The time interval from surgery to start of chemotherapy significantly impacts prognosis in patients with advanced serous ovarian carcinoma — Analysis of patient data in the prospective OVCAD study

Objective

Cytoreductive surgery and platinum-based systemic therapy constitute the standard treatment of patients with advanced ovarian cancer. The aim of the present study was to evaluate whether the time interval from surgery to start of chemotherapy has an impact on clinical outcome.

Methods

Data of 191 patients with advanced serous (FIGO III–IV) ovarian cancer from the prospective multicenter study OVCAD (OVarian CAncer Diagnosis) were analyzed. All patients underwent primary surgery followed by platinum-based chemotherapy.

Results

The 25%, 50%, and 75% quartiles of intervals from surgery to start of chemotherapy were 22, 28, and 38 days, respectively (range, 4–158 days). Preoperative performance status (P < 0.001), extent of surgery (P < 0.001), and perioperative complications (P < 0.001) correlated with intervals from surgery to initiation of chemotherapy. Timing of cytotoxic treatment [≤ 28 days versus > 28 days; hazard ratio (HR) 1.73 (95% confidence interval 1.08–2.78), P = 0.022], residual disease [HR 2.95 (95% confidence interval 1.87–4.67), P < 0.001], and FIGO stage [HR 2.26 (95% confidence interval 1.41–3.64), P = 0.001] were significant prognostic factors for overall survival in multivariate analysis. While the interval from surgery to start of chemotherapy did not possess prognostic significance in patients without postoperative residual disease (n = 121), it significantly correlated with overall survival in patients with postoperative residual disease [n = 70, HR 2.24 (95% confidence interval 1.08–4.66), P = 0.031].

Conclusion

Our findings suggest that delayed initiation of chemotherapy might compromise overall survival in patients with advanced serous ovarian cancer, especially when suboptimally debulked.     

Quality of life and treatment response among women with platinum-resistant versus platinum-sensitive ovarian cancer treated for progression: A prospective analysis

Objective

Most women with ovarian cancer relapse and undergo further chemotherapy however evidence regarding the benefits of this for women with platinum-resistant disease is limited. Our objective was to determine whether there was a quality of life improvement or treatment response among women treated for platinum-resistant recurrent ovarian cancer.

Methods

We combined data from 2 studies where women treated with chemotherapy for recurrent ovarian cancer (n = 172) completed a quality of life questionnaire every 3 months. Cancers were classified as platinum-resistant if they progressed within 6 months of completing first-line chemotherapy. Mixed effects models were used to analyze change in quality of life during the first 6 months after second-line chemotherapy.

Results

One-quarter of women (n = 44) were classified as having platinum-resistant disease. Overall, their quality of life did not significantly increase or decrease, following commencement of second-line chemotherapy (least square mean scores = 107, 105, 103 at chemotherapy start, 3 and 6 months later, respectively), although 26% of these women reported a meaningful increase and 31% reported a meaningful decline. One-third of the platinum-resistant group responded (11% complete and 21% partial response) to second-line chemotherapy, and this figure increased to 54% among the subset (36%) re-treated with platinum-based agents with or without other agents. Preliminary analyses suggest that quality of life may be higher at chemotherapy initiation in women whose disease responded (median score 121 vs 110).

Conclusions

Overall, quality of life appears to be maintained in women with platinum-resistant ovarian cancer who receive further chemotherapy and some women respond to re-treatment.     

Phase II study of bevacizumab and pemetrexed for recurrent or persistent epithelial ovarian,fallopian tube or primary peritoneal cancer

Objective

We aimed to evaluate the efficacy and safety of combination bevacizumab/pemetrexed for the treatment of recurrent epithelial ovarian cancer (EOC).

Methods

Platinum-sensitive or -resistant patients with recurrent or persistent EOC were eligible if they had received up to 2 prior chemotherapy regimens, including a platinum/taxane regimen without prior bevacizumab. Pemetrexed 500 mg/m² IV and bevacizumab 15 mg/kg IV were administered every 3 weeks. The primary endpoint was 6-month progression-free survival (PFS); other endpoints included toxicities, PFS and overall survival (OS).

Results

Thirty-four patients received a median of 7 treatment cycles (range, 2–26). Median follow-up was 25.7 months (range, 3.0–47.2). Six month progression-free survival (PFS) was 56% (95% CI: 38–71). The following response rates were documented (%; 95% CI): 0 complete response, 14 partial responses (41%; 25–59), 18 stable disease (53%; 35–70) and 2 progressive disease (6%; 1–20). Median PFS was 7.9 months (95% CI, 4.6–10.9), with a median OS of 25.7 months (95% CI, 15.4–29.8). Twenty-two patients (64.7%) had a platinum-free interval (PFI) of > 6 months prior to enrollment. Grade 3–4 hematologic toxicities included neutropenia (50%), leukopenia (26%), thrombocytopenia (12%) and anemia (9%). Non-hematologic grade 3–4 toxicities included metabolic (29%), constitutional (18%), pain (18%) and gastrointestinal (15%). Two patients developed hematologic malignancies within one year of treatment.

Conclusions

Combination bevacizumab/pemetrexed is an active option for both platinum-sensitive and -resistant recurrent EOC. Further investigation of cost and novel toxicities associated with this regimen may be warranted.     

A comparison of primary intraperitoneal chemotherapy to consolidation intraperitoneal chemotherapy in optimally resected advanced ovarian cancer

Objective

To compare survival outcomes for patients with advanced epithelial ovarian cancer (EOC) who received primary intravenous/intraperitoneal (IV/IP) chemotherapy to those who received IV followed by consolidation (treatment given to patients in remission) IP chemotherapy.

Methods

Data were analyzed and compared for all patients with stage III–IV EOC who underwent optimal primary cytoreduction (residual disease ≤ 1 cm) followed by cisplatin-based consolidation IP chemotherapy (1/2001–12/2005) or primary IV/IP chemotherapy (1/2005–7/2011).

Results

We identified 224 patients; 62 (28%) received IV followed by consolidation IP chemotherapy and 162 (72%) received primary IV/IP chemotherapy. The primary IP group had significantly more patients with serous tumors. The consolidation IP group had a significantly greater median preoperative platelet count, CA-125, and amount of ascites. There were no differences in residual disease at the end of cytoreduction between both groups. The median progression-free survival (PFS) was greater for the primary IP group; however, this did not reach statistical significance (23.7 months vs 19.7 months; HR 0.78; 95% CI, 0.57–1.06; p = 0.11). The median overall survival (OS) was significantly greater for the primary IP group (78.8 months vs 57.5 months; HR 0.56; 95% CI, 0.38–0.83; p = 0.004). On multivariate analysis, after adjusting for confounders, the difference in PFS was not significant (HR 0.78; 95% CI, 0.56–1.11; p = 0.17), while the difference in OS remained significant (HR 0.59; 95% CI, 0.39–0.89; p = 0.01).

Conclusions

In our study, primary IV/IP chemotherapy was associated with improved OS compared to IV followed by consolidation IP chemotherapy in patients with optimally cytoreduced advanced EOC.     

The value of imaging of the lungs in the diagnostic workup of patients with endometrial cancer

Objective

Imaging of the lungs is part of the routine diagnostic workup of patients with endometrial cancer. The present study aimed to determine the incidence of lung metastases in patients with endometrial cancer and to evaluate the clinical relevance of preoperative chest imaging in this population.

Methods

A retrospective cross-sectional study was performed in four regional and one university hospital in the southeastern part of the Netherlands. A total of 784 patients with epithelial endometrial cancer diagnosed between 2002 and 2010 in five hospitals were included. Patients were followed up for at least 1 year.

Results

Of 784 patients, 541 (69.0%) underwent thoracic imaging and 11 showed findings suspicious for metastases perioperatively or during the 1-year follow-up period. In eight patients, the thoracic metastases were related to their endometrial cancer, resulting in an overall incidence of 1.0% (8/784, 95% CI = 0.3–1.7%). These eight patients had high-risk subtypes of endometrial cancer (serous, clear cell or poorly differentiated endometrioid), and the incidence was 4.1% (8/193, 95% CI = 1.9–8.3%) for these subtypes. Lung metastases were not detected in any of the patients with low-risk subtypes of endometrial cancer (n = 566) at the time of diagnosis (95% CI = 0–0.8%).

Conclusions

The probability of detecting thoracic metastases during the diagnostic workup of patients with endometrial cancer is low. The present data suggest that thoracic imaging could be omitted from the diagnostic workup of patients with low-risk endometrial cancer.     

Phase II study of oral ridaforolimus in women with recurrent or metastatic endometrial cancer

Objective

The phosphatidylinositol-3 kinase/serine–threonine kinase PI3K/AKT pathway is postulated to be central to cancer cell development. Activation of this pathway is believed to promote angiogenesis, protein translation and cell cycle progression. A large percentage of endometrial carcinomas have demonstrated mutations within this regulation pathway which result in constitutional activation. The downstream effector protein mammalian target of rapamycin (mTOR) acts as a critical checkpoint in cancer cell cycling and is a logical target for drug development. The efficacy and tolerability of the oral mTOR inhibitor ridaforolimus were evaluated in this study.

Methods

This phase II study evaluated the single agent tolerability and activity of oral ridaforolimus administered at a dose of 40 mg for 5 consecutive days followed by a 2 day break, in women with recurrent or metastatic endometrial carcinoma who had received no chemotherapy in the metastatic setting.

Results

31 of 34 patients were evaluable. Three partial responses (8.8%) were observed with response duration ranging between 7.9 and 26.5 months. An additional 18 patients showed disease stabilization (52.9%) for a median duration of 6.6 months. Response rates were not affected by previous chemotherapy exposure. No correlation was found between response and mutation status.

Conclusion

Oral ridaforolimus was reasonably tolerated and demonstrated modest activity in women with recurrent or metastatic endometrial cancers. Potential synergy between mTOR inhibition, angiogenesis and hormonal pathways warrants ongoing evaluation.     

Oxaliplatin salvage for recurrent ovarian cancer: A single institution's experience in patient populations with platinum resistant disease or a history of platinum hypersensitivity

Objective

Hypersensitivity reactions can preclude platinum re-challenge for patients receiving second-line and higher carboplatin/cisplatin salvage therapy. The objective is to report our patient experience with oxaliplatin in recurrent or progressive epithelial ovarian (EOC), primary peritoneal (PPC) or fallopian tube cancer (FTC), including those with prior hypersensitivity reaction.

Methods

A single institution, retrospective review from 1995 to 2012 of patients receiving oxaliplatin for treatment of recurrent or progressive EOC, PPC, or FTC was performed. Data collected included patient demographics, diagnosis date, prior chemotherapy regimens, platinum-free interval(s), prior hypersensitivity reactions, oxaliplatin toxicity, length of therapy, disease response, and last follow-up. Those who received ≥ 1 cycles were included. A response to therapy was determined after ≥ 2 cycles.

Results

Forty-four patients were identified. All had prior carboplatin and 38.6% had prior cisplatin therapy. Twenty-three had a prior platinum hypersensitivity reaction. Patients received a median of 2 prior platinum containing regimens and 5 chemotherapy lines prior to oxaliplatin exposure. One patient experienced grade 3 pain. No grade 4 toxicities occurred. No treatment delays for pancytopenia noted. Nausea and dysesthesias were controlled medically and weren't dose-limiting. No nephropathy or neuropathy progressed on oxaliplatin or were dose-limiting. Disease response was observed in 43.2%. Of the responders, 36.8% had a prior platinum hypersensitivity reaction. Median number of 5 cycles of an oxaliplatin containing regimen was given. Median follow-up was 15.5 months.

Conclusions

In our experience, oxaliplatin is well tolerated and should be considered for platinum challenge after hypersensitivity even in patients with platinum resistant disease with a reasonable chance of response.     

A large scale population-based cohort study on the risk of ovarian neoplasm in patients with type 2 diabetes mellitus

Objective

To investigate whether the risk of developing ovarian cancer is elevated in women with diabetes mellitus.

Methods

The study is a population-based cohort study. Women with type 2 diabetes (n = 319,310) and age-matched controls (n = 319,308) were selected from the ambulatory care claims and beneficiary registry in 2000, respectively. Selected patients were linked to the in-patient claims (2000–2008) to identify admissions due to ovarian (ICD-9-CM: 183.xx) cancer. The person-year approach with Poisson assumption was used to estimate the incidence density rate. The age-specific hazard ratios (HRs) of ovarian cancer in relation to diabetes were calculated using multivariate Cox proportional hazard regression model.

Results

The overall incidence density rate of ovarian cancer was estimated at 1.87 (95% confidence interval (CI) 1.70–2.05) per 10,000 patient-years for patients with diabetes. The corresponding figures for controls were slightly lower at 1.79 per 10,000 patient-years. The incidence density of ovarian cancer was increased with age in diabetes but not in controls. The covariate-adjusted HR for ovarian cancer was statistically compared with null (adjusted HR = 1.06, 95% CI = 0.92–1.22) in women with diabetes. Moderately elevated HR was noted in women with diabetes aged < 50 (adjusted HR = 1.17, 95% CI = 0.82–1.65) and in women with diabetes aged > 65 (adjusted HR = 1.10, 95% CI = 0.92–1.42). The null association between diabetes and ovarian cancer remains true regardless of the disease duration of diabetes.

Conclusion

This large-scale cohort study provides little support on the putative association between type 2 diabetes and the risk of ovarian cancer.     

Weekly carboplatin with paclitaxel compared to standard three-weekly treatment in advanced epithelial ovarian carcinoma — a retrospective study

Objective

To retrospectively compare primary treatment with weekly carboplatin/paclitaxel (PC-W) to the standard 3-weekly carboplatin/paclitaxel (PC-3W) in women with advanced epithelial ovarian cancer, tubal carcinoma and primary peritoneal carcinoma.

Methods

Medical records were assessed for age, stage of disease, tumor histology and grade, BRCA mutation status, and platinum sensitivity. Patients were treated with either paclitaxel (175 mg/m²) and carboplatin (AUC 6) every three weeks (PC-3W; 133 patients), or with weekly paclitaxel (80 mg/m²) and weekly carboplatin (AUC 2) on days 1, 8, and 15 every 28 days (PC-W; 267 patients).

Results

Patient baseline characteristics were similar in both groups. Median overall survival (OS) was similar for PC-W and PC-3W (64.5 months vs. 61.5 months), but PC-W had longer median progression-free survival [PFS: 27.4 months (95% CI, 22.7–31.4) vs. 19.5 months (95% CI, 15.6–22.2) for PC-3W, p = 0.0024] and a longer median platinum-free interval [PFI: 22.1 months (95% CI, 16.0–24.5) vs. 14.2 months (95% CI, 10.7–17.2) for PC-3W, p = 0.0075]. PC-W showed a significantly higher response rate (86.4% vs. 77.9% for PC-3W, p = 0.0435). Multivariate analysis including for age at diagnosis, stage of disease, optimal debulking, histology, BRCA status, pretreatment CA-125 and PFI revealed that the PC-W women had lower risk of death (HR = 0.587, 95% CI, 0.402–0.857, p = 0.0058), lower risk of disease progression (HR = 0.494, 95% CI, 0.359–0.680, p < 0.0001), higher 2- and 3-year survival rates, and decreased grade II hair loss, neuropathy and thrombocytopenia compared with the PC-3W women.

Conclusion

The PC-W protocol improved PFS and had a similar OS as PC-3W.     

A phase II trial of sunitinib in women with metastatic or recurrent endometrial carcinoma: A study of the Princess Margaret,Chicago and California Consortia

Objective

Treatment options remain limited for women with relapsed/metastatic endometrial cancer (EC). Angiogenesis is one of the major components of tumor progression and thus an attractive target. The aim of this phase II trial was to assess the efficacy and tolerability of sunitinib, an oral multitargeted receptor tyrosine-kinase inhibitor with antiangiogenic and antitumor activity in the treatment of recurrent EC.

Methods

We performed a multicenter, single arm, two-stage phase II study of sunitinib, 50 mg daily administered on a 4 weeks on–2 weeks off schedule. Eligibility criteria included recurrent/metastatic EC or carcinosarcoma with no more than one prior line of chemotherapy. The primary endpoint was objective response rate.

Results

34 women were enrolled; 33 received at least one dose of sunitinib and were included in the analyses. Six women (18.1%) had a partial response and six additional women (18.1%) stable disease. In total, ten patients (30.3%) had disease control for at least 6 months and of these, seven were controlled for more than one year. Median progression free and overall survival times were 3 months and 19.4 months, respectively. Adverse events related to treatment were frequent. At least one grade 3 toxicity occurred in 30 patients and dose reductions were required in 17 patients (52%). The most common grade 3 toxicities were fatigue, hypertension, palmar–plantar erythrodysesthesia, diarrhea and hematologic.

Conclusion

Sunitinib therapy showed promising activity in women with recurrent EC. Toxicity was seen frequently but was manageable. Anti-angiogenic agents warrant further investigation in EC to define which patients will derive the greatest benefit.     

Assessing the efficacy of targeting the phosphatidylinositol 3-kinase/AKT/mTOR signaling pathway in endometrial cancer

Objective

Alterations in the PI3K pathway are prevalent in endometrial cancer due to PIK3CA mutation and loss of PTEN. We investigated the anti-tumor activity of the PI3K inhibitor NVP BKM-120 (BKM) as a single agent and in combination with standard cytotoxic chemotherapy in a human primary endometrial xenograft model.

Methods

NOD/SCID mice bearing xenografts of primary human tumors with and without PIK3CA gene mutations were divided into two and four arm cohorts with equivalent tumor volumes. BKM was administered alone and in combination with paclitaxel and carboplatin (P/C) and endometrial xenograft tumor volumes were assessed. Tumors from the BKM, P/C, P/C + BKM and vehicle treated mice were processed for determination of PI3K/AKT/mTOR pathway activation.

Results

In both single agent experiments, BKM resulted in significant tumor growth suppression starting at days 5–10 compared to the linear growth observed in vehicle treated tumors (p < 0.04 in all experiments). Tumor resurgence manifested between days 14 and 25 (p < 0.03). When BKM was combined with P/C, this resistance pattern failed to develop in three separate xenograft lines (p < 0.05). Synergistic tumor growth suppression (p < 0.05) of only one xenograft tumor with no detected PIK3CA mutation was observed. Acute treatment with BKM led to a decrease in pAKT levels.

Conclusion

Independent of PIK3CA gene mutation, BKM mediated inhibition of the PI3K/AKT/mTOR pathway in endometrial tumors precludes tumor growth in a primary xenograft model. While a pattern of resistance emerges, this effect appears to be mitigated by the addition of conventional cytotoxic chemotherapy.     

Racial disparities and patterns of ovarian cancer surgical care in California

Objective

To investigate disparities in the frequency of ovarian cancer-related surgical procedures and access to high-volume surgical providers among women undergoing initial surgery for ovarian cancer according to race.

Methods

The California Office of Statewide Health Planning and Development database was accessed for women undergoing a surgical procedure that included oophorectomy for a malignant ovarian neoplasm between 1/1/06 and 12/31/10. Multivariate logistic regression analyses were used to evaluate differences in the odds of selected surgical procedures and access to high-volume centers (hospitals ≥ 20 cases/year) according to racial classification.

Results

A total of 7933 patients were identified: White = 5095 (64.2%), Black = 290 (3.7%), Hispanic/Latino =1400 (17.7%), Asian/Pacific Islander = 836 (10.5%) and other = 312 (3.9%). White patients served as reference for all comparisons. All minority groups were significantly younger (Black mean age 57.7 years, Hispanic 53.2 years, Asian 54.5 years vs. 61.1 years, p < 0.01). Hispanic patients had lower odds of obtaining care at a high-volume center (adjusted OR (adj. OR) = 0.72, 95% CI = 0.64–0.82, p < 0.01) and a lower likelihood of lymphadenectomy (adj. OR = 0.80, 95% CI = 0.70–0.91, p < 0.01), bowel resection (adj. OR = 0.80, 95% CI = 0.71–0.91, p < 0.01), and peritoneal biopsy/omentectomy (adj. OR = 0.69, 95% CI = 0.58–0.82, p < 0.01). Black racial classification was associated with a lower likelihood of lymphadenectomy (adj. OR = 0.76, 95% CI = 0.59–0.97, p = 0.03).

Conclusions

Among women undergoing initial surgery for ovarian cancer, Hispanic patients are significantly less likely to be operated on at a high-volume center, and both Black and Hispanic patients are significantly less likely to undergo important ovarian cancer-specific surgical procedures compared to White patients.     

Status of treatment for the overall population of patients with stage IVb endometrial cancer,and evaluation of the role of preoperative chemotherapy: A retrospective multi-institutional study of 426 patients in Japan

Objective

We previously reported on the role of cytoreduction in 248 patients with surgical stage IVb endometrial cancer (EMCA). This study aimed to evaluate the clinical characteristics, prognosis according to initial treatment, and impact of preoperative chemotherapy in the overall population of patients with clinical and surgical stage IVb EMCA.

Methods

A multi-institutional retrospective analysis was performed in 426 patients diagnosed with clinical and surgical stage IVb EMCA from 1996 to 2005. Factors associated with overall survival (OS) were identified using univariate and multivariate analyses.

Results

The median OS for all 426 patients was 14 months. Patients were divided into three groups according to their initial treatment: primary surgery group (n = 279), primary chemotherapy group (n = 125), and palliative care group (n = 22). The median OS times for these groups were 21, 12, and 1 month, respectively (p < 0.0001). Patients in the primary surgery group had better performance status (PS) and lower numbers of extra-abdominal metastases than those in the primary chemotherapy group. Multivariate analysis identified good PS, endometrioid histology, absence of clinical intra-abdominal stage IVb metastasis, hysterectomy, and chemotherapy as independent predictors of OS. In the primary chemotherapy group, 59 patients subsequently underwent surgery, and these patients had similar OS to those in the primary surgery group.

Conclusions

Hysterectomy and chemotherapy may prolong OS in selected patients with stage IVb EMCA. Our data suggest that primary chemotherapy followed by surgery may be a useful treatment choice in patients not suitable for primary surgery.     

TP53 K351N mutation-associated platinum resistance after neoadjuvant chemotherapy in patients with advanced ovarian cancer

Objective

TP53 K351N mutation is associated with acquired cisplatin resistance in ovarian cancer cells following exposure to cisplatin. We investigated the effect of TP53 K351N mutation on outcome in patients with epithelial ovarian cancer (EOC) who received platinum-based chemotherapy.

Methods

We assessed TP53 K351N mutations by allele specific real-time PCR (AS-PCR) and DNA sequencing in tumor samples of 153 patients with stage IIIC/IV EOC. Clinicopathologic and follow-up data were collected by a retrospective chart review.

Results

TP53 K351N mutations were detected in 8 (11.27%) of 71 patients who underwent neoadjuvant chemotherapy with interval debulking surgery (NACT-IDS) but not in 82 patients who underwent primary debulking surgery (PDS) (P < 0.01). In patients with relapse within 6 months, the relapse rate was 14 (19.72%) of 71 patients for NACT-IDS compared to 15 (18.29%) of 82 patients for PDS (P = 0.49), and TP53 K351N mutation was observed in 8 of NACT-IDS 14 patients (57.14% P < 0.01). In the patients retreated at first recurrence within 6 months, 7 with TP53 K351N mutation of 14 NACT-IDS patients exhibited progression of disease, compared to 2 of PDS 15 patients (50.00% vs. 13.33%, P = 0.04). The median disease-free survival (DFS) for NACT-IDS was 13.0 months compared to 15.0 months for PDS (P = 0.02). In multivariate analysis, TP53 K351N mutation is an independent factor for shorter DFS in the patients who underwent NACT-IDS (HR = 19.05; P = 0.01).

Conclusions

TP53 K351N mutation may be associated with induction of platinum resistance after NACT in advanced EOC.     

A phase II study of ramucirumab (IMC-1121B) in the treatment of persistent or recurrent epithelial ovarian,fallopian tube or primary peritoneal carcinoma

Objective

Vascular endothelial growth factor (VEGF) receptor-mediated signaling contributes to ovarian cancer pathogenesis. Elevated VEGF expression is associated with poor clinical outcomes. We investigated ramucirumab, a fully human anti-VEGFR-2 antibody, in patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Primary endpoints were progression-free survival at 6 months (PFS-6) and confirmed objective response rate (ORR).

Methods

Women who received ≥ 1 platinum-based chemotherapeutic regimen and had a platinum-free interval of < 12 months with measurable disease were eligible. Patients received 8 mg/kg ramucirumab intravenously every 2 weeks.

Results

Sixty patients were treated; one patient remained on study as of September 2013. The median age was 62 years (range: 27–80), and median number of prior regimens was 3. Forty-five (75%) patients had platinum refractory/resistant disease. Thirty-nine patients (65.0%) had serous tumors. PFS-6 was 25.0% (n = 15/60, 95% CI: 14.7–37.9%). Best overall response was: partial response 5.0% (n = 3/60), stable disease 56.7% (n = 34/60), and progressive disease 33.3% (n = 20/60). The most common treatment-emergent adverse events possibly related to study drug were headache (65.0%; 10.0% Grade ≥ 3), fatigue (56.7%; 3.3% Grade ≥ 3), diarrhea (28.3%; 1.7% Grade ≥ 3), hypertension (25.0%; 3.3% Grade ≥ 3), and nausea (20.0%; no Grade ≥ 3). Two patients experienced intestinal perforations (3.3% Grade ≥ 3). Pharmacodynamic analyses revealed changes in several circulating VEGF proteins following initial ramucirumab infusion, including increased VEGF-A, PlGF and decreased sVEGFR-2.

Conclusions

Although antitumor activity was observed, the predetermined efficacy endpoints were not met.     

Adjuvant radiation in early stage,unfavorable histology endometrial carcinoma is associated with improved local control and survival

Objective

Unfavorable histology endometrial carcinomas confer worse prognosis. We determined the association of adjuvant radiation on local recurrence and survival for unfavorable, early stage endometrial cancer.

Methods

We retrospectively identified 125 patients who had a hysterectomy for early stage (FIGO IA), unfavorable histology (clear cell, papillary serous or grade 3 endometrioid), endometrial carcinoma treated between 1992 and 2011. Patients were restaged according to current FIGO 2009 guidelines. Primary endpoint was local control and secondary endpoints were distant recurrence and overall survival.

Results

The median age of the cohort was 67 years old with a mean follow up 152 months. Adjuvant radiation was delivered in 60 patients (48%). There were a total of 24 recurrences; 5 had local–regional recurrences, 4 local and distant recurrence, 12 distant only recurrences, and 3 had unspecified recurrences. The 5-year local–regional control was 97.8% in patients who received radiation and 80.1% in patients who did not receive radiation (p = 0.018). The 5-year overall survival rate was 68.1% if patients did not receive radiation and 84.9% if they did receive radiation (p = 0.0062). On univariate analysis, only radiation (HR 0.12, 95% CI: 0.03 to 0.49, p-value = 0.018) was associated with a significant increase in local relapse free survival.

Conclusions

Adjuvant radiation therapy was significantly associated with an improvement in local–regional control and overall survival in patients with unfavorable histology, early stage endometrial cancer.     

Efficacy and safety of AEZS-108 (INN: Zoptarelin Doxorubicin Acetate) an LHRH agonist linked to doxorubicin in women with platinum refractory or resistant ovarian cancer expressing LHRH receptors: A multicenter Phase II trial of the ago-study group (AGO GYN 5)

Objectives

To evaluate the activity and toxicity of AEZS-108 (Zoptarelin Doxorubicin Acetate) an LHRH agonist linked to doxorubicin in women with platinum refractory or resistant ovarian cancer expressing LHRH receptors.

Methods

Women with epithelial ovarian, fallopian tube or primary peritoneal cancer, expressing LHRH receptors were eligible for this trial, when they had progression during treatment with a platinum based regimen or within 6 months after receiving a platinum based regimen and a previous taxane treatment. At least one measurable target lesion (RECIST) or CA-125 levels higher than twice the upper limit of normal range (GCIG-criteria) were required. Patients received AEZS-108 (267 mg/m² equimolar to 76.8 mg/m² of free doxorubicin) every 3 weeks as a two hour i.v. infusion.

Results

Fifty-five of 59 (93%) of ovarian cancer samples screened expressed LHRH receptors. 42 patients were enrolled in this study and received at least 1 infusion of AEZS-108 (ITT population). Of these 42 patients 6 (14.3%) had a partial response, 16 (38%) stable disease, 16 (38%) progressive disease and 4 patients were not evaluable. Median time to progression was 12 weeks (95% CI: 8–20 weeks), and median overall survival was 53 weeks (95% CI: 39–73 weeks). Toxicity profile was favorable.

Conclusion

AEZS-108 has a clinical activity in platinum refractory/resistant ovarian cancer which seems to be comparable to that of pegylated liposomal doxorubicin or to topotecan. Toxicity was comparably low. These data support the concept of a targeted chemotherapy for tumors expressing LHRH receptors.     

Adjuvant platinum-based chemotherapy for borderline serous ovarian tumors with invasive implants

Background

Most borderline ovarian tumors (BOTs) are cured with surgery. However BOTs with invasive implants have a poor prognosis with a mortality of 20–40%. The benefit of adjuvant chemotherapy (CT) in this setting remains poorly defined.

Methods

Retrospective study of serous BOT + invasive implants treated with adjuvant CT.

Results

36 patients were referred with serous BOTs + invasive implants and treated with surgery and platinum-based CT between 06/1982 and 02/2011. 83% were stage III/IV. Tumors demonstrated microinvasion, micropapillary pattern or desmoplastic implants in 53%, 47% and 67% of cases, respectively. 8% had fertility-sparing surgery. Taking into account initial and completion surgeries, R0 was achieved in 84% (27/32) (NA, N = 4). The majority (72%) received a combination of platinum + taxane. 11% of patients experienced a G3/G4 toxicity. 13 of 36 (36%) patients relapsed at a median of 27.3 months after diagnosis of invasive implants. Among 12 patients with histologically confirmed relapse, 8 patients progressed with invasive disease in the form of carcinoma or invasive implants. 5 year PFS/OS were 67%/96%. Neither microinvasion, micropapillary pattern, nor desmoplastic implants predicted relapse. In cases with evaluable disease, an objective response to chemotherapy was observed in 4 of 6 patients.

Conclusion

This is the largest study of BOT with invasive implants treated with surgery and adjuvant platinum-based CT. Treatment was well tolerated and the invasive relapse rate was 22% (8/36). Although numbers are small, the objective responses suggest a possible role for adjuvant CT in BOTs with invasive implants.     

Malignant ovarian germ cell tumors: Presentation,survival and second cancer in a population based Norwegian cohort (1953–2009)

Purpose

To quantify and compare survival in women with malignant ovarian germ cell tumors (MOGCTs) in Norway before and after the introduction of cisplatin-based chemotherapy (around 1980), and to explore the association between different types of treatment and the development of a second cancer.

Patients and methods

We identified 351 patients diagnosed with MOGCTs from 1953 to 2009 in the Cancer Registry of Norway. Ovarian cancer-specific survival was calculated separately for patients diagnosed before and after 1980. Patients were divided into subgroups by histological subtype (pure dysgerminoma, malignant teratoma, other MOGCTs) and extent of disease (localized and metastatic). We estimated the cumulative incidence of a second cancer in 10-year MOGCT survivors. Kaplan–Meier estimates were used, and p < 0.05 was considered significant.

Results

20-Year ovarian cancer-specific survival increased from 59% (95% CI 51% to 66%) before 1980 to 88% (95% CI 83%–93%) thereafter. Significant improvement was observed in all subgroups. No second cancer was diagnosed in any of 31 10-year MOGCT survivors treated with surgery only; second cancer was diagnosed in 23 of 139 patients who underwent cytotoxic treatment (98 radiotherapy ± chemotherapy, 41 chemotherapy only; p = 0.08). Patients aged > 50 years had a significantly poorer ovarian cancer-specific survival than younger patients (HR = 5.98, 95% CI 3.39–10.57) after adjustment for histological subtype and stage at presentation. Our results favor the treatment of patients with metastatic MOGCTs at large cancer centers.

Conclusion

Today women with MOGCTs have an excellent prognosis if treated according to modern therapeutic principles.