Paraneoplastic Thrombocytosis in Ovarian Cancer Stone, Rebecca L; Nick, Alpa M; McNeish, Iain A ...
New England journal of medicine/The New England journal of medicine,
02/2012, Letnik:
366, Številka:
7
Journal Article
Recenzirano
Odprti dostop
In patients with ovarian cancer and thrombocytosis, tumors may express interleukin-6, which stimulates production of thrombopoietin. The increase in platelets is associated with more rapid disease ...progression. Therapies that lower platelet counts may enhance antitumor effects of other agents.
Platelets are highly reactive cellular effectors of hemostasis, immunity, and inflammation.
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The concept that platelets play key roles in cancer growth and metastasis is long-standing. In fact, the clinical observation that thrombocytosis (defined as a platelet count of >450,000 per cubic millimeter) occurs in patients with solid tumors was made more than 100 years ago.
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,
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Nearly 40% of persons incidentally found to have platelet counts exceeding 400,000 per cubic millimeter in the absence of iron deficiency and benign inflammatory conditions have an occult cancer, most commonly a primary gastrointestinal, lung, breast, or ovarian cancer.
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Beyond clinical observations, experimental evidence . . .
PURPOSE Sorafenib is a kinase inhibitor targeting Raf and other kinases (ie, vascular endothelial growth factor receptor VEGFR, platelet-derived growth factor receptor PDGFR, Flt3, and c-KIT). This ...study assessed its activity and tolerability in patients with recurrent ovarian cancer (OC) or primary peritoneal carcinomatosis (PPC). METHODS This open-label, multi-institutional, phase II study used a two-stage design. Eligible patients had persistent or recurrent OC/PPC after one to two prior cytotoxic regimens, and they experienced progression within 12 months of platinum-based therapy. Treatment consisted of sorafenib 400 mg orally twice per day. Primary end points were progression-free survival (PFS) at 6 months and toxicity by National Cancer Institute criteria. Secondary end points were tumor response and duration of PFS and overall survival. Biomarker analyses included measurement of ERK and b-Raf expression in tumors and phosphorylation of ERK (pERK) in peripheral-blood lymphocytes (PBLs) before and after 1 month of treatment. Results Seventy-three patients were enrolled, of which 71 were eligible. Fifty-nine eligible patients (83%) had measurable disease, and 12 (17%) had detectable disease. Significant grade 3 or 4 toxicities included the following: rash (n = 7), hand-foot syndrome (n = 9), metabolic (n = 10), GI (n = 3), cardiovascular (n = 2), and pulmonary (n = 2). Only patients with measurable disease were used to assess efficacy. Fourteen survived progression free for at least 6 months (24%; 90% CI, 15% to 35%). Two patients had partial responses (3.4%; 90% CI, 1% to 10%); 20 had stable disease; 30 had progressive disease; and seven could not have their tumor assessed. ERK and b-Raf were expressed in all tumors. Exploratory analyses indicated that pERK in post-treatment PBL specimens was associated with PFS. CONCLUSION Sorafenib has modest antitumor activity in patients with recurrent OC, but the activity was at the expense of substantial toxicity.
In randomized trials the combination of cisplatin and paclitaxel was superior to cisplatin and cyclophosphamide in advanced-stage epithelial ovarian cancer. Although in nonrandomized trials, ...carboplatin and paclitaxel was a less toxic and highly active combination regimen, there remained concern regarding its efficacy in patients with small-volume, resected, stage III disease. Thus, we conducted a noninferiority trial of cisplatin and paclitaxel versus carboplatin and paclitaxel in this population.
Patients with advanced ovarian cancer and no residual mass greater than 1.0 cm after surgery were randomly assigned to receive cisplatin 75 mg/m2 plus a 24-hour infusion of paclitaxel 135 mg/m2 (arm I), or carboplatin area under the curve 7.5 intravenously plus paclitaxel 175 mg/m2 over 3 hours (arm II).
Seven hundred ninety-two eligible patients were enrolled onto the study. Prognostic factors were similar in the two treatment groups. Gastrointestinal, renal, and metabolic toxicity, as well as grade 4 leukopenia, were significantly more frequent in arm I. Grade 2 or greater thrombocytopenia was more common in arm II. Neurologic toxicity was similar in both regimens. Median progression-free survival and overall survival were 19.4 and 48.7 months, respectively, for arm I compared with 20.7 and 57.4 months, respectively, for arm II. The relative risk (RR) of progression for the carboplatin plus paclitaxel group was 0.88 (95% confidence interval CI, 0.75 to 1.03) and the RR of death was 0.84 (95% CI, 0.70 to 1.02).
In patients with advanced ovarian cancer, a chemotherapy regimen consisting of carboplatin plus paclitaxel results in less toxicity, is easier to administer, and is not inferior, when compared with cisplatin plus paclitaxel.
Platinum and taxane compounds have demonstrated activity in uterine carcinosarcoma (malignant mixed Mullerian tumor). Ifosfamide plus paclitaxel is the regimen with established superiority based on a ...randomized phase III trial conducted through the Gynecologic Oncology Group. However, the toxicity, multiday schedule, and limited activity of this regimen support further development of novel regimens. Our primary objective was to estimate the antitumor activity and toxicity of paclitaxel plus carboplatin in patients with uterine carcinosarcomas.
Eligible patients had advanced stage (III or IV), persistent or recurrent measurable disease, and no prior chemotherapy. Patients received paclitaxel at 175 mg/m(2) intravenously (IV) over 3 hours plus carboplatin (area under the serum concentration-time curve = 6) IV over 30 minutes every 3 weeks until disease progression or until adverse effects occurred. Common Terminology Criteria for Adverse Events v3.0 was used to grade adverse events.
Fifty-five patients were entered onto the study with nine being excluded from analysis, leaving 46 evaluable for analysis. Treatment was well tolerated with expected hematologic toxicity and minimal nonhematologic grade 4 toxicity (one cardiovascular and two pain) with 59% of patients completing six or more cycles of chemotherapy. The proportions of patients with confirmed complete and partial responses were 13% and 41%, respectively, resulting in a total overall response rate of 54% (95% CI, 37% to 67%).
Paclitaxel plus carboplatin demonstrates antitumor activity against uterine carcinosarcoma with acceptable toxicity and warrants further evaluation in phase III randomized trials.
Abstract Objective Doxorubicin-based treatment is standard therapy for metastatic uterine leiomyosarcoma. There is no standard second-line therapy. We determined activity of fixed-dose rate ...gemcitabine plus docetaxel as second-line treatment for metastatic uterine leiomyosarcoma. Methods Eligible women with unresectable uterine leiomyosarcoma progressing after prior cytotoxic therapy were treated with gemcitabine 900 mg/m2 days one and eight over 90 min, plus docetaxel 100 mg/m2 on day 8 of a 21-day cycle with granulocyte growth factor. Patients with prior pelvic radiation received lower doses. Response Evaluation Criteria in Solid Tumors (RECIST) response was assessed by computed tomography (CT). Results Forty-eight of 51 women were evaluable for response (one wrong histology, two never treated). Prior therapy was doxorubicin-based in 90%, and ifosfamide-based in 6%. The overall objective response rate is 27%, with complete response in 6.3% (3/48), and partial response in 20.8% (10/48). An additional 50% (24/48) had stable disease (median duration 5.4 months). The median number of cycles per patient was 5.5 (range 1–22); 73% of patients remained progression-free at 12 weeks and 52% at 24 weeks. The predominant toxicity was uncomplicated myelosuppression: thrombocytopenia grade 3 (29%), grade 4 (10.4%); neutropenia grade 3 (12.5%), grade 4 (8.3%) anemia grade 3 (20.8%), grade 4 (4.2%). While pulmonary toxicity was reported, no patient had drug-related pneumonitis/hypoxia-type toxicity. Median progression-free survival (PFS) was 5.6+ months (range 0.7–27+ months). The median duration of objective response was 9+ months (range 3.9–24.5+ months). Conclusion Fixed-dose rate gemcitabine plus docetaxel is active second-line therapy for uterine leiomyosarcoma.
Chronic stress is associated with hormonal changes that are known to affect multiple systems, including the immune and endocrine systems, but the effects of stress on cancer growth and progression ...are not fully understood. Here, we demonstrate that human ovarian cancer cells exposed to either norepinephrine or epinephrine exhibit lower levels of anoikis, the process by which cells enter apoptosis when separated from ECM and neighboring cells. In an orthotopic mouse model of human ovarian cancer, restraint stress and the associated increases in norepinephrine and epinephrine protected the tumor cells from anoikis and promoted their growth by activating focal adhesion kinase (FAK). These effects involved phosphorylation of FAKY397, which was itself associated with actin-dependent Src interaction with membrane-associated FAK. Importantly, in human ovarian cancer patients, behavioral states related to greater adrenergic activity were associated with higher levels of pFAKY397, which was in turn linked to substantially accelerated mortality. These data suggest that FAK modulation by stress hormones, especially norepinephrine and epinephrine, can contribute to tumor progression in patients with ovarian cancer and may point to potential new therapeutic targets for cancer management.
Inflammatory processes have been implicated in the pathogenesis of both depression and cancer. Links between depressive symptoms, interleukin-6 (IL-6), and cortisol dysregulation have been ...demonstrated in cancer patients, but vegetative versus affective components of depression have been minimally examined. The objective of the current study was to examine associations between IL-6, diurnal cortisol rhythms, and facets of depression in epithelial ovarian cancer patients.
Patients awaiting surgery for a pelvic mass suspected for ovarian cancer completed questionnaires, collected salivary samples for 3 days presurgery, and gave a presurgical blood sample. Ascites was obtained during surgery. IL-6 was measured by enzyme-linked immunosorbent assay and cortisol by a chemiluminescence immunoassay. The final sample included 112 invasive ovarian cancer patients (86 advanced stage, 26 early stage) and 25 patients with tumors of low malignant potential (LMP).
Advanced-stage ovarian cancer patients demonstrated elevations in vegetative and affective depressive symptoms, plasma IL-6, and the cortisol area under the curve (AUC) compared with patients with LMP tumors (all P < .05). Among invasive ovarian cancer patients, greater vegetative depression was related to elevated IL-6 in plasma (P = .008) and ascites (P = .024), but affective depression was unrelated to IL-6. Elevations in total depression (P = .026) and vegetative depression (P = .005) were also related to higher evening cortisol levels. Plasma IL-6 was related to greater afternoon and evening cortisol and cortisol AUC (all P values < .005).
These results demonstrate significant relationships between IL-6, cortisol, and vegetative depression, and may have implications for treatment of depression in ovarian cancer patients.
Purpose: Stromal cells in the tumor microenvironment, such as macrophages, play an active role in tumor growth and angiogenesis. However,
little is known about relationships of biobehavioral factors ...with angiogenic cytokines and matrix metalloproteinases (MMP)
produced by stromal cells. This study examined distress, MMPs, and angiogenic cytokines in ovarian cancer patients and in vitro .
Experimental Design: Patients suspected of ovarian cancer completed preoperative questionnaires. At surgery, 56 were confirmed to have epithelial
ovarian cancer. Tumor samples were analyzed for macrophage (CD68 + ) and tumor cell levels of MMP-2, MMP-9, and vascular endothelial growth factor. In vitro stimulation of isolated macrophage cells by the stress hormones norepinephrine and cortisol was done to assess effects on
MMP-9.
Results: Depressed patients showed significant elevations of MMP-9 in CD68 + cells, adjusting for stage ( P < 0.0001). Patients with higher levels of current stress ( P = 0.01), life stress over the last 6 months ( P = 0.004), and general negative affect ( P = 0.007) also showed significantly greater MMP-9 in CD68 + cells. In contrast, higher social support was associated with lower levels of MMP-9 ( P = 0.023) and vascular endothelial growth factor ( P = 0.036) in tumor cells. In vitro analyses showed that macrophage MMP-9 production could be directly enhanced (up to a 2-fold increase) by the stress hormones
norepinephrine and cortisol.
Conclusions: Ovarian cancer patients with elevated depressive symptoms, chronic stress, and low social support showed elevations in MMP-9
in tumor-associated macrophages. Direct in vitro enhancement of stromal MMP-9 production by stress hormones was also shown. These findings may have implications for patient
outcomes in ovarian cancer.
Objectives. The coexistence of carcinomas of the endometrium and ovary occurs in about 10% of women with ovarian carcinoma. It is often unclear whether this represents synchronous primary tumors or ...metastasis from endometrium to ovary, or from ovary to endometrium; consequently, staging, therapy, and expected outcome are uncertain. The Gynecologic Oncology Group sought to study patients with simultaneously detected adenocarcinomas in the endometrium and ovary with disease grossly confined to the pelvis to explore the possible correlation among discrete tumor subsets, natural history, and survival.
Methods. Between 1985 and 1991, 85 patients were prospectively enrolled, of whom 74 were eligible. All were initially treated with total abdominal hysterectomy, bilateral salpingo-oophorectomy, and staging laparotomy, with radiation and chemotherapy left to the discretion of the treating physician and patient. Fifteen pathologic variables were examined to identify differences in tumor behavior.
Results. Of the 74 patients, 23 (31%) had microscopic spread of tumor in the pelvis or abdomen. Sixty-four (86%) patients had endometrioid carcinomas in both the endometrium and the ovary, and endometriosis was found in the ovary of 23 (31%) patients. There was concordance between the histologic grade of the tumor in the ovary and the uterus in 51 (69%) patients. The estimated probability of recurrence 5 years following staging surgery is 15.1% (95% confidence interval (CI): 8.7–25.2%). The presence of metastasis discriminated two groups of patients that experienced different probabilities of recurrence within 5 years: 10.0% (95% CI: 4.32–21.3%) for those with tumors confined to the uterus and ovary and 27.1% (95% CI: 13.0–48.5%) for those with metastasis (hazard ratio = 4.6, P = 0.006). The histologic grades of ovarian and uterine tumors also distinguished groups of patients with different probabilities of recurrence at 5 years: 8.0% (95% CI: 2.8–21.3%) for those patients with no more than grade 1 disease at either site and 22.4% (95% CI: 11.8–38.4%) for those with a higher grade in either the ovary or the endometrium (hazard ratio = 3.1, P = 0.047). The estimated overall probability of surviving 5 years is 85.9% and that of surviving 10 years is 80.3%.
Conclusion. The prognosis for women with simultaneously detected carcinomas in the uterus and ovary with gross disease confined to the pelvis is surprisingly good, particularly for those with disease microscopically limited to the uterus and ovary or of low histologic grade.
Abstract Objective Potential predictive/prognostic angiogenic markers were prospectively examined in a phase II trial of bevacizumab in epithelial ovarian cancer (EOC)/primary peritoneal cancer ...(PPC). Methods Recurrent/persistent EOC/PPC patients were treated with bevacizumab (15 mg/kg IV q21days) until disease progression. Validated-immunohistochemistry (IHC) assays were performed on pre-cycle 1/4 tumor biopsies for CD31-microvessel density (MVD), VEGF-histoscore (HS), p53-HS, and TSP1 image analysis score (IA). Pre-cycle 1/4 serum and plasma VEGF were quantified using a validated-ELISA. Results CD31-MVD and serum VEGF, evaluated pre-cycle 1 in 41/61 and 51/61 eligible patients, respectively, did not appear to be correlated. High CD31-MVD, categorized at the median, appeared to be associated with tumor response, a 13-month shorter median survival, and an increased risk of death (unadjusted hazard ratio HR = 2.2, 95% confidence interval CI = 1.067–4.467). In addition, each standard deviation (SD) increase in CD31-MVD appeared to be associated with worse survival in unadjusted and adjusted analyses. IHC and plasma biomarkers did not change with bevacizumab treatment except for serum VEGF, which appeared to decrease during bevacizumab treatment. This decrease was not associated with response. High pre-cycle 1 serum VEGF, categorized at the median, was associated with 22-month shorter median survival and an increased risk of death (unadjusted HR = 2.7, 95% CI = 1.369–5.191). Categorized p53 appeared to be associated with unadjusted survival and each SD increase in TSP1-IA appeared to be associated with a decreased risk of progression in unadjusted and adjusted analyses. Conclusions Despite the limitations in sample size and exploratory nature of the study, angiogenic markers in tumor and serum may provide prognostic value in recurrent/persistent EOC/PPC, and are being prospectively evaluated in the GOG phase III trial of carboplatin, paclitaxel and bevacizumab/placebo in previously untreated EOC/PPC.
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