Pembrolizumab with low-dose carboplatin for recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer: survival and immune correlates.

BACKGROUND: Anti-programmed death 1 (PD1)/programmed cell death ligand 1 (PD-L1) therapies have shown modest activity as monotherapy in recurrent ovarian cancer. Platinum chemotherapies induce T-cell proliferation and enhance tumor recognition. We assessed activity and safety of pembrolizumab with carboplatin in recurrent platinum-resistant ovarian cancer. PATIENTS AND METHODS: This phase I/II, single-arm clinical trial studied concurrent carboplatin and pembrolizumab in recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer. Primary platinum refractory patients were excluded. Patients were treated after progression on subsequent non-platinum systemic therapy after becoming platinum resistant or refractory. Pembrolizumab 200 mg was given on day 1 and carboplatin area under the curve 2 on days 8 and 15 of a 3-week cycle until progression. Imaging was assessed by blinded independent review. PD-L1 expression was assessed by immunohistochemistry. Flow cytometry on peripheral blood mononuclear cells was performed for CD3, CD4, CD8, PD1, CTLA4 and Ki67. RESULTS: The most common treatment-related adverse events were lymphopenia (18%) and anemia (9%) with most being grade 1 or 2 (93%). Of 29 patients treated, 23 patients were evaluable for best objective response: 10.3% (95% CI 2.2 to 27.4) had partial response (PR), 51.7% (95% CI 32.5 to 70.6) had stable disease (SD). 56.5% of patients had decreases in target lesions from baseline. All PD-L1-positive patients achieved PR (3/7, 42.8%) or SD (4/7, 57.2%). Median progression-free survival was 4.63 months (95% CI 4.3 to 4.96). Median OS was 11.3 months (95% CI 6.094 to 16.506). Peripheral CD8+PD1+Ki67+ T cells expanded after 3 (p=0.0015) and 5 (p=0.0023) cycles. CTLA4+PD1+CD8+ T cells decreased through the course of treatment up to the 12th cycle (p=0.004). When stratified by ratio of peripheral CD8+PD1+Ki67+ T cells to tumor burden at baseline, patients with a ratio ≥0.0375 who had a significantly longer median OS of 18.37 months compared with those with a ratio <0.0375 who had a median OS of 8.72 months (p=0.0099). No survival advantage was seen with stratification by tumor burden alone (p=0.24) or by CD8+PD1+Ki67+ T cells alone (p=0.53). CONCLUSIONS: Pembrolizumab with carboplatin was well-tolerated and active in recurrent platinum-resistant ovarian cancer. A ratio of peripheral T-cell exhaustion to radiographic tumor burden may identify patients more likely to benefit from this chemoimmunotherapy. TRIAL REGISTRATION NUMBER: NCT03029598.

Phase II trial of albumin-bound paclitaxel and granulocyte macrophage colony-stimulating factor as an immune modulator in recurrent platinum resistant ovarian cancer.

BACKGROUND: Granulocyte macrophage colony-stimulating factor (GM-CSF) stimulates immunity via recruitment of antigen presenting cells and tumor specific T-cell stimulation. Albumin-bound paclitaxel (nab-paclitaxel) followed by GM-CSF may enhance antitumor responses and prolong remissions in ovarian cancer. Immune phenotypes present before treatment may identify responders to chemo-immunotherapy. METHODS: Recurrent platinum-resistant ovarian, peritoneal, or fallopian tube cancer patients received nab-paclitaxel, 100mg/m2 days 1, 8, 15 followed by GM-CSF 250µg days 16-26 every 28days for 6 planned cycles. The primary endpoint was remission duration compared to immediate prior remission. Peripheral blood was evaluated by flow cytometry and interferon-γ ELISPOT. RESULTS: Twenty-one patients were enrolled. Six patients (29%) achieved a biochemical complete response and 9 (43%) a partial response for an overall response rate of 72%. Median time to progression was 4months and 10% of patients achieved longer remissions than the immediate prior regimen. Median overall survival (OS) was 16.8months. Fewer myeloid derived suppressor cells (MDSC) at enrollment significantly associated with complete response (p=0.05). T-cell responses to IGF1R-p1332-1346 (r=0.827, p=0.0003) and IGF1R-p1242-1256 (r=0.850, p=0.0001) during treatment correlated with time to progression. CONCLUSIONS: Nab-paclitaxel combined with GM-CSF demonstrated biochemical responses in a majority of patients, although responses were not sustained. This combination did not demonstrate an advantage in OS over prior studies of nab-paclitaxel monotherapy. Agents that modulate MDSC should be studied as potential adjuvants to therapy. Strategies to expand T cells recognizing tumor-associated antigens biologically significant in ovarian cancer should also continue to be investigated.

Implementing the "Flipped Classroom" on a Gynecologic Oncology Service.

OBJECTIVE: To determine the impact of a new cur- riculum based on the "flipped classroom" model on the gynecologic oncology (gyn onc) section of the annual in-service examination for residents in obstetrics and gynecology. STUDY DESIGN: We intro- duced a curriculum focused on a weekly topic for teach- ing the residents on the gyn onc service in January of 2009. We compared the over- all mean gyn onc-specific percent-correct scores on the in-service examination be- fore (1999-2009) and after (2010-2011) the implemen- tation of the curriculum using linear regression to estimate the mean percentage point change and 95% confidence interval, adjusting for clustering by residents. RESULTS: Our analysis included 90 residents (73 females and 17 males), which yielded 295 scores for analysis. We found a significant increase of 6.5 per- centage points (95% CI 3.5-9.6) in the gyn .onc mean percent correct for all postgraduate year levels combined after initiation of our curriculum. During that same period the overall in-service examination percent-correct scores did not significantly change. CONCLUSION: Our curriculum,focusing on a weekly topic, resulted in improve- ment in in-service exam- ination scores. This type of curriculum could be applied to other areas of resident edu- cation within obstetrics and gynecology.

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.

Disparities in treatment and survival between African American and White women with vaginal cancer.

OBJECTIVE: The study aims to compare the difference in treatment and survival between White (W) and African American (AA) patients with vaginal cancer (VC). METHODS: Patients with a diagnosis of invasive vaginal cancer were identified from Surveillance, Epidemiology, and End Results (SEER) program from 1988 to 2007 and were divided into White (W) and African American (AA) subgroups. Student's t test, Kaplan-Meier survival methods, and Cox regression proportional hazards were performed. RESULTS: A total of 2675 patients met the inclusion criteria, with histologic distribution of squamous cell carcinoma (SCC; 2190, 82%) and adenocarcinoma (AC; 485, 18%); 2294 (85.8%) were W, and 381 (14.2%) were AA. Median age was 69 for W and 65 for AA (p<0.001). SCC and AC were equally distributed between W and AA. Advanced stage disease (FIGO III and IV) was more prominent in AA compared with W (30.4% vs. 23.1%, p=0.019). Radiation therapy was utilized equally in both racial groups; however, surgical treatment alone or combined with radiation therapy was more frequent in W compared with AA (27.7% vs. 17.5%, p<0.001). The 5-year survival was 45% in W and 38.6% in AA (p=0.008). In multivariate analysis, AA had significantly poorer survival compared with Whites when controlling for age, histology, stage, grade and treatment modality (HR 1.2, 95% CI 1.1-1.4, p=0.007). CONCLUSIONS: African American women with vaginal cancer were more likely to present, at a younger age, advanced stage and less likely to receive surgical treatment. Our data suggests that AA race is an independent predictor of poor survival in vaginal cancer.

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.

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

OBJECTIVE: To characterize clinical features of vulvar Paget's disease, and examine the quantity of immunosuppressive regulatory T-cells in vulvar Paget's tissue. METHODS: Vulvar Paget's 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 Paget's, 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 Paget's and 66/HPF in recurrent Paget's, 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 Paget's disease that result in positive surgical margins and are associated with recurrence of disease, suggesting immunosuppression as a key factor.

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.

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.

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.

Kinetics of tumor-specific T-cell response development after active immunization in patients with HER-2/neu overexpressing cancers.

The ability of a cancer vaccine to elicit a specific measurable T-cell response is increasingly being used to prioritize immunization strategies for therapeutic development. Knowing the optimal time during a vaccine regimen to measure the development of tumor-specific immunity would greatly facilitate the assessment of T-cell responses. The purpose of this study was to overview the kinetics of HER-2/neu-specific T-cell immunity evolution during and after the administration of HER-2/neu peptide-based vaccination in the adjuvant setting. Furthermore, we questioned whether the presence of preexistent HER-2/neu T-cell immunity or the timing of immunity development over the course of active immunization influenced the intensity of the elicited HER-2/neu-specific T-cell immunity. Our findings demonstrate that maximal tumor-specific immune responses may occur toward the end of the vaccination regimen or even after the scheduled vaccines have been completed. Additionally, the presence of tumor antigen-specific immunity prior to vaccination is associated with greater magnitude immune responses.

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.

Weekly gemcitabine and cisplatin in combination with pelvic radiation in the primary therapy of cervical cancer: a phase I trial of the Puget Sound Oncology Consortium.

OBJECTIVE: Define the maximum tolerated dose of weekly gemcitabine given concomitantly with standard weekly cisplatin and pelvic radiotherapy for primary treatment of cervical cancer. METHODS: Gemcitabine at specified dose levels was given concomitantly with weekly cisplatin at 40 mg/m2 for six cycles with concurrent radiotherapy in primary therapy of stage IB-IVA cervix cancer. Radiation consisted of 4500-5000 cGy in 25 daily fractions combined with brachytherapy to take point A to > or = 8500 cGy. RESULTS: At gemcitabine 100 mg/m2, three of six patients demonstrated a dose limiting toxicity (DLT). At gemcitabine 50 mg/m2, two of two had DLTs. DLTs consisted of severe fatigue, lymphopenia, diarrhea, and tinnitus. All patients had a clinical complete response; four pathologically confirmed. Two patients recurred outside the radiated field and seven are disease-free (median follow-up 30 months). Following the second DLT at gemcitabine 50 mg/m2, the trial was stopped according to predetermined criteria. CONCLUSIONS: Adding low dose weekly gemcitabine to cisplatin and pelvic radiotherapy resulted in an excellent response but unacceptable toxicities. Addition of gemcitabine prior to weekly cisplatin with radiation for cervical cancer will likely require reduction of cisplatin doses.

Surgery for ovarian cancer: rationale and guidelines.

Ovarian cancer is the second most common gynecologic cancer in women and the leading cause of death caused by gynecologic malignancy. Surgery plays a fundamental role in treating this challenging disease. Goals of primary surgery for ovarian cancer are to establish diagnosis, proper staging, determination of prognosis, and optimal cytoreduction of gross disease before chemotherapy for improved outcome. In addition to standard removal of the ovaries, uterus, omentum, and pelvic and para-aortic lymph nodes for early disease, extended surgical techniques used to debulk advanced disease include bowel resection, splenectomy, partial liver resection, peritoneal or diaphragmatic stripping, and use of laser or ultrasound (CUSA). Secondary surgery is used in a variety of situations. Second-look procedures were performed historically to determine response to chemotherapy to delineate duration of treatment, but now are best used in a research setting with the advent of improved chemotherapeutic agents. As a high percentage of patients have a gynecologic malignancy recurrence after primary treatment, many practitioners perform secondary cytoreductive procedures for recurrent disease. Additionally, in the recurrent setting, surgery may be necessary for relief of bowel obstruction and palliation of symptoms. Surgical management of ovarian cancer must be performed by surgeons, such as gynecologic oncologists, who have a firm understanding of the disease process, display good clinical judgment, and are adequately trained to perform the complex surgery that commonly is required for appropriate care.

Cyclooxygenase (COX)-2 and granulosa cell apoptosis in vitro.

PURPOSE: C-myc was studied in cyclooxygenase (COX)-2 associated granulosa cell apoptosis, METHODS: Granulosa cells (N = 5 cases) were incubated for 24 h in either 1 or 50 microM COX-2 inhibitor, 1 or 50 microM COX-1/COX-2 inhibitor, negative or positive controls Single primer polymerase chain reaction of c-myc exon 1 were performed. Bisbenzimide-stained control single-stranded (ssDNA) were hybridized to SYBR Gold-stained ssDNA and fluorescent images analyzed. RESULTS: C-myc was disrupted by the high-dose COX-2 inhibitor. Cell viability decreased with COX-1 and COX-2 inhibition. However, cell viability was similar for the positive control and at low-dose COX-2 inhibition. CONCLUSIONS: Inhibition of both COX-1 and COX-2 initiated apoptosis without disrupting c-myc suggesting a protective effect on c-myc. The low dosage of the COX-2 inhibitor did not disrupt c-myc and cell viability. C-myc sensitization was not part of apoptosis.