Mack N. Barnes

Epithelial ovarian cancer: Prevention, diagnosis, and treatment

The leading cause of death from gynecologic malignancies in the United States is epithelial ovarian cancer. The significant risk factor for development of ovarian cancer is advancing age, although there is clearly a genetic predisposition—often associated with the BRCA1 and BRCA2 genes—in at least 5% to 10% of all epithelial ovarian cancers.

Phase II Trial of Cetuximab and Carboplatin in Relapsed Platinum-Sensitive Ovarian Cancer and Evaluation of Epidermal Growth Factor Receptor Expression: A Gynecologic Oncology Group Study

PURPOSE This phase II trial assessed the activity and tolerability of cetuximab (C225, Erbitux) in combination with carboplatin in patients with relapsed platinum-sensitive ovarian or primary peritoneal carcinoma. PATIENTS AND METHODS Patients were to receive combination therapy with cetuximab (initial dose of 400 mg/m2 intravenously on cycle 1, day 1, followed by weekly infusions of 250 mg/m2) and carboplatin (AUC of 6 on day 1 and every 3 weeks). The primary objectives of this trial were to estimate the anti-tumor activity and adverse events of this combination therapy. Immunohistochemical expression of EGFR was evaluated in tumor specimens from patients enrolled in this trial. RESULTS Of the 29 patients, 28 (97%) were eligible and evaluable for analysis of the efficacy and toxicity of cetuximab administered in combination with carboplatin. Of the evaluable entries, 26 had EGFR-positive tumors and the response rate in this group of patients was as follows: 9 demonstrated an objective response (3 CR; 6 PR) and 8 had stable disease. The response rate did not meet criteria for opening a second stage of accrual. The median time to progression was 9.4+ months (range: .9-22.2+). The most commonly observed adverse events were dermatologic toxicity (grade 3 in 32%), thrombocytopenia (grade 3 in 14%), and hypersensitivity reactions (grade 3 and 4 in 18%). CONCLUSIONS Cetuximab administered in combination with carboplatin had modest activity in screened patients with EGFR-positive, relapsed platinum-sensitive ovarian or primary peritoneal carcinoma. Cetuximab was associated with an acneiform rash in a majority of patients and occasional serious hypersensitivity reactions.

A phase II trial of radiation therapy and weekly cisplatin chemotherapy for the treatment of locally-advanced squamous cell carcinoma of the vulva: a gynecologic oncology group study.

OBJECTIVES To determine the efficacy and toxicity of radiation therapy and concurrent weekly cisplatin chemotherapy in achieving a complete clinical and pathologic response when used for the primary treatment of locally-advanced vulvar carcinoma. METHODS Patients with locally-advanced (T3 or T4 tumors not amenable to surgical resection via radical vulvectomy), previously untreated squamous cell carcinoma of the vulva were treated with radiation (1.8 Gy daily × 32 fractions=57.6 Gy) plus weekly cisplatin (40 mg/m(2)) followed by surgical resection of residual tumor (or biopsy to confirm complete clinical response). Management of the groin lymph nodes was standardized and was not a statistical endpoint. Primary endpoints were complete clinical and pathologic response rates of the primary vulvar tumor. RESULTS A planned interim analysis indicated sufficient activity to reopen the study to a second stage of accrual. Among 58 evaluable patients, there were 40 (69%) who completed study treatment. Reasons for prematurely discontinuing treatment included: patient refusal (N=4), toxicity (N=9), death (N=2), other (N=3). There were 37 patients with a complete clinical response (37/58; 64%). Among these women there were 34 who underwent surgical biopsy and 29 (78%) who also had a complete pathological response. Common adverse effects included leukopenia, pain, radiation dermatitis, pain, or metabolic changes. CONCLUSIONS This combination of radiation therapy plus weekly cisplatin successfully yielded high complete clinical and pathologic response rates with acceptable toxicity.

Stage IC adenocarcinoma of the endometrium: survival comparisons of surgically staged patients with and without adjuvant radiation therapy.

OBJECTIVE The goal of this study was to determine the outcomes of stage IC endometrial carcinoma patients who are managed with and without adjuvant radiation therapy after comprehensive surgical staging. METHODS Patients with FIGO stage IC adenocarcinoma of the endometrium diagnosed from 1988 to 1999 were identified from tumor registry databases at four institutions. A retrospective chart review identified 220 women who underwent comprehensive surgical staging including a total hysterectomy, bilateral salpingo-oophorectomy, pelvic/paraaortic lymphadenectomy, and peritoneal cytology. RESULTS Of the 220 stage IC patients, 56 (25%) patients received adjuvant brachytherapy (BT), 19 (9%) received whole-pelvis radiation (WPRT), and 24 (11%) received both WPRT and BT. One hundred twenty-one patients (55%) did not receive adjuvant radiation. There were 6 recurrences (6%) in the radiated group and 14 (12%) in the observation group (P = 0.20). Seven of fourteen recurrences in the observation group were local, and all local recurrences were salvaged with radiation therapy. Two of seven distant recurrences in this group were also salvaged with surgery and chemotherapy. The overall salvage rate for the observation group was 64%. There was a statistical difference in 5-year disease-free survival between the radiated and observation groups (93% vs 75%, P = 0.013). However, the 5-year overall survival was similar in the two groups (92% vs 90%, P = 0.717). CONCLUSION Adjuvant radiation therapy improves disease-free survival in surgical stage IC patients; however, overall survival is not improved with adjuvant radiation therapy since the majority of local recurrences in conservatively managed patients can be salvaged with radiation therapy.

A Phase I Study of a Tropism-Modified Conditionally Replicative Adenovirus for Recurrent Malignant Gynecologic Diseases

Purpose: To determine the maximum tolerated dose (MTD), toxicity spectrum, clinical activity, and biological effects of the tropism-modified, infectivity-enhanced conditionally replicative adenovirus (CRAd), Ad5–Δ24–Arg-Gly-Asp (RGD), in patients with malignant gynecologic diseases. Experimental Design: Cohorts of eligible patients were treated daily for 3 days through an i.p. catheter. Vector doses ranged from 1 × 109 to 1 × 1012 viral particles per day. Toxicity was evaluated using CTCv3.0. CA-125 and Response Evaluation Criteria in Solid Tumors (RECIST) criteria were used to determine clinical efficacy. Corollary biological studies included assessment of CRAd replication, wild-type virus generation, viral shedding, and neutralizing antibody response. Results: Twenty-one patients were treated. Adverse clinical effects were limited to grade 1/2 fever, fatigue, or abdominal pain. No vector-related grade 3/4 toxicities were noted. No clinically significant laboratory abnormalities were noted. The maximum tolerated dose was not reached. Over a 1 month follow-up, 15 (71%) patients had stable disease and six (29%) had progressive disease. No partial or complete responses were noted. Seven patients had a decrease in CA-125; four had a >20% drop. RGD-specific PCR showed the presence of study vector in ascites of 16 patients. Seven revealed an increase in virus after day 3, suggesting replication of Ad5-Δ24-RGD. Minimal wild-type virus generation was detected. Viral shedding studies showed insignificant shedding in the serum, saliva, and urine. Anti-adenoviral neutralizing antibody effects were prevalent. Conclusions: This study, the first to evaluate an infectivity-enhanced CRAd in human cancer, shows the feasibility, safety, potential antitumor response, and biological activity of this approach in ovarian cancer. Further evaluation of infectivity enhanced virotherapy approaches for malignant gynecologic diseases is warranted. Clin Cancer Res; 16(21); 5277–87. ©2010 AACR.

Phase-I clinical trial of IL-12 plasmid/lipopolymer complexes for the treatment of recurrent ovarian cancer

A phase-I trial to assess the safety and tolerability of human interleukin-12 (IL-12) plasmid (phIL-12) formulated with a synthetic lipopolymer, polyethyleneglycol–polyethyleneimine–cholesterol (PPC), was conducted on women with chemotherapy-resistant recurrent ovarian cancer. A total of 13 patients were enrolled in four dose-escalating cohorts and treated with 0.6, 3, 12 or 24 mg m−2 of the formulated plasmid once every week for 4 weeks. Administration of phIL-12/PPC was generally safe and well-tolerated. Common side effects included low-grade fever and abdominal pain. Stable disease and reduction in serum CA-125 levels were clinically observed in some patients. Measurable levels of IL-12 plasmid were detectable in PF samples collected throughout the course of phIL-12/PPC treatment. In comparison, serum samples either did not contain detectable amounts of plasmid DNA or contained <1% of the amount found in the corresponding PF samples. Treatment-related increases in IFN-γ levels were observed in PF but not in serum. These data demonstrate that IL-12 gene delivery with a synthetic delivery system is feasible for ovarian cancer patients.

The secretory leukoprotease inhibitor (SLPI) promoter for ovarian cancer gene therapy.

Adenoviruses allow efficient transduction of dividing and non‐dividing cells and their safety for the treatment of cancer has been established in clinical trials. However, one disadvantage is their promiscuous tropism. In this regard, tissue‐specific promoters (TSPs) could be useful for directing transgene expression to target tissues and for reducing adverse effects in non‐target tissues. We hypothesize that selective adenovirus‐mediated transgene expression could be achieved through the use of the secretory leukoprotease inhibitor (SLPI) promoter in the context of ovarian cancer.

Lynch Syndrome in Women Less Than 50 Years of Age With Endometrial Cancer

OBJECTIVE: To estimate the frequency of mismatch repair deficiencies associated with hereditary nonpolyposis colorectal cancer, or Lynch syndrome, in women less than age 50 with endometrial cancer. METHODS: Consecutive patients less than age 50 diagnosed with endometrial adenocarcinoma were identified. Available pathologic specimens were freshly sliced, and protein expression for MLH1, MSH2, MSH6, and PMS2 was evaluated by immunohistochemistry. Slides were scored on a semiquantitative method with complete absence of any of the four proteins suggesting a deficiency. All results were confirmed by microsatellite instability testing. RESULTS: Sixty-one pathology specimens were analyzed. Twenty-one (34%) of the tumors had absence of staining of at least one of the four mismatch repair proteins determined by immunohistochemistry and confirmed by microsatellite instability testing. Obese patients were less likely than nonobese patients to have a mismatch repair deficiency (21% versus 59%, respectively). Non-obese patients had a relative risk for a mismatch repair deficiency of 5.5 (95% confidence interval 1.6–19.1; P=.01). CONCLUSION: Many women diagnosed with endometrial cancer before age 50 will have a mismatch repair deficiency discovered by immunohistochemistry and microsatellite instability testing. A number of young women diagnosed with endometrial cancer will require further genetic testing for mismatch repair mutations. LEVEL OF EVIDENCE: III

Gene therapy and ovarian cancer: A review

Objective To provide the obstetrician-gynecologist with the basic concepts of gene therapy, an overview of cancer gene therapy treatment strategies, and a summary of currently approved human gene therapy protocols for ovarian carcinoma. Data Sources A computerized search of articles published through December 1995 was performed on the MEDLINE data base. Additional sources were identified through cross-referencing. Methods of Study Selection All identified references were reviewed with particular attention to their relevance to gene therapy for ovarian cancer. Tabulation, Integration, and Results Each reference was reviewed to determine the relevant contribution to the fundamental science of gene therapy. Particular attention was paid to those studies that offered a rational strategy that might contribute to therapy for ovarian malignancy. Conclusion Advances in molecular biology, immunology, and virology have enabled the concept of gene therapy for neoplastic disorders to become a reality. Given the lack of effective conventional therapy, those patients with recurrent or refractory ovarian cancer should be considered for currently approved investigational gene therapy protocols.

Paradigms for primary prevention of ovarian carcinoma.

Objective: To provide the clinician with current concepts regarding prevention of ovarian cancer. Specifically, in this review, we provide a rationale for chemoprevention of ovarian cancer, a description of promising chemopreventive agents, and an overview of surgical strategies used in the prevention of ovarian cancer.