 years (2.8 months, p = 0.019), and patients aged 65–74 years (1.5 months, p = 0.018). The adjusted hazard of death did not differ between the cohorts (HR: 0.96, 95% CI: 0.86–1.06); however, during the first year of follow-up, when most deaths (>60%) occurred, the hazard of death was 18% lower for the BCP cohort (HR: 0.82, 95% CI: 0.71–0.94). BCP patients also had 18% fewer hospital admissions than CP patients (adjusted incidence rate ratio (IRR): 0.82, 95% CI: 0.72–0.94) and 23% fewer inpatient days (IRR: 0.77, 95% CI: 0.65–0.91).ConclusionsIn this retrospective analysis of Medicare patients in the SEER database, first-line therapy with BCP was associated with longer survival and fewer hospitalizations than CP.