Predictors of progression free survival, overall survival and early cessation of chemotherapy in women with potentially platinum sensitive (PPS) recurrent ovarian cancer (ROC) starting third or subsequent line(≥3) chemotherapy - The GCIG symptom benefit study (SBS).

BACKGROUND: Potentially platinum sensitive recurrent ovarian cancer (PPS ROC) is defined by a platinum-free interval of >6 months, and usually treated with platinum-based chemotherapy with variable response and benefit in women who have had 3 or more lines of chemotherapy(≥3). We identified baseline characteristics (health-related quality of life[HRQL] and clinicopathological factors), associated with PFS, OS and early progression (within 8 weeks). The goal is to improve patient selection for chemotherapy based on a nomogram predicting PFS. METHODS: HRQL was assessed with EORTC QLQ-C30/QLQ-OV28. Associations with PFS and OS were assessed with Cox proportional hazards regression. Variables significant in univariable analysis were included in multivariable analyses using backward elimination to select those significant. Associations with stopping chemotherapy early were assessed with logistic regression. RESULTS: 378 women were enrolled, with median(m)OS and PFS of 16.6 months and 5.3 months, respectively. The majority had ECOGPS 0-1. Chemotherapy was stopped early in 45/378 participants (12%); with mOS 3.4 months (95% CI: 1.7-7.2). Physical function(PF), role function(RF), cognitive function(CF), social function(SF), Global Health Status(GHS) and abdominal/GI symptoms(AGIS) were significant univariable predictors of PFS(p < 0.030). SF remained significant after adjusting for clinicopathological factors; p = 0.03. PF, RF, CF, SF, GHS and AGIS were significant univariable predictors of OS (p < 0.007); PF, RF, SF and GHS remained significant predictors of OS in multivariable models; p < 0.007. Poor baseline PF and GHS were significant univariable predictors of stopping chemotherapy early (p < 0.007) but neither remained significant after adjusting for clinicopathological factors. CONCLUSION: Baseline HRQL is simple to measure, is predictive of PFS and OS and when used in conjunction with clinicopathological prognostic factors, can assist with clinical decision making and treatment recommendations for women with PPSROC≥3.

Safety and dose modification for patients receiving niraparib.

Background: Niraparib is a poly(ADP-ribose) polymerase inhibitor approved in the USA and Europe for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. In the pivotal ENGOT-OV16/NOVA trial, the dose reduction rate due to treatment-emergent adverse event (TEAE) was 68.9%, and the discontinuation rate due to TEAE was 14.7%, including 3.3% due to thrombocytopenia. A retrospective analysis was carried out to identify clinical parameters that predict dose reductions. Patients and methods: All analyses were carried out on the safety population, comprising all patients who received at least one dose of study drug. Patients were analyzed according to the study drug consumed (i.e., as treated). A predictive modeling method (decision trees) was used to identify important variables for predicting the likelihood of developing grade ≥3 thrombocytopenia within 30 days after the first dose of niraparib and determine cut-off points for chosen variables. Results: Following dose modification, 200 mg was the most commonly administered dose in the ENGOT-OV16/NOVA trial. Baseline platelet count and baseline body weight were identified as risk factors for increased incidence of grade ≥3 thrombocytopenia. Patients with a baseline body weight <77 kg or a baseline platelet count <150 000/µl in effect received an average daily dose ∼200 mg (median = 207 mg) due to dose interruption and reduction. Progression-free survival in patients who were dose reduced to either 200 or 100 mg was consistent with that of patients who remained at the 300 mg starting dose. Conclusions: The analysis presented suggests that patients with baseline body weight of <77 kg or baseline platelets of <150 000/µl may benefit from a starting dose of 200 mg/day. ClinicalTrials.gov ID: NCT01847274.

Cytoreductive surgery for ovarian cancer: quality assessment.

Surgery is the cornerstone of treatment of ovarian cancer. Given the importance of achieving no or minimal macroscopic residual disease at primary surgery, performing an assessment of the quality of ovarian cancer surgery is crucial. Assessing the quality of care and surgical outcome allows us to establish baseline information, set standards of care and clear priorities, enable benchmarking against peers, and sustain quality improvement. We know that suboptimal care exists and variation in outcomes results. One way to monitor variation in outcomes is through a clinical quality registry (CQR). A CQR collects a defined minimum dataset to measure performance of an individual or center against a range of clinical quality indicators and provides risk-adjusted, benchmarked data to participating institutions. CQR's are an excellent quality assurance measure as they capture all cases (an opt out system). They permit detection and analysis of unwarranted variations in care. This can provide indications of a systems or process problem, thereby motivating health care providers to improve services and care. Several groups have either developed quality indicators for advanced ovarian cancer surgery (The Scottish Cancer Taskforce and the European Society of Gynecological Oncology) or are in the process of doing so (Australian Society of Gynaecological Oncologists). Indicators should be evidence-based and determined by extensive discussion with experts and stakeholders to ensure appropriateness and buy-in. The Scottish Cancer Taskforce and European Society of Gynecological Oncology have set targets for their quality performance measures, which should provide a quantitative framework for improving care in the surgical management of ovarian cancer.

Fifth Ovarian Cancer Consensus Conference: individualized therapy and patient factors.

This manuscript reports the consensus statements regarding the design and conduct of clinical trials in patients with newly diagnosed and recurrent epithelial ovarian cancer (EOC), following deliberation at the Fifth Ovarian Cancer Consensus Conference (OCCC), held in Tokyo in November 2015. Three important questions were identified for discussion prior to the meeting and achieved consensus during the meeting: (i) What are the most important factors to be evaluated prior to initial therapy? (ii) What are the most important factors to be evaluated specifically in recurrent disease? (iii) Are there specific considerations for special patient subpopulations? In addition, we report a list of important unmet needs compiled during the consensus process, which is intended to guide future research initiatives.

Predictors of survival in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery based on the pooled analysis of an international collaborative cohort.

BACKGROUND: This study aims to identify prognostic factors and to develop a risk model predicting survival in patients undergoing secondary cytoreductive surgery (SCR) for recurrent epithelial ovarian cancer. METHODS: Individual data of 1100 patients with recurrent ovarian cancer of a progression-free interval at least 6 months who underwent SCR were pooled analysed. A simplified scoring system for each independent prognostic factor was developed according to its coefficient. Internal validation was performed to assess the discrimination of the model. RESULTS: Complete SCR was strongly associated with the improvement of survival, with a median survival of 57.7 months, when compared with 27.0 months in those with residual disease of 0.1-1 cm and 15.6 months in those with residual disease of >1 cm, respectively (P<0.0001). Progression-free interval (≤23.1 months vs >23.1 months, hazard ratio (HR): 1.72; score: 2), ascites at recurrence (present vs absent, HR: 1.27; score: 1), extent of recurrence (multiple vs localised disease, HR: 1.38; score: 1) as well as residual disease after SCR (R1 vs R0, HR: 1.90, score: 2; R2 vs R0, HR: 3.0, score: 4) entered into the risk model. CONCLUSION: This prognostic model may provide evidence to predict survival benefit from secondary cytoreduction in patients with recurrent ovarian cancer.

Imaging and cancer of the cervix in low- and middle-income countries.

Cervix cancer is the fourth most common cancer globally but the second most cancer in women in resource-limited countries. It has remained a clinically-staged neoplasm as per the International Federation of Gynecology and Obstetrics staging classification. As the imaging machines are becoming more available worldwide, the resource-stratified guidelines recommended the inclusion of imaging whenever possible to guide treatment planning. In this report, the utility of imaging in low- and middle-income countries for diagnosis and treatment of cancer of the cervix will be reviewed.

Collaborations in gynecologic oncology education and research in low- and middle- income countries: Current status, barriers and opportunities.

Eighty-five percent of the incidents and deaths from cervical cancer occur in low and middle income countries. In many of these countries, this is the most common cancer in women. The survivals of the women with gynecologic cancers are hampered by the paucity of prevention, screening, treatment facilities and gynecologic oncology providers. Increasing efforts dedicated to improving education and research in these countries have been provided by international organizations. We describe here the existing educational and research programs that are offered by major international organizations, the barriers and opportunities provided by these collaborations and hope to improve the outcomes of cervical cancer through these efforts.

Natural killer inhibitory substance produced by the peritoneal cells of patients with ovarian cancer.

Peritoneal cells obtained from 8 patients with minimal residual ovarian cancer produced a substance during in vitro culture that markedly inhibited the expression of natural killer (NK) cell-mediated lysis. Its molecular weight was less than 2,000, the same size as the NK-inhibiting substance (NK-IS), a similar NK-suppressive molecule produced by the peritoneal cells of rats. Human NK-IS suppressed the expression of antibody-dependent cell cytotoxicity as well as NK lysis, but it had no effect on erythrocyte-rosette formation and was not cytotoxic to peripheral blood lymphocytes or cell fractions enriched for large granular lymphocytes. NK-IS inhibited lysis mediated by interferon-activated lymphocytes and completely prevented NK activation when used in a preincubation. During intraperitoneal immunotherapy with Corynebacterium parvum, an agent that can activate peritoneal cytotoxic effectors, the production of NK-IS by peritoneal cells decreased considerably. Human peritoneal cells produce an NK-IS similar to the peritoneal cells of rats, and this material may create an environment within the peritoneal cavity that is permissive to the growth of NK-sensitive tumor cells.

Role of inflammatory neutrophils in antitumor effects induced by intraperitoneal administration of Corynebacterium parvum in mice.

We studied the role of inflammatory neutrophils in the antitumor effects that follow i.p. injection of Corynebacterium parvum (1400 micrograms) into C3HeB/FeJ mice challenged with the murine ovarian teratocarcinoma. Peritoneal neutrophils, obtained from mice 6 hr after injection of C. parvum, exerted significant antitumor effects when injected admixed with murine ovarian terato-carcinoma cells into the peritoneal cavities of normal mice. Treatment of recipient mice with whole-body irradiation or repeated injections of silica prevented the antitumor effects, indicating that neutrophils were activating a second effector mechanism in recipient mice. Peritoneal cells obtained at 24 or 72 hr or at 7 or 11 days following C. parvum injection were considerably less effective in activation of this effector mechanism. Heat-killed C. parvum (6 hr)-induced neutrophils activated antitumor responses, but thioglycolate-induced cells were without effect. Antitumor responses in mice receiving peritoneal neutrophils were not due to simple transfer of C. parvum organisms in the inocula. These results indicate that inflammatory neutrophils, elicited into the peritoneal cavity by injection of C. parvum, play an important role in the activation of subsequent antitumor effects.

Intraperitoneal administration of human recombinant interferon-alpha in patients with ovarian cancer: effects on lymphocyte phenotype and cytotoxicity.

Eleven patients with persistent Stage III ovarian cancer, documented at second look laparotomy, received i.p. human recombinant interferon-alpha (5-50 x 10(6) units/week). Prior to immunotherapy, patients' peritoneal cell lymphocytes (PCLs) contained decreased proportions of Leu-7+ and Fc-receptor+ cells and almost nondetectable natural killer (NK) and antibody-dependent cell cytotoxic (ADCC) activity. In contrast, patients' peripheral blood lymphocytes (PBLs) contained normal proportions of lymphocyte subsets and cytotoxic activity compared to control donor PBLs. During therapy, there was a concurrent increase in PCL Leu-7+ cells and NK lysis. Both peaked predictably at 24 h after each treatment, regardless of the dose injected, and usually returned to baseline by Day 7 of each weekly cycle. PCL NK enhancement was striking, usually increasing from 2-6% (effector:target ratio, 25:1) to over 30% lysis. Enhancement of PCL ADCC was less impressive. PCLs of several patients developed lytic activity towards NK-resistant Raji targets. During therapy, patients' PBLs demonstrated: (a) modestly enhanced NK lysis at Day 4 of each cycle, and; (b) no development of Raji lysis. These data clearly demonstrate the efficacy of i.p. interferon in activation of peritoneal NK activity. However, increased NK lysis did not correlate with individual tumor responses in this cohort of patients.

Constitutive production of interleukin 6 by ovarian cancer cell lines and by primary ovarian tumor cultures.

We examined the production and utilization of interleukin 6 (IL-6), a multifunctional cytokine with diverse biological effects, by both ovarian cancer cell lines and primary ovarian tumor cultures. We have found that epithelial ovarian cancer cell lines (CAOV-3, OVCAR-3, and SKOV-3) constitutively produce varying amounts of IL-6. This molecule is biologically active as determined by the proliferation of an IL-6-dependent hybridoma cell line, MH60.BSF-2, and is detectable by an IL-6 enzyme-linked immunosorbent assay. By cytoplasmic immunoperoxidase staining, greater than 98% of the cells produce at least some IL-6, with variation in the staining intensity between individual cells. The ovarian cancer cell-produced protein has a molecular weight of approximately 24,000, and exhibits some molecular weight heterogeneity, with Mr 27,000 and 28,000 minor forms of IL-6. The levels of IL-6 produced by ovarian cancer cells can be modulated by other inflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1 beta, and interferon-gamma. Our results suggest that IL-6 is not an autocrine growth factor for these established ovarian tumor cell lines, because the addition of either exogenous IL-6 or antibodies to IL-6 did not affect the cellular proliferation of the cell lines. We also found significant levels (greater than 3 ng/ml) of IL-6 in ascitic fluids of ovarian cancer patients and in the supernants of primary cultures from freshly excised ovarian tumors. The production of IL-6 by epithelial ovarian cancer cells may prove to be a useful diagnostic tool and aid in investigation of the host immune response to ovarian cancer.

Resistance of human ovarian cancer cells to tumor necrosis factor and lymphokine-activated killer cells: correlation with expression of HER2/neu oncogenes.

Since overexpression of HER2/neu oncogenes in breast cancer cells is associated with resistance to the cytotoxic effect of tumor necrosis factor (TNF), we investigated whether this correlation also existed for ovarian cancer targets. Nine continuously cultured human ovarian cancer lines were studied and compared to 3 breast cancer lines. Three of the ovarian and 1 breast cancer line demonstrated amplified HER2/neu genes by Southern analysis, increased HER2/neu RNA by Northern analysis, and marked immunoperoxidase staining for HER2/neu protein. The other 8 lines contained unamplified genes and undetectable RNA and protein. All 4 overexpressed lines were relatively resistant to the cytotoxic effects of TNF. Interestingly, they were also resistant to lymphokine-activated killer cells. In contrast, 7 of 8 nonexpressed lines showed sensitivity to TNF and all 8 were sensitive to lymphokine-activated killer cells. There was no difference in sensitivity to lysis by hydrogen peroxide or peptide defensins between over- and nonexpressed lines. These data indicate that expression of HER2/neu oncogenes may impart a proliferative advantage in tumor cells due to induction of resistance to several different cytotoxic mechanisms.

Intraperitoneal immunotherapy of human ovarian carcinoma with Corynebacterium parvum.

Corynebacterium parvum has been administered i.p. to 14 patients with advanced ovarian cancer. Two patients had responded completely to cytoreductive surgery and combination chemotherapy prior to immunotherapy, and one patient with residual disease had received only a single course of C. parvum due to i.p. catheter malfunction. Among the 11 patients with residual disease evaluable for response, from three to eight i.p. treatments with C. parvum produced surgically confirmed tumor regression in five patients (45%) with three partial responses and two complete responses of 5 and 12 months duration. All responders had (a) multiple tumor nodules less than 0.5 cm at the initiation of immunotherapy, and (b) severe abdominal pain and fever after C. parvum injection. Overall, 58 courses of immunotherapy were associated with abdominal pain (91%), fever (67%), nausea (52%), vomiting (31%), and hypotension that responded promptly to i.v. infusion of fluids (10%). Use of i.p. cathethers was associated with two episodes each of infection and intraabdominal bleeding. Administration of C. parvum i.p. has augmented the ability of human peritoneal cells to lyse human ovarian carcinoma cell lines in the presence of specific rabbit heteroantiserum. C. parvum administered i.p. has inhibited the growth of human ovarian carcinoma and may prove useful for modulating the activity of human effectors for antibody-dependent cell-mediated cytotoxicity.

Synergistic effects of combination sequential immunotherapies in a murine ovarian cancer model.

The antitumor effects of Corynebacterium parvum in a murine ovarian teratocarcinoma model depend upon a sequential activation of neutrophils and macrophages within the peritoneal cavity. We studied the sequential administration of biological response modifiers that independently activate each phase of the response. Tumor-challenged mice treated by i.p. injection of a pyridine-extracted fraction of cell-free Propionibacterium acnes (PA-PE, 1400 micrograms) demonstrated prolonged survival in less than 20% of the cases. An i.p. injection of a detoxified Salmonella endotoxin (DSE) preparation (150 micrograms) had no effect on tumor outgrowth. However, i.p. treatment with PA-PE (1400 micrograms), followed by 150 micrograms of DSE 1 day later, resulted in long-term survival (greater than 100 days) in 40 to 60% of mice. This antitumor effect was only evident when PA-PE was administered first (before DSE) and optimal when DSE was administered 24 h after PA-PE. The synergistic antitumor effect could be duplicated when tumor-challenged mice were first treated i.p. with peritoneal polymorphonuclear leukocytes, elicited by injection of PA-PE, and then treated with DSE 18 h later. These data indicate that appropriately timed injection of biological response modifiers with complementary effects can result in a synergistic prevention of tumor growth.

Intraperitoneal recombinant alpha-interferon for "salvage" immunotherapy in stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study.

Fourteen patients with persistent epithelial ovarian cancer documented at second look laparotomy after combination chemotherapy were treated with 146 cycles of alpha-recombinant interferon (rIFN-alpha 2) administered i.p. The initial dose was 5 X 10(6) units which was escalated weekly to 50 X 10(6) units over 4 weeks and then continued weekly for a total of 16 weeks. Eleven patients underwent surgical reevaluation after therapy which confirmed four pathological complete responses (36%), one partial response (9%), and disease progression in six patients (55%). Five of seven patients (71%) with residual tumor less than 5 mm had a surgically documented response, whereas there was no response in the four patients whose tumors were greater than or equal to 5 mm. Three patients were evaluable for clinical response only: one patient who refused surgery had a complete clinical response with total resolution of ascites; one had stable disease; and one had disease progression. Fever greater than or equal to 38 degrees C was seen in 58%, fever greater than or equal to 39.0 degrees C was seen in 18%, vomiting in 37%, abdominal pain was reported in 22%, and one patient had infectious peritonitis. Peripheral white blood cell counts and i.p. washings were obtained pretreatment and on days 1, 3, and 7 after treatment. While there was no consistent alteration in peripheral white blood cell counts, the numbers of i.p. monocytes and lymphocytes showed a significant boost on day 1 after each dose of rIFN-alpha 2. Natural killer lymphocyte cytotoxicity was elevated in the i.p. cavity fluid obtained from most patients on day 1 after treatment, while blood natural killer lymphocyte cytotoxicity values showed considerable variability. Pharmacokinetic studies show that i.p. levels of rIFN-alpha 2 were 30-1000 times blood levels. rIFN-alpha 2 i.p. may act by increasing concentrations of drug and augmenting regional host cells in patients with minimal residual ovarian cancer.

Immunotherapy with biochemically dissociated fractions of Propionibacterium acnes in a murine ovarian cancer model.

The antitumor effect of two strains of Propionibacterium acnes (PAI and PAII) and chemically derived fractions from the whole bacterial cell were studied using a murine ovarian teratocarcinoma (MOT) model. When injected i.p. in high doses (700 to 1400 micrograms/mouse), both strains produce survival of a significant proportion of tumor-bearing mice (30 to 90%). On a weight to weight basis, however, PAI was significantly more effective than PAII. PAI and PAII were extracted using pyridine, which yielded four fractions, i.e., pyridine-extracted strains PAI and PAII (PA-PEI and PA-PEII, respectively) which are composed of the cell wall material extracted by pyridine, and the residues of PA-PEI and PA-PEII (PA-RI and PA-RII, respectively) which are composed of the residue material following the chemical extraction. The chemical composition of PA-PEI was different from that of PA-PEII (the latter had proportionately three times as many carbohydrates and one-third of the protein content of the former) and so were their antitumor properties in the MOT model. PA-PEI had markedly reduced antitumor effect when compared to the untreated cell on a per weight basis. Furthermore, curability was only seen when using a high dose (1400 micrograms/mouse). By contrast, the cell wall components extracted by pyridine from PAII (PA-PEII) had powerful antitumor effects, i.e., greater than 50% of mice given 1400-micrograms injections survived. The material contained in PA-PEII was further fractionated on the basis of its organic solubility in chloroform:methanol solvent. The water-soluble and solvent-insoluble fractions retained most of the antitumor effects of PA-PEII, while the water-insoluble and solvent-soluble fractions were only moderately effective, suggesting that the active moiety(ies) was associated with the nonlipid components of this fraction. Both residue fractions (PA-RI and PA-RII) were as effective on a per weight basis in controlling the growth of 10(5) tumor inoculum as were whole untreated cells. However, periodate oxidation of PA-RI resulted in complete loss of its antitumor effects. When surviving mice that had no evidence of tumor persistence following a tumor challenge (10(5) MOT cells) and i.p. treatment with PA were subsequently rechallenged with 10(4) tumor cells, survival was significantly prolonged, as compared to tumor-challenged (10(4) MOT) naive mice. In addition, 10 to 20% of these rechallenged mice had complete eradication of the tumor inoculum (no evidence of disease for greater than 120 days).(ABSTRACT TRUNCATED AT 400 WORDS)

Progression-free and overall survival in ovarian cancer patients treated with CVac, a mucin 1 dendritic cell therapy in a randomized phase 2 trial.

BACKGROUND: CAN-003 was a randomized, open-label, Phase 2 trial evaluating the safety, efficacy and immune outcomes of CVac, a mucin 1 targeted-dendritic cell (DC) treatment as a maintenance therapy to patients with epithelial ovarian cancer (EOC). METHODS: Patients (n = 56) in first (CR1) or second clinical remission (CR2) were randomized (1:1) to standard of care (SOC) observation or CVac maintenance treatment. Ten doses were administered over 56 weeks. Both groups were followed for progression-free survival (PFS) and overall survival (OS). RESULTS: Fifty-six patients were randomized: 27 to SOC and 29 to CVac. Therapy was safe with only seven patients with Grade 3-4 treatment-emergent adverse events. A variable but measurable mucin 1 T cell-specific response was induced in all CVac-treated and some standard of care (SOC) patients. Progression free survival (PFS) was not significantly longer in the treated group compared to SOC group (13 vs. 9 months, p = 0.36, hazard ratio [HR] = 0.73). Analysis by remission status showed in the CR1 subgroup a median PFS of 18 months (SOC) vs. 13 months (CVac); p = 0.69 (HR = 1.18; CI 0.52-2.71). However CR2 patients showed a longer median PFS in the CVac-treated group (median PFS not yet reached, >13 vs. 5 months; p = 0.04, HR = 0.32 CI). OS for CR2 patients at 42 months of follow-up showed a difference of 26 months for SOC vs. > 42 months for CVac-treated (as median OS had not been reached; HR = 0.17 (CI 0.02-1.4) with a p = 0.07). CONCLUSIONS: CVac, a mucin 1-dendritic cell maintenance treatment was safe and well tolerated in ovarian cancer patients. A variable but observed CVac-derived, mucin 1-specific T cell response was measured. Notably, CR2 patients showed an improved PFS and lengthened OS. Further studies in CR2 ovarian cancer patients are warranted (NCT01068509). TRIAL REGISTRATION: NCT01068509. Study Initiation Date (first patient screened): 20 July 2010. Study Completion Date (last patient observation): 20 August 2013, the last patient observation for progression-free survival; 29 April 2015, the last patient was documented regarding overall survival.