A case for the use of receiver operating characteristic analysis of potential clinical efficacy biomarkers in advanced renal cell carcinoma.

AIM: Assess patient-level utility of suggested pretreatment biomarkers of sunitinib in advanced renal cell carcinoma. PATIENTS & METHODS: Kaplan-Meier analysis of data from a randomized, Phase II study (n = 292) suggested baseline predictive value for circulating soluble Ang-2 and MMP-2 and HIF-1α percentage of tumor expression. Using this dataset, the sensitivity, specificity and area under the curve (AUC) were calculated, using receiver operating characteristic (ROC) curves. RESULTS: Based on a ROC (sensitivity vs 1 - specificity) threshold AUC value of >0.8, neither Ang-2 (0.67) nor MMP-2 (0.65), nor HIF-1α percentage of tumor expression (0.65), performed appropriately from a patient-selection standpoint. CONCLUSION: To properly assess potential biomarkers, sensitivity and specificity characteristics should be obtained by ROC analysis.

Roles of KLF6 and KLF6-SV1 in ovarian cancer progression and intraperitoneal dissemination.

PURPOSE: We investigated the role of the KLF6 tumor suppressor gene and its alternatively spliced isoform KLF6-SV1 in epithelial ovarian cancer (EOC). EXPERIMENTAL DESIGN: We first analyzed tumors from 68 females with EOC for KLF6 gene inactivation using fluorescent loss of heterozygosity (LOH) analysis and direct DNA sequencing and then defined changes in KLF6 and KLF6-SV1 expression levels by quantitative real-time PCR. We then directly tested the effect of KLF6 and KLF6-SV1 inhibition in SKOV-3 stable cell lines on cellular invasion and proliferation in culture and tumor growth, i.p. dissemination, ascites production, and angiogenesis in vivo using BALB/c nu/nu mice. All statistical tests were two sided. RESULTS: LOH was present in 59% of samples in a cell type-specific manner, highest in serous (72%) and endometrioid (75%) subtypes, but absent in clear cell tumors. LOH was significantly correlated with tumor stage and grade. In addition, KLF6 expression was decreased in tumors when compared with ovarian surface epithelial cells. In contrast, KLF6-SV1 expression was increased approximately 5-fold and was associated with increased tumor grade regardless of LOH status. Consistent with these findings, KLF6 silencing increased cellular and tumor growth, angiogenesis, and vascular endothelial growth factor expression, i.p. dissemination, and ascites production. Conversely, KLF6-SV1 down-regulation decreased cell proliferation and invasion and completely suppressed in vivo tumor formation. CONCLUSION: Our results show that KLF6 and KLF6-SV1 are associated with key clinical features of EOC and suggest that their therapeutic targeting may alter ovarian cancer growth, progression, and dissemination.

The relationship of molecular markers of p53 function and angiogenesis to prognosis of stage I epithelial ovarian cancer.

PURPOSE: Multiple angiogenic factors may influence tumor progression and metastasis. Several are modified by the p53 gene. We sought to identify molecular markers for high-risk stage I epithelial ovarian cancers. EXPERIMENTAL DESIGN: Seventy-seven consecutive stage I epithelial ovarian cancers were evaluated for p53, CD31 microvessel density, thrombospondin-1, vascular endothelial growth factor (VEGF), p21 immunohistochemical staining, and p53 gene mutations. Molecular marker impact upon disease-specific survival, disease recurrence, and distant recurrence was evaluated with Cox regression. RESULTS: There were 12 deaths from disease. Twelve of the 77 tumors contained p53 mutations-10 missense and 3 null (one tumor had two mutations). Fesddration Internationale des Gynaecologistes et Obstetristes substage (IA/IB versus IC; P < 0.001) and VEGF staining (P = 0.02) were significant in bivariate models with relationship to disease-specific survival. Stage (P = 0.0004), grade (P = 0.008), histology (P = 0.0025), p53 dysfunction (positive stain and/or mutation; P = 0.048), and microvessel density (P = 0.04) were significant in bivariate models with relationship to time to recurrence. In multivariate analyses among stage IC patients, failure to receive chemotherapy and microvessel density were associated with disease-specific survival, time to recurrence, and time to distant recurrence with hazard ratios of 4.8 to 44.1. CONCLUSIONS: The p53-dependent molecular markers of angiogenesis are of limited utility in developing a clinical strategy for postoperative management of stage I ovarian carcinoma. Microvessel density impacts survival and metastasis for high-risk stage IC disease. Adjuvant chemotherapy is necessary, but not sufficient, for cure of high-risk stage I epithelial ovarian cancers.

Frequency of BRCA1 dysfunction in ovarian cancer.

BACKGROUND: Ovarian cancer is one of the most common hereditary cancers in women. Mutations in the BRCA1 gene increase a woman's risk of ovarian cancer. Testing for BRCA1 mutations is cumbersome and impractical for large populations. Therefore, we developed an efficient strategy to detect various types of BRCA1 dysfunction and also determined the relative frequency of BRCA1 dysfunction in ovarian cancer. METHODS: Tumors from 221 patients with epithelial ovarian cancer were screened for loss of heterozygosity (LOH) at the BRCA1 locus. BRCA1 complementary DNA (cDNA) and genomic DNA from all cancers with BRCA1 LOH (106 tumors) or noninformative status (15 tumors) were polymerase chain reaction (PCR) amplified and analyzed for protein truncation in a coupled transcription/translation test. When truncated BRCA1 protein was detected, the BRCA1 gene from both the tumor and a paired blood sample was sequenced. When BRCA1 expression in tumor cDNA was not detected with a protein truncation test, a methylation-specific PCR was used to determine whether the promoter region of BRCA1 was methylated and thus inactivated. All statistical tests were two-sided. RESULTS: Fifty-one (23.1%) of 221 tumors had BRCA1 dysfunction, including 18 with germline mutations, 15 with somatic mutations, and 18 with monoallelic or biallelic hypermethylated promoters. By the consideration of only tumors with LOH or that were noninformative, the efficiency for detecting BRCA1 dysfunction improved to 45 (37.2%) of 121 tumors. Therefore, LOH/noninformative was a strong predictor of mutation status (Fisher's exact test, P<.001). However, this subset of tumors did not include those with BRCA1 missense mutations (estimated at six [2.7%] of 221 not detected by our method) or biallelic promoter methylation (estimated at six [2.7%] of 221). CONCLUSIONS: BRCA1 dysfunction in ovarian cancer is common and occurs via multiple mechanisms. The use of LOH, rather than a family history of ovarian cancer, as a first step in a screening strategy, followed by protein truncation testing, appears to increase the chance of identifying tumors with BRCA1 dysfunction.

Inactivation of BRCA1 and BRCA2 in ovarian cancer.

BACKGROUND: Although BRCA1 and BRCA2 play important roles in hereditary ovarian cancers, the extent of their role in sporadic ovarian cancers and their mechanisms of inactivation are not yet well understood. Our goal was to characterize BRCA2 mutations and mRNA expression in a group of ovarian tumors previously evaluated for BRCA1 mutations and mRNA expression. METHODS: The tumors of 92 unrelated women with "ovarian" cancer (i.e., ovarian, peritoneal, or fallopian tube cancer) were screened for BRCA2 null mutations using a protein truncation test. Methylation-specific polymerase chain reaction (PCR) was used to examine the BRCA2 promoter for hypermethylation in tumors that did not express BRCA2 mRNA. All statistical tests were two-sided. RESULTS: Nine tumors had a germline (n = 5) or somatic (n = 4) BRCA2 mutation; each was associated with loss of heterozygosity. All of the somatic (1445delC, E880X, 4286del8, and 5783delT) and one of the germline (5984ins4) mutations were unique to this study. One tumor had somatic mutations in both BRCA1 and BRCA2. Two tumors are, to our knowledge, the first cases of germline BRCA2-associated peritoneal cancer. Twelve additional tumors lacked detectable BRCA2 mRNA, but the BRCA2 promoter was hypermethylated in only one of them, suggesting that other mechanisms effect transcriptional silencing of BRCA2. Tumors lacking BRCA1 mRNA were more likely to lack BRCA2 mRNA than tumors expressing BRCA1 mRNA (P<.001). Overall, 82% (95% confidence interval [CI] = 74% to 90%) of the tumors contained alterations in BRCA1, BRCA2, or both genes. Of 41 informative tumors with some alteration in BRCA2, 36 also had an alteration in BRCA1. The frequency, but not the mechanism, of BRCA1 or BRCA2 dysfunction in ovarian cancer was independent of family history. CONCLUSIONS: Multiple mechanisms cause nearly universal dysfunction of BRCA1 and/or BRCA2 in hereditary and sporadic ovarian carcinoma. Ovarian cancers with BRCA2 dysfunction often have simultaneous BRCA1 dysfunction.

p21 expression predicts outcome in p53-null ovarian carcinoma.

PURPOSE: p21 is a direct p53 response gene. Although several studies have correlated p21 and p53 expression, only one has evaluated p21 expression as a function of sequenced p53 gene mutation. We hypothesize that such an analysis may be useful in prognosticating outcome for individuals diagnosed with epithelial ovarian cancer. EXPERIMENTAL DESIGN: DNA from the primary ovarian cancers of 267 patients was studied. p53 mutations were directly sequenced. Two percent or greater nuclear staining with WAF1/CIP1 monoclonal antibody was determined by a hazard ratio analysis to constitute positive p21 expression. RESULTS: Positive p21 nuclear staining occurred more frequently in p53 wild-type ovarian tumors than tumors found to have a p53 mutation (P = 0.001). Positive p21 staining conferred an overall survival advantage (P = 0.02). p21 expression in cancers with p53 missense mutations was not prognostic but did show a strong trend toward significance in the wild-type p53 subset (P = 0.056). Surprisingly, positive p21 staining reflected compromised survival for individuals with p53-null ovarian cancers (P = 0.005). The mean expression level for p21-positive stains in the wild-type group was greater than in null p53 cancers (23 versus 11%; P = 0.001). A Cox multivariable analysis revealed p21 to be a strong independent prognostic factor in p53-null ovarian cancer (P = 0.02). CONCLUSION: p21 expression is closely related to sequenced p53 mutations. This is the first study of positive p21 staining as an independent poor prognostic factor in p53-null ovarian cancer. A dual role for p21 activity, dependent on levels of expression, appears to explain these paradoxical results and is consistent with a complex model for regulation of p21.

Preoperative serum vascular endothelial growth factor levels: significance in ovarian cancer.

PURPOSE: To assess the clinical relevance of serum vascular endothelial growth factor (VEGF) levels in distinguishing patients with ovarian cancer from those with benign adnexal masses. EXPERIMENTAL DESIGN: Preoperative serum VEGF levels were assessed in 101 women with invasive epithelial ovarian cancer, 16 with low malignant potential (LMP) ovarian tumors, and 34 women with benign ovarian tumors. VEGF levels were determined using an ELISA (R&D Systems, Minneapolis, MN). RESULTS: Ovarian cancer patients had a mean preoperative VEGF level of 549 pg/ml (median 379 pg/ml), which was significantly higher than those with benign adnexal masses (mean 228 pg/ml, median 155 pg/ml; P < 0.001) and LMP tumors (mean 200 pg/ml, median 129 pg/ml; P < 0.001). There were no significant differences in VEGF levels between individuals with benign masses and LMP tumors. The ability of VEGF to differentiate malignancy from benign masses at a cutoff VEGF level of 246 pg/ml gave a sensitivity of 74%, a specificity of 71%, a positive predictive value of 88%, and a negative predictive value of 48%. VEGF levels were also significantly higher in patients with stage I ovarian cancer compared with those with benign disease or LMP tumors. Among patients with ovarian cancer, there were no significant differences in VEGF levels based on age, stage, grade, or level of cytoreduction. The presence of ascites was associated with a significantly higher VEGF level (mean 667 pg/ml, median 445 pg/ml versus mean 317 pg/ml, median 293 pg/ml; P < 0.001). Various preoperative VEGF levels were assessed as a predictor of survival, and a VEGF level >380 pg/ml was associated with a hazard ratio of 2.13 (P = 0.009) by univariate analysis. In multivariate analysis of age, stage, cytoreduction, preoperative CA-125, grade, ascites, and VEGF levels above 380 pg/ml, only VEGF levels >380 pg/ml (hazard ratio 2.33; P = 0.02) and advanced stage (hazard ratio 9.03; P = 0.004) were significant. CONCLUSIONS: Preoperative VEGF levels may be useful in differentiating benign adnexal masses from malignancy. Preoperative VEGF levels >380 pg/ml are an independent risk factor for death because of disease.

Failure of BRCA1 dysfunction to alter ovarian cancer survival.

PURPOSE: Many factors modify ovarian cancer survival. There are conflicting reports regarding survival of individuals with hereditary BRCA1-related ovarian cancer. None have controlled for other mechanisms of BRCA1 silencing in the control cohort. EXPERIMENTAL DESIGN: Fifty-nine cancers with presumed BRCA1 dysfunction because of mutation (24 germ-line and 16 somatic) or absent BRCA1 mRNA because of promoter hypermethylation (n = 19) were identified among 250 consecutively screened ovarian cancers. Controls were matched from the same population based on p53 mutation type, age at diagnosis, Fédération Internationale des Gynaecologistes et Obstetristes surgical stage and histological grade, residual disease, preoperative CA125, disease site, and the presence of BRCA1 mRNA translatable in an in vitro protein expression assay. BRCA1 promoter hypermethylation was determined by the methylation-specific PCR technique. The significance of promoter hypermethylation was confirmed by the absence of detectable BRCA1 mRNA. RESULTS: The median survival for individuals with ovarian cancer BRCA1 dysfunction was 4.1 years versus 3.5 years in the case matched controls (P = 0.98). Grouped on the basis of the mechanism of BRCA1 dysfunction, median survival was 4.5, 2.8, and 2.3 years for germ-line, somatic, and BRCA1 promoter-silenced ovarian cancers. However, for the corresponding matched controls with wild-type BRCA1 sequence, the median survival was virtually identical: 4.6, 2.8, and 3.3 years, respectively. In a Cox proportional hazards analysis, only residual disease (P = 0.0001), age (P = 0.01), and Fédération Internationale des Gynaecologistes et Obstetristes stage (P = 0.011) entered the survival model. CONCLUSIONS: In contrast with other published reports, we are unable to detect large survival differences between matched case-control cohorts of ovarian cancers with BRCA1 inactivation by any of three independent mechanisms.

Sequential intraperitoneal topotecan and oral etoposide chemotherapy in recurrent platinum-resistant ovarian carcinoma: results of a phase II trial.

PURPOSE: The purpose is to investigate the safety and efficacy of i.p. topotecan and oral etoposide as salvage treatment for patients with platinum-resistant ovarian or primary peritoneal cancer. EXPERIMENTAL DESIGN: Patients were treated with i.p. topotecan initial dose, 1 mg/m2 on days 1 to 5, followed by oral etoposide 100 mg on days 6 to 9 of a 28-day cycle for six cycles. Dose reduction of topotecan was used for severe bone marrow suppression. Peritoneal (topotecan) and plasma (topotecan and etoposide) levels were assessed at multiple time points using high-pressure liquid chromatography. RESULTS: Twenty-two patients (mean age, 61 years) with a median of 1.5 prior treatments were enrolled. Etoposide peak plasma concentrations ranged from 1.9 to 6.9 microg/mL (mean, 3.6 microg/mL). Topotecan plasma levels rose with increasing peritoneal concentration and were detectable within 1 hour but tended to decrease rapidly to below detectable levels within 24 hours. The peak plasma concentration of topotecan was 12.82 +/- 8.55 microg/mL with a plasma half-life of 6.17 +/- 2.75 hours. A total of 104 cycles was administered; 14 patients (64%) completed all six planned cycles. All patients were evaluable for toxicity, and 21 patients were evaluable for response. The most common grade 4 toxicities were neutropenia and thrombocytopenia in eight and four patients (36 and 18%), respectively. There were no treatment-related deaths. The overall response rate was 38% [complete response, three (14%); partial response, five (24%)]. Seven patients had stable disease and six progressed while on treatment. CONCLUSIONS: The combination of i.p. topotecan and oral etoposide is an active and well-tolerated regimen in platinum-resistant ovarian carcinoma. Additional studies investigating topotecan in combination with etoposide are warranted.

The impact of p53 protein core domain structural alteration on ovarian cancer survival.

PURPOSE: Although survival with a p53 missense mutation is highly variable, p53-null mutation is an independent adverse prognostic factor for advanced stage ovarian cancer. By evaluating ovarian cancer survival based upon a structure function analysis of the p53 protein, we tested the hypothesis that not all missense mutations are equivalent. EXPERIMENTAL DESIGN: The p53 gene was sequenced from 267 consecutive ovarian cancers. The effect of individual missense mutations on p53 structure was analyzed using the International Agency for Research on Cancer p53 Mutational Database, which specifies the effects of p53 mutations on p53 core domain structure. Mutations in the p53 core domain were classified as either explained or not explained in structural or functional terms by their predicted effects on protein folding, protein-DNA contacts, or mutation in highly conserved residues. Null mutations were classified by their mechanism of origin. RESULTS: Mutations were sequenced from 125 tumors. Effects of 62 of the 82 missense mutations (76%) could be explained by alterations in the p53 protein. Twenty-three (28%) of the explained mutations occurred in highly conserved regions of the p53 core protein. Twenty-two nonsense point mutations and 21 frameshift null mutations were sequenced. Survival was independent of missense mutation type and mechanism of null mutation. CONCLUSIONS: The hypothesis that not all missense mutations are equivalent is, therefore, rejected. Furthermore, p53 core domain structural alteration secondary to missense point mutation is not functionally equivalent to a p53-null mutation. The poor prognosis associated with p53-null mutation is independent of the mutation mechanism.

A phase I/II trial of rAd/p53 (SCH 58500) gene replacement in recurrent ovarian cancer.

PURPOSE: To determine the safety, gene transfer, host immune response, and pharmacokinetics of a replication-deficient adenovirus encoding human, recombinant, wild-type p53 (SCH 58500) delivered into the peritoneal cavity (i.p.) alone and sequentially in combination with platinum-based chemotherapy, of patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer containing aberrant or mutant p53. METHODS: SCH 58500 was administered i.p. to three groups of patients with heavily pretreated recurrent disease. Group 1 (n=17) received a single dose of SCH 58500 escalated from 7.5 x 10(10) to 7.5 x 10(12) particles. Group 2 (n=9) received two or three doses of SCH 58500 given alone for one cycle, and then with chemotherapy for two cycles. The SCH 58500 dose was further escalated to 2.5 x 10(13) particles/dose in group 2. A third group (n=15) received a 5-day regimen of SCH 58500 given at 7.5 x 10(13) particles/dose per day i.p. alone for cycle 1 and then with intravenous carboplatin/paclitaxel chemotherapy for cycles 2 and 3. RESULTS: No dose-limiting toxicity resulted from the delivery of 236/287 (82.2%) planned doses of SCH 58500. Fever, hypotension abdominal complaints, nausea, and vomiting were the most common adverse events. Vector-specific transgene expression in tumor was documented by RT-PCR in cells from both ascitic fluid and tissue biopsies. Despite marked increases in serum adenoviral antibody titers, transgene expression was measurable in 17 of 20 samples obtained after two or three cycles of SCH 58500. Vector was detectable in peritoneal fluid by 24 hours and persisted for as long as 7 days whereas none was detected in urine or stool. There was poor correlation between CT scans and CA125 responses. CA125 responses, defined as a greater than 50% decrement in serum CA125 from baseline, were documented in 8 of 16 women who completed three cycles of the multidose regimen. CONCLUSION: CT scans are not a valid measure of response to i.p. SCH 58500 due to extensive adenoviral-induced inflammatory changes. Intraperitoneal SCH 58500 is safe, well tolerated, and combined with platinum-based chemotherapy can be associated with a significant reduction of serum CA125 in heavily pretreated patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer.

Long term follow-up of patients with recurrent ovarian cancer after Ad p53 gene replacement with SCH 58500.

OBJECTIVE: We have previously reported the safety, efficient gene transfer, and favorable CA125 responses of individuals with recurrent ovarian cancer treated by p53 gene replacement with the adenoviral vector SCH 58500. The purpose of the present investigation was to evaluate the long-term follow-up of these heavily pretreated patients subsequent to SCH 58500 dosing. METHODS: Patients (n=36) were treated with either single-dose SCH 58500 in the phase I study or with multiple doses (MD) of SCH 58500 over multiple cycles in combination of platinum-based chemotherapy in the phase I/II portion of the study. Five patients were initially treated in the single-dose group and re-enrolled in the MD group. The MD group was evaluated both without the re-enrolled patients as MD1 (n=19), and as MD2 (n=24), which included them. Patients who were only treated on the single-dose arm were designated as SD (n=12). Most patients received additional chemotherapy at the discretion of their physicians on completion of the trial. The current analysis is a retrospective sequential cohort survival analysis. RESULTS: The first patient was treated in March 1997 and the last patient completed SCH 58500 in September 1998. There was no difference in age at diagnosis, Karnofsky performance status, interval between diagnosis to SCH 58500, prior cycles or regimen of chemotherapy, platinum-free interval, percent platinum refractory patients, pretreatment CA125, or largest tumor volume between groups. Both MD groups had a slightly longer chemotherapy-free interval before SCH 58500 than the SD group. Median survival of individuals who received MD SCH 58500 with chemotherapy was 12-13.0 months, compared to only 5 months for those treated with SD SCH 58500. There are 10 long-term survivors more than 20 months after MD treatment for recurrent disease compared to only 2 long-term survivors after SD SCH 58500. CONCLUSION: The 12- to 13.0-month median survival in a heavily pretreated population with recurrent ovarian cancer compares favorably to the 16-month median survival for individuals treated with paclitaxel at the time of initial recurrence of this disease and is more than double the 5-month survival seen with palliative radiotherapy or paclitaxel failure. These data suggest that further study of SCH58500 is clearly indicated.

p53 null mutations are associated with a telomerase negative phenotype in ovarian carcinoma.

Telomerase activation and p53 dysfunction are important events in the development and progression of most cancers including ovarian cancer. However, many cancer cell lines and human tumors have been shown to lack telomerase, and maintain telomerase through the ALT (alternative lengthening of telomeres). It is not known whether specific types of p53 mutations are correlated with telomerase activity in human tumors. Invasive ovarian cancers (109) were analyzed for telomerase by ELISA and its subunits human telomerase RNA (hTR), and human telomerase reverse transcriptase (hTERT) by RT-PCR. p53 protein was analyzed in the same samples using immunohistochemistry, and p53 exons 2-11 were analyzed using SSCP and sequence analysis. Telomerase activity was detected in 80 (74%) of 109 tumors. The subunit hTR was consistently present in all ovarian cancer samples, and hTERT was expressed in 96 (88%) tumors. Thirteen (16%) tumors were negative for hTERT and none of these expressed telomerase. Fifty-seven (52%) tumors stained positive for p53, and there was no correlation with telomerase activity based on p53 staining (p = 0.08). Eighty-two (75%) tumors were found to have a p53 mutation, and 40 (36%) tumors contained a null mutation. Only 14% of the tumors with wild type or missense p53 were negative for telomerase activity. In contrast, 19 (48%) of 40 tumors with a p53 null mutation were negative for telomerase activity (p <0.001). There was no difference in the incidence of telomerase positivity between critical site versus non-critical site missense p53 mutations. Seventy-five percent of the tumors with a p53 mutation in the central region were telomerase positive. In contrast, only 47% of the tumors with a mutation in either the amino- or carboxy-terminus were telomerase positive (p = 0.03). Ovarian cancers with a p53 null mutation are more likely to lack telomerase activity. This may have implications for therapeutic approaches based on telomerase.

Preoperative CA 125 levels: an independent prognostic factor for epithelial ovarian cancer.

OBJECTIVE: To estimate the association of preoperative CA 125 levels with outcome in primary ovarian cancer patients. METHODS: One hundred forty-two patients with epithelial ovarian cancer, who had a serum CA 125 level drawn before surgery, were retrospectively evaluated. The relationship of preoperative CA 125 levels and various preoperative and postoperative variables was evaluated. CA 125 levels were determined using a solid-phase immunoassay. RESULTS: The median CA 125 value for all patients was 582 U/mL (range 7-52,930 U/mL). Preoperative CA 125 values did not correlate with increasing age (P =.40), but were found to be significantly associated with serous histology compared with other histology (median CA 125 of 870 versus 334 U/mL, P =.02), high-stage (III/IV) compared with low-stage (median CA 125 of 893 versus 174 U/mL, P <.001), high tumor grade (3) compared with grade 1 or 2 (median CA 125 of 928 versus 323 U/mL, P <.001), and the presence of ascites compared with absence of ascites (median CA 125 of 893 versus 220 U/mL, P <.001). Suboptimal cytoreduction (more than 1 cm residual) was associated with significantly higher CA 125 levels (1067 U/mL) compared with individuals with optimal cytoreduction (399 U/mL, P <.001). Preoperative CA 125 values less than 500 U/mL had a positive predictive value for optimal cytoreduction of 82%, but a poor negative predictive value of 48%. After adjusting for covariates, there was a significant association between CA 125 levels and disease-specific survival. As preoperative CA 125 levels increased, the risk of death increased except at the highest values of CA 125. CONCLUSION: Preoperative CA 125 is an independent risk factor for death due to disease in ovarian cancer, but not a reliable predictor of optimal cytoreduction.

Neoadjuvant chemotherapy in vulvar cancer: avoiding primary exenteration.

OBJECTIVE: To determine whether neoadjuvant cisplatin and 5-fluorouracil chemotherapy can be used to preserve the anal sphincter and/or urethra in patients with advanced vulvar cancer involving these sites. METHODS: Fourteen patients with advanced vulvar cancer (1997-2003) involving the anal sphincter and/or urethra were given 3-4 cycles of neoadjuvant chemotherapy to attempt preservation of these pelvic structures rather than undergoing a primary pelvic exenteration. Following 3 cycles, a radical vulvectomy and groin lymph node dissection were planned. All patients had lesion size documented by measurement and photograph prior to and following chemotherapy. RESULTS: The median age was 63 years (range 39-88). Thirteen patients received a median of 3 cycles (range 2-4) of neoadjuvant chemotherapy. Ten patients received cisplatin and 5-fluorouracil, while three received cisplatin alone. The median time from diagnosis to surgery was 77 days (range 54-143). All patients with cisplatin and 5-fluorouracil chemotherapy underwent surgery except one patient who had a synchronous renal cell carcinoma and died prior to surgery. Patients receiving cisplatin alone showed no measurable response, while all patients receiving cisplatin and 5-fluorouracil demonstrated at least a partial response. Two patients had no residual invasive carcinoma on final pathology. All patients receiving cisplatin and 5-fluorouracil followed by surgery are disease-free, while two of three receiving cisplatin have progressive disease. The anal sphincter and urethra were conserved in all patients receiving cisplatin and 5-fluorouracil. CONCLUSION: Neoadjuvant cisplatin and 5-fluorouracil in advanced vulvar cancer demonstrated a response rate of 100%. The anal sphincter and urethra were conserved in all patients receiving cisplatin and 5-fluorouracil. Responders are disease-free at this time. This response rate demonstrates superior activity of 5-fluorouracil in vulvar cancer and spares these patients the morbidity of exenteration or radiation.

Serum CA 125 is an independent prognostic factor in cervical adenocarcinoma.

OBJECTIVE: The purpose of this study was to determine the prognostic significance of a pretreatment serum CA 125 value in patients who were diagnosed with adenocarcinoma of the cervix. STUDY DESIGN: All patients who were diagnosed with adenocarcinoma or adenosquamous carcinoma of the cervix and treated definitively between 1986 and 1998 were eligible. The relationship between pretreatment serum CA 125 values and various clinical factors was evaluated. RESULTS: Seventy-three patients had pretreatment CA 125 drawn, with values that ranged from 5 to 683 U/mL and all patients were included in this study. A CA 125 value of >or=30 U/mL was defined as elevated by the receiver operating characteristic curve analysis and used for all subsequent analyses. Elevated serum CA 125 values were identified in 33% of the 73 patients. On the basis of the univariate analyses, an elevated pretreatment CA 125 value was associated significantly with advanced International Federation of Gynecology and Obstetrics stage (>IIA, P =.01), high grade (2 or 3, P =.04), tumor diameter >4 cm (P <.01), and positive pelvic or para-aortic lymph nodes (P =.002). The median survival time was 2.8 years for patients with a pretreatment CA 125 value of >or=30 U/mL and not yet reached for patients with values of <30 U/mL(P <.001). Pretreatment clinical variables that included CA 125 value, age, stage, grade, and tumor diameter were evaluated in a Cox proportional hazards model, and an elevated CA 125 value was the most significant predictor of survival (P <.001). CONCLUSION: Serum CA 125 is an independent prognostic marker for patients with cervical adenocarcinoma.

Ovarian cancer p53 mutation is associated with tumor microvessel density.

OBJECTIVE: The objective of this study was to investigate the relationship between microvessel density, as measured by CD31 staining, and histopathologic factors as well as p53 tumor suppressor gene mutation in ovarian cancer. METHODS: Ovarian cancers (n = 77) were analyzed for p53 gene mutations and CD31 immunohistochemical expression. Histopathologic and mutational data were related to CD31 staining utilizing the Mantel correlation statistic. The microvessel density was scored by averaging counts from three high-power (200x) fields. Survival was based upon maximizing the hazard ratio. RESULTS: The mean microvessel density counts based on CD31 staining (vessels/HPF) for each FIGO stage and mutation type are as follows: Stage I (10.2), Stage II (10.7), Stage III (13.8), Stage IV (22.0), wild-type p53 (9.3), missense p53 mutation (14.4), and null p53 mutation (23.1). There was a significant correlation between microvessel density count and FIGO stage (P = 0.026), grade (P = 0.04), and p53 mutation type (P = 0.02). Median survival was more than doubled (6.4 vs 2.9 years; P = 0.009) for tumors with microvessel density counts less than or equal to 14 vessels/HPF. CONCLUSIONS: These data are consistent with the hypothesis that ovarian cancer p53 mutation functions to directly influence angiogenesis, which in turn compromises disease-specific survival. It also suggests validity to targeting p53 alterations with gene replacement as well as the use of antiangiogenesis agents as novel molecular-based therapeutics for ovarian cancer.

Prolonged oral etoposide in recurrent or advanced non-squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study.

OBJECTIVE: Previous studies by the Gynecologic Oncology Group have demonstrated a 7% response rate with bolus etoposide as second-line therapy in nonsquamous cell carcinoma of the cervix. Prolonged oral etoposide, which exploits the schedule dependency of this agent, has demonstrated increased activity in squamous carcinoma of the cervix compared with bolus administration. To evaluate prolonged oral etoposide in nonsquamous cell carcinoma of the cervix, the current phase II trial was conducted. METHODS: Eligibility included nonsquamous cell cancer of the cervix, measurable disease, no more than one prior chemotherapy regimen no prior etoposide, WBC > or = 3000/microl, platelets > or = 100,000/microl, serum creatinine < or = 2 mg%, and adequate hepatic function. The starting dose was 50 mg/m(2)/day (40 mg/m(2)/day for prior radiotherapy) for 21 days, every 28 days. Based on toxicity, dose escalation to a maximum dose of 60 mg/m(2)/day was prescribed. RESULTS: Fifty-two patients were entered on this study, with 47 evaluable for toxicity and 42 evaluable for response. A median of three (range: 1-12) courses were given. Thirty-four patients received prior radiation therapy and 15 received prior chemotherapy. Oral etoposide was well tolerated, with grade 4 neutropenia occurring in 29.8% and grade 4 thrombocytopenia occurring in 8.5% of patients. Three complete (7.1%) and two partial (4.8%) responses were observed. All of the responses were seen in chemotherapy-naïve patients (5/27); four of five had disease in nonirradiated sites. CONCLUSION: Prior radiation therapy significantly limited our ability to deliver prolonged oral etoposide. At this dose, this regimen is moderately active in chemotherapy-naïve patients with nonsquamous cell carcinoma of the cervix.

Quality of life and mood in women with gynecologic cancer: a one year prospective study.

BACKGROUND: Quality of life (QOL) and mood were prospectively investigated during the first year of treatment among women with gynecologic cancers. Relationships of coping styles to QOL and mood were examined. METHODS: Ninety-eight patients with early stage or regionally advanced gynecologic cancers were recruited. Mood and QOL were assessed at initial clinic visit and at one year, and medical information was abstracted from charts at both time-points. RESULTS: Although decrements in physical, functional, and total well-being were reported at baseline by regionally advanced patients, by one year, all patients reported significant improvements in QOL and mood. There were no differences between early stage and regionally advanced patients in their improvement for these measures. Controlling for medical variables and age, patients who coped using greater acceptance and positive reframing at their initial visits reported better one year QOL; those with continued higher levels of these adaptive coping strategies at one year reported better concurrent functional and emotional well-being. Greater seeking of social support at one year was associated with better concurrent social well-being and doctor-patient relationships. In contrast, disengaged coping at study entry was associated with poorer doctor-patient relationships at one year; continued disengagement at one year was associated with poorer concurrent QOL and greater distress. CONCLUSIONS: During the first year following treatment, QOL and mood improved among both early stage and regionally advanced gynecologic oncology patients. Patients using disengaged coping are particularly at risk for poor QOL and distress.

Vascular endothelial growth factor and social support in patients with ovarian carcinoma.

BACKGROUND: The modulation of immunologic activities relevant to cancer by behavioral factors, such as stress, depression, and social support, is well documented. However, associations of behavioral factors with cytokines involved in tumor angiogenesis have not been studied. Vascular endothelial growth factor (VEGF) is a key cytokine that is capable of stimulating tumor angiogenesis, and it has been associated with poorer survival in patients with ovarian carcinoma. VEGF is modulated by a variety of behaviorally sensitive factors, including sympathetic activation. This study examined relationships of social support and depressive symptoms with VEGF levels in preoperative patients with ovarian carcinoma. METHODS: Twenty-four women with ovarian carcinoma and 5 women with benign pelvic masses were recruited at the presurgical clinic visit, received psychosocial surveys, including the Functional Assessment of Cancer Therapy (Quality of Life) survey and the Profile of Mood States, and a blood draw. Serum VEGF levels were assessed by enzyme-linked immunosorbent assay. Analyses controlled for disease stage. RESULTS: Women with ovarian carcinoma who reported higher levels of social well being had lower levels of VEGF (P = 0.005). Greater support from friends and neighbors (P = 0.005) and less distance from friends (P = 0.04) were facets of social well being that were associated with lower VEGF levels. Individuals who reported greater helplessness (P = 0.03) or worthlessness (P = 0.08) had higher VEGF levels, but depression as a whole (P > 0.50) was not related to VEGF levels. CONCLUSIONS: Higher levels of social well being were correlated with lower VEGF levels in presurgical patients with ovarian carcinoma. These findings suggest a possible mechanism by which poor social support may be associated with disease progression. Further study of these relations may demonstrate novel pathways relating biobehavioral factors to tumor growth and disease progression.