Ron E. Swensen

Antibody Immunity to the p53 Oncogenic Protein Is a Prognostic Indicator in Ovarian Cancer

PURPOSE Presence of intratumoral T-cell infiltration has been linked to improved survival in ovarian cancer patients. We questioned whether antibody immunity specific for ovarian cancer tumor antigens would predict disease outcome. We evaluated humoral immune responses against ovarian cancer antigens p53, HER-2/neu, and topoisomerase IIalpha. PATIENTS AND METHODS Serum was collected from 104 women (median age, 59 years; range, 34 to 89 years) at the time of their initial definitive surgery for ovarian cancer. Serum was analyzed by enzyme-linked immunosorbent assay for antibodies to p53, HER-2/neu, and topoisomerase IIalpha proteins. Antibody immunity to tetanus toxoid was assessed as a control. The incidence of humoral immunity at the time of diagnosis to any of these three antigens was tabulated. For patients with advanced-stage disease (III/IV), correlation was made between the presence of tumor-specific immunity at the time of diagnosis and overall survival. Patients were followed for a median of 1.8 years. RESULTS Multivariate analysis showed the presence of p53 antibodies to be an independent variable for prediction of overall survival in advanced-stage patients. Overall survival was significantly higher for patients with antibodies to p53 when compared with patients without p53 antibodies (P = .01). The median survival for p53 antibody-positive patients was 51 months (95% CI, 23.5 to 60.5 months) compared with 24 months (95% CI, 19.4 to 28.6 months) for patients without antibodies to p53. CONCLUSION Data presented here demonstrate that advanced stage ovarian cancer patients can have detectable tumor-specific antibody immunity and that immunity to p53 may predict improved overall survival in patients with advanced-stage disease.

Prognostic impact of lymphadenectomy in clinically early stage malignant germ cell tumour of the ovary

Background:The aim of this study was to determine the impact of lymphadenectomy and nodal metastasis on survival in clinical stage I malignant ovarian germ cell tumour (OGCT).Methods:Data were obtained from the National Cancer Institute registry from 1988 to 2006. Analyses were performed using Students t-test, Kaplan–Meier and Cox proportional hazard methods.Results:In all, 1083 patients with OGCT who have undergone surgical treatment and deemed at time of the surgery to have disease clinically confined to the ovary were included 590 (54.48%) had no lymphadenectomy (LND−1) and 493 (45.52%) had lymphadenectomy. Of the 493 patients who had lymphadenectomy, 441 (89.5%) were FIGO surgical stage I (LND+1) and 52 (10.5%) were upstaged to FIGO stage IIIC due to nodal metastasis (LND+3C). The 5-year survival was 96.9% for LND−1, 97.7% for LND+1 and 93.4% for LND+3C (P=0.5). On multivariate analysis, lymphadenectomy was not an independent predictor of survival when controlling for age, histology and race (HR: 1.26, 95% CI: 0.62–2.58, P=0.5). Moreover, the presence of lymph node metastasis had no significant effect on survival (HR: 2.7, 95% CI: 0.67–10.96, P=0.16).Conclusion:Neither lymphadenectomy nor lymph node metastasis was an independent predictor of survival in patients with OGCT confined to the ovary. This probably reflects the highly chemosensitive nature of these tumours.

Ovarian cancer in the elderly: Outcomes with neoadjuvant chemotherapy or primary cytoreduction

BACKGROUND Recent studies have suggested inferior outcomes for elderly women with ovarian cancer. Our goal was to evaluate neoadjuvant chemotherapy versus primary cytoreduction in elderly women. METHODS A retrospective chart review was performed for women aged 65+ diagnosed with ovarian cancer at our institution between 1997 and 2007. Univariate and multivariate logistic regression models were used to evaluate complication rates. Survival was evaluated with Cox regression and the Kaplan-Meier method. RESULTS One hundred seventy-five patients were identified, 34 (19%) of whom were aged 80+. Those aged 65-79 and those 80+ received neoadjuvant chemotherapy with equal frequency (19% vs. 21%, p=0.92). Treatment with neoadjuvant chemotherapy was associated with odds ratios of 0.80 (95% CI 0.37-1.75) for surgical complications and 0.79 (95% CI 0.33-1.90) for chemotherapeutic complications. In those aged 80+, the frequency of surgical complications (OR 1.01, p=0.62) and chemotherapeutic complications (OR 1.04, p=0.78) did not differ compared to younger patients. Overall survival did not differ based on initial treatment regimen, with 34 months in the primary surgery group and 29 months in the neoadjuvant chemotherapy group (p=0.65). The median disease specific survival for those aged 65-79 was 35 months, and 24 months in those aged 80+ (p=0.15). Post-operative mortality for patients aged 80+ was zero. CONCLUSIONS In our patient population, those aged 80+ have similar surgical and chemotherapy-related complication rates and comparable survival to those aged 65-79. The choice of initial treatment modality does not appear to impact survival when the decision is made in a selective fashion.

Pelvic exenteration in the age of modern chemoradiation.

BACKGROUND To examine outcomes after pelvic exenteration in women treated with modern chemoradiation and surgical techniques. METHODS All patients at our institution with a diagnosis of gynecologic malignancy who underwent pelvic exenteration after treatment with chemoradiation between 1/90 and 6/08 were evaluated with a retrospective chart review. RESULTS 44 women were identified, of whom 29 (66%) had cervical, 6 (14%) had uterine, 5 (11%) had vaginal, and 4 (9%) had vulvar cancer. The majority of patients (82%) were initially treated with external beam whole-pelvic radiation with concurrent cisplatin. 38 patients (86%) underwent exenteration for a central pelvic recurrence, and the remaining 6 patients (14%) for radiation necrosis. The most common surgical complication was transfusion requirement in 36 patients (82%), followed by wound infection in 15 (34%), small bowel obstruction in 8 (18%), and sepsis in 6 (14%). The median time spent in the ICU post-operatively was 2 days. One patient (2%) died during her post-operative hospital stay. The mean EBL overall was 2497 cc and the mean operative time was 544 min. Use of electrothermal bipolar coagulation, which was used in 64% of the exenterations, significantly reduced blood loss (3679 cc vs. 1836 cc, p=0.014). After exenteration, 21 patients (48%) were diagnosed with a recurrence of cancer, and the mean progression free survival was 31 months. Patients who received exenteration less than 2 years after their initial chemoradiation had a significantly shorter overall survival time (8 months vs. 33 months, p=0.016). CONCLUSIONS Approximately 50% of women develop recurrence following exenterations done after chemoradiation. Survival is significantly longer in patients who necessitate exenteration greater than 2 years out from initial treatment. Electrothermal bipolar coagulation appears to significantly reduce blood loss during these surgeries.

Prognostic impact of marital status on survival of women with epithelial ovarian cancer

The objective of this study is to examine the impact of marital status on survival of patients with epithelial ovarian cancer (EOC).

Alternative intraperitoneal chemotherapy regimens for optimally debulked ovarian cancer

OBJECTIVE GOG 172 showed a survival benefit with intraperitoneal (IP) cisplatin for advanced ovarian cancer, but patients tolerated the regimen poorly. We hypothesized that women treated with alternative IP chemotherapy strategies may have less toxicity and improved compliance. METHODS We reviewed the records of women with ovarian cancer and optimal surgical debulking who underwent IP chemotherapy at our institution. Primary outcomes analyzed were completion rates and toxicities of IP chemotherapy. Secondary outcomes were progression-free and overall survival. Statistical analysis was performed using STATA 10.0. RESULTS Thirty-nine patients with primary ovarian or peritoneal cancer who underwent IP chemotherapy were identified over a 2 year period. Patients were treated with IV paclitaxel followed by IP cisplatin (64%) or IP carboplatin (36%). Median two cycles of intravenous (IV) taxane and carboplatin were given prior to initiating IP therapy in 77% of patients. Median number of IP chemotherapy cycles was 5 and median total number of cycles was 8. Seventy-four percent (74%) of patients received four or greater cycles of IP chemotherapy. There was a higher rate of completion of intended number of IP cycles in the carboplatin group (92%) versus 60% in the IP cisplatin group (p=0.05). Grade 3 non-hematologic toxicities were more common in the IP cisplatin group than in the IP carboplatin group (24% and 0%, p=0.046). At median follow-up of 24 months, the median progression-free interval and overall survival have not yet been reached for either group. CONCLUSION Intraperitoneal chemotherapy regimens using carboplatin or cisplatin and dropping day 8 IP paclitaxel have less toxicity and less discontinuation of therapy.

The prognostic impact of the ratio of positive lymph nodes on survival of epithelial ovarian cancer patients.

To study the prognostic significance of ratio of positive to examined lymph nodes (LNR) on survival of patients with node positive epithelial ovarian cancer (NPEOC).

Suicide in women with gynecologic cancer

OBJECTIVE(S) To characterize the suicide rates among patients with gynecologic cancer in the Unites States and to identify factors associated with high suicide rates. METHOD(S) Subjects with a diagnosis of gynecologic cancer were identified from the Surveillance, Epidemiology, and End Results (SEER) program for the period 1988-2007. Comparison with women in the general US population was based on WHO data 2005, matched for age in 10-year categories. Cox regression models were used to perform multivariate modeling for factors associated with suicide. RESULT(S) Among 252,235 patients followed for 1,207,278 person-years, the suicide rate was 8.3 per 100,000 person-years, with a standardized mortality ratio (SMR) of 1.4 (95% CI 1.2-1.7, p<0.001). The highest suicide rates were observed in patients with ovarian cancer and within the first year following diagnosis. Suicide risk was associated with younger age at diagnosis, high grade disease and absence of surgical intervention. CONCLUSION(S) Patients with gynecologic cancer have an increased suicide risk when compared to the general population. Suicide rates vary by cancer site and time since diagnosis. Effective screening and appropriate treatment of psychosocial stress among women with gynecologic cancer are warranted.

An evaluation of cervical cancer in women age sixty and over

OBJECTIVE To assess prior cervical cancer screening, stage at time of diagnosis and outcome in women sixty years of age and over with cervical cancer. METHODS A retrospective review of cervical cancer patients evaluated at the University of Washington identified a cohort of women age sixty and older with cervical cancer diagnosed between January 1, 1993 and December 31, 2003. Electronic medical records and the University of Washington Tumor Registry were reviewed for age, ethnicity, cervical cancer risk factors, pathology, treatment, and outcome. RESULTS Six hundred forty-five women with cervical cancer were identified. One hundred (15.5%) women were age 60 or older with a median age of 64 years. At time of diagnosis, 41 were early stage (1A1-1B1) and 59 were advanced stage (1B2-4B). Length of time from last Pap smear significantly correlated with stage. Radical hysterectomy was performed on 29 patients, and 15 received adjuvant treatment. Forty-nine women received primary chemo-radiation, and 22 were treated with primary radiation. Lymph node metastases were identified in 65% of women with locally advanced cervical cancer. At conclusion of the study period, 80% were alive. Stage and time since last Pap smear correlated with overall outcome. CONCLUSIONS Women 60 and older make up a significant proportion of cervical cancer patients, often fail to receive screening, present with locally advanced disease, and tolerate standard treatment protocols. Careful consideration of these findings should be made when establishing Pap smear screening guidelines for this population of women.

FOXP3+ regulatory T-cells are abundant in vulvar Paget's disease and are associated with recurrence

OBJECTIVE To characterize clinical features of vulvar Pagets disease, and examine the quantity of immunosuppressive regulatory T-cells in vulvar Pagets tissue. METHODS Vulvar Pagets cases from 1992 to 2007 from two institutions were identified by pathology database search. Regulatory T-cells were identified with FOXP3 immunohistochemistry and quantified at the dermal-epidermal junction using image analysis software. Thirteen non-neoplastic inflammatory cases were stained for comparison. RESULTS Cases included 33 women treated for primary vulvar Pagets, and 7 referred at recurrence. Of the 24 primary cases with greater than 5 months follow-up, recurrence was documented in 12/24(50%). Eight women (20%) recurred multiple times, but no recurrences were invasive. Significantly more patients with positive margins developed recurrent disease (82% vs 23%, p=0.01). Secondary neoplasms occurred in 10/40(25%). FOXP3+ cells at the dermal-epidermal junction were quantified in 29 primary and 13 recurrent tissue samples. FOXP3+ cells were absent in surrounding normal vulvar skin. FOXP3+ cells averaged 66/HPF in primary vulvar Pagets and 66/HPF in recurrent Pagets, compared to 22/HPF in non-neoplastic inflammatory cases (p=0.0003, p=0.001). Primary cases with positive surgical margins had more FOXP3+ cells than those with negative margins (85 vs 49, p=0.01). Recurrent cases with positive margins had more FOXP3+ cells than negative cases (84 vs 33, p=0.06). FOXP3 levels in primary specimens were higher in cases which recurred (78 vs 35, p=0.02). CONCLUSIONS Increased regulatory T-cells may be associated with more extensive cases of vulvar Pagets disease that result in positive surgical margins and are associated with recurrence of disease, suggesting immunosuppression as a key factor.