R. Wendel Naumann

PRECEDENT: A Randomized Phase II Trial Comparing Vintafolide (EC145) and Pegylated Liposomal Doxorubicin (PLD) in Combination Versus PLD Alone in Patients With Platinum-Resistant Ovarian Cancer

PURPOSE Vintafolide (EC145) is a folic acid-desacetylvinblastine conjugate that binds to the folate receptor (FR), which is expressed on the majority of epithelial ovarian cancers. This randomized phase II trial evaluated vintafolide combined with pegylated liposomal doxorubicin (PLD) compared with PLD alone. The utility of an FR-targeted imaging agent, (99m)Tc-etarfolatide (EC20), in selecting patients likely to benefit from vintafolide was also examined. PATIENTS AND METHODS Women with recurrent platinum-resistant ovarian cancer who had undergone ≤ two prior cytotoxic regimens were randomly assigned at a 2:1 ratio to PLD (50 mg/m(2) intravenously [IV] once every 28 days) with or without vintafolide (2.5 mg IV three times per week during weeks 1 and 3). Etarfolatide scanning was optional. The primary objective was to compare progression-free survival (PFS) between the groups. RESULTS The intent-to-treat population comprised 149 patients. Median PFS was 5.0 and 2.7 months for the vintafolide plus PLD and PLD-alone arms, respectively (hazard ratio [HR], 0.63; 95% CI, 0.41 to 0.96; P = .031). The greatest benefit was observed in patients with 100% of lesions positive for FR, with median PFS of 5.5 compared with 1.5 months for PLD alone (HR, 0.38; 95% CI, 0.17 to 0.85; P = .013). The group of patients with FR-positive disease (10% to 90%) experienced some PFS improvement (HR, 0.873), whereas patients with disease that did not express FR experienced no PFS benefit (HR, 1.806). CONCLUSION Vintafolide plus PLD is the first combination to demonstrate an improvement over standard therapy in a randomized trial of patients with platinum-resistant ovarian cancer. Etarfolatide can identify patients likely to benefit from vintafolide.

Management Strategies for Recurrent Platinum-Resistant Ovarian Cancer

Although ovarian cancer is often a chemosensitive malignancy, patients who are resistant to platinum-based chemotherapy represent a therapeutic challenge. Currently, the only drugs that are US FDA approved to treat this subset of patients are paclitaxel, pegylated liposomal doxorubicin (PLD) and topotecan. The response rates with these agents is in the 10–15% range and overall survival is around 12 months. Other drugs that have shown some activity in platinum-resistant ovarian cancer include the taxane analogues, oral etoposide, pemetrexed and bevacizumab. Unfortunately, randomized phase III trials of second-line chemotherapy in patients with platinum-resistant ovarian cancer have not shown an advantage over existing therapy with respect to progression-free survival or overall survival. The only trial that has reported a significant progression-free survival advantage over standard therapy is a randomized phase II trial of PLD with or without EC145, a folate-linked vinca alkaloid. Final survival results of this trial are pending.

The phosphoprotein Op18/stathmin is differentially expressed in ovarian cancer.

Abstract To identify potential prognostic indicators of ovarian cancer and identify targets for therapeutic strategies, mRNA differential display was used to analyze gene expression differences in normal, benign, and cancerous ovarian tissue. One cDNA isolated by this technique, Op18/stathmin, is a highly conserved gene that is reported to have many different functions within a cell, including signal transduction, control of the cell cycle, and the regulation of microtubules. Quantitative Northern blot analysis of 12 malignant ovarian samples, 8 benign ovarian tumors, and 10 normal ovarian tissue samples demonstrated overexpresaion of Op18/stathmin mRNA in the malignant cancers. Immunohistochemistry showed an apparent overex-pression of Op18/stathmin protein level and an association with proliferating cells

Role of minimally invasive surgery in gynecologic oncology: An updated survey of members of the Society of Gynecologic Oncology

Objectives To evaluate the current patterns of use of minimally invasive surgical procedures, including traditional, robotic-assisted, and single-port laparoscopy, by Society of Gynecologic Oncology (SGO) members and to compare the results to those of our 2004 and 2007 surveys. Methods The Society of Gynecologic Oncology members were surveyed through an online or mailed-paper survey. Data were analyzed and compared with results of our prior surveys. Results Four hundred six (32%) of 1279 SGO members responded. Eighty-three percent of respondents (n = 337) performed traditional laparoscopic surgery (compared with 84% in 2004 and 91% in 2007). Ninety-seven percent of respondents performed robotic surgery (compared with 27% in 2007). When respondents were asked to indicate procedures that they performed with the robot but not with traditional laparoscopy, 75% indicated radical hysterectomy and pelvic lymphadenectomy for cervical cancer. Overall, 70% of respondents indicated that hysterectomy and staging for uterine cancer was the procedure they most commonly performed with a minimally invasive approach. Only 17% of respondents who performed minimally invasive surgery performed single-port laparoscopy, and only 5% of respondents indicated that single-port laparoscopy has an important or very important role in the field. Conclusions Since our prior surveys, we found a significant increase in the overall use and indications for robotic surgery. Radical hysterectomy or trachelectomy and pelvic lymphadenectomy for cervical cancer and total hysterectomy and staging for endometrial cancer were procedures found to be significantly more appropriate for the robotic platform in comparison to traditional laparoscopy. The indications for laparoscopy have expanded beyond endometrial cancer staging to include surgical management of early-stage cervical and ovarian cancers, but the use of single-port laparoscopy remains limited.

The commercialization of robotic surgery: unsubstantiated marketing of gynecologic surgery by hospitals.

OBJECTIVE We analyzed the content, quality, and accuracy of information provided on hospital web sites about robotic gynecologic surgery. STUDY DESIGN An analysis of hospitals with more than 200 beds from a selection of states was performed. Hospital web sites were analyzed for the content and quality of data regarding robotic-assisted surgery. RESULTS Among 432 hospitals, the web sites of 192 (44.4%) contained marketing for robotic gynecologic surgery. Stock images (64.1%) and text (24.0%) derived from the robot manufacturer were frequent. Although most sites reported improved perioperative outcomes, limitations of robotics including cost, complications, and operative time were discussed only 3.7%, 1.6%, and 3.7% of the time, respectively. Only 47.9% of the web sites described a comparison group. CONCLUSION Marketing of robotic gynecologic surgery is widespread. Much of the content is not based on high-quality data, fails to present alternative procedures, and relies on stock text and images.

Practice patterns of intraperitoneal chemotherapy in women with ovarian cancer

OBJECTIVES To determine the current patterns of IP chemotherapy use in women with ovarian cancer. METHODS A survey concerning the use of intraperitoneal (IP) chemotherapy was sent to all members of the SGO listed in the 2005 SGO directory and to 200 members of ASCO randomly selected from the ASCO directory in two mailings. RESULTS There were 209 completed responses to the survey, which included 24% of the SGO and 3% of the ASCO members sampled (P<0.0001). Of the respondents, 77% indicated that they currently offer IP chemotherapy, 14% either refer patients, or plan to offer IP chemo in the near future, and 9% do not offer IP chemotherapy. The top reasons given by those not using IP chemo was toxicity (63%) and not having the facilities to give an IP infusion (16%). Significant concern over toxicity by all respondents was highest for neurological toxicity (55%) followed by nausea and vomiting (51%), catheter infections (39%) and nephropathy (39%). The most common dose of IP cisplatin was 75 mg/m(2) (54%), followed by 100 mg/m(2) (38%). Only 6% use carboplatin primarily, but 60% reduce the cisplatin dose based on age. Currently 58% have modified the paclitaxel infusion to allow administration of this regimen in the outpatient setting and 17% plan to do so in the near future. Those using lower doses of platinum are also more likely to offer chemotherapy in the outpatient setting. Concern over toxicity, lack of coverage by residents or fellows, or type of practice did not predict a reduction in platinum dose. A single lumen IP catheter was used by 60% of respondents and a fenestrated is preferred by 40%. This catheter is placed at the time of primary surgery by 58% and 37% routinely place the catheter during a second procedure. CONCLUSION The toxicity of IP therapy remains a concern and there does not appear to be any standard IP regimen that is used in women with ovarian cancer. The majority of the SGO members give IP chemotherapy in an outpatient setting at a dose lower than was used in clinical trials. This survey probably represents an overestimate in the use of IP therapy as there is likely a bias in completing the survey by those who currently use this modality. Based on this assumption, it appears that the use of IP chemotherapy by medical oncologists is low.

Randomized Phase II Trial of Seribantumab in Combination With Paclitaxel in Patients With Advanced Platinum-Resistant or -Refractory Ovarian Cancer

Purpose Seribantumab is a fully human immunoglobulin G2 monoclonal antibody that binds to human epidermal growth factor receptor (HER) 3 (ErbB3), blocking heregulin (HRG) -mediated ErbB3 signaling and inducing ErbB3 receptor downregulation. This open-label randomized phase II study evaluated progression-free survival (PFS) with seribantumab in combination with once-per-week paclitaxel compared with paclitaxel alone in patients with platinum-resistant or -refractory ovarian cancer. A key secondary objective was to determine if any of five prespecified biomarkers predicted benefit from seribantumab. Patients and Methods Patients with platinum-resistant or -refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomly assigned at a ratio of two to one to receive seribantumab plus paclitaxel or paclitaxel alone. Patients underwent pretreatment core needle biopsy; archival tumor samples were also obtained to support biomarker analyses. Results A total of 223 patients were randomly assigned (seribantumab plus paclitaxel, n = 140; paclitaxel alone, n = 83). Median PFS in the unselected intent-to-treat population was 3.75 months with seribantumab plus paclitaxel compared with 3.68 months with paclitaxel alone (hazard ratio [HR], 1.027; 95% CI, 0.741 to 1.425; P = .864). Among patients whose tumors had detectable HRG mRNA and low HER2 (n = 57 [38%] of 151 with available biomarker data), increased treatment benefit was observed in those receiving seribantumab plus paclitaxel compared with paclitaxel alone (PFS HR, 0.37; 95% CI, 0.18 to 0.76; P = .007). The HR in patients not meeting these criteria was 1.80 (95% CI, 1.08 to 2.98; P = .023). Conclusion The addition of seribantumab to paclitaxel did not result in improved PFS in unselected patients. Exploratory analyses suggest that detectable HRG and low HER2, biomarkers that link directly to the mechanism of action of seribantumab, identified patients who might benefit from this combination. Future clinical trials are needed to validate this finding and should preselect for HRG expression and focus on cancers with low HER2 levels.

Primary Endometrial T-Cell Lymphoma A Case Report

Primary lymphomas of the female genital tract are rare. Most involve the cervix rather than the uterine corpus. All of those previously reported have been B-cell lymphomas, with the exception of 1 case report of an endometrial T-cell lymphoma in a Japanese woman. We report the case of a white woman from the United States with a diffuse large cell lymphoma of the endometrium, characterized as a peripheral T-cell type on the basis of immunophenotypic and molecular probe studies. Staging evaluation revealed tumor limited to the endometrium (stage IE). The patient underwent a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and lymph node dissection and received 6 cycles of combination chemotherapy, after which she remained free of disease at last follow-up of 36 months. Unusual features of this lymphoma case are discussed, with emphasis on differential diagnosis and speculation on histogenesis. This case illustrates that, while most peripheral T-cell lymphomas are widely disseminated at presentation, those limited to a single extranodal site may have a favorable outcome akin to that associated with high-grade extranodal B-cell lymphomas of early stage.

The role of the phosphatidylinositol 3-kinase (PI3K) pathway in the development and treatment of uterine cancer

OBJECTIVE Uterine cancer is the most common gynecologic malignancy in the United States. Although surgery is often curative for women diagnosed in the early stages, prognosis for patients with advanced disease is poor. Alterations in the phosphatidylinositol 3-kinase (PI3K) pathway are known to play a significant role in the development of uterine cancer and provide a possible target for new therapies. METHODS PubMed was searched for articles of relevance to uterine cancer and the PI3K pathway. In addition, abstracts from key oncology congresses were scanned for data on novel therapeutic agents targeting the PI3K pathway. RESULTS The PI3K pathway is an important promoter of cellular growth, metabolism, differentiation, proliferation, survival, and angiogenesis. It is often upregulated in uterine cancer, with the most frequent genetic alterations occurring in phosphatase and tensin homolog (PTEN), PIK3CA, and KRAS. Deregulation of the pathway has been associated with resistance to hormonal therapy and chemotherapy. Inhibitors of the PI3K pathway are in clinical testing in patients with solid tumors, including uterine cancer. Results with monotherapy demonstrate some clinical responses, but mainly as prolonged stable disease. PI3K pathway inhibitors are currently being evaluated in patients with tumors in which the PI3K pathway is deregulated. Another strategy being evaluated is the ability of PI3K pathway inhibitors to restore sensitivity to standard therapy. CONCLUSIONS Investigational PI3K pathway inhibitors represent a promising new therapeutic strategy in uterine cancer. Exploration of effective drug combinations and their applicability to individual tumors will be important in the future clinical development of these agents.

Make new friends but keep the old: Minimally invasive surgery training in gynecologic oncology fellowship programs

Objectives To evaluate the role of minimally invasive surgery (MIS) in gynecologic oncology fellowship training and fellows’ predictions of their use of MIS in their future practice. Methods All fellows-in-training in American Board of Obstetrics and Gynecology–approved training programs were surveyed in 2012 through an online or mailed-paper survey. Data were analyzed and compared to results of a similar 2007 survey. Results Of 172 fellows, 69 (40%) responded. Ninety-nine percent of respondents (n = 68) indicated that MIS was either very important or important in gynecologic oncology, a proportion essentially unchanged from 2007 (100%). Compared to 2007, greater proportions of fellows considered laparoscopic radical hysterectomy and node dissection for cervical cancer (87% vs 54%; P < 0.0001) and trachelectomy and staging for cervical cancer (83% vs 32%; P < 0.0001) appropriate for MIS. Of the respondents, 92% believed that maximum or some emphasis should be placed on robotic-assisted surgery and 89% on traditional laparoscopy during fellowship training. Ten percent rated their fellowship training in laparoendoscopic single-site surgery as very poor; 44% said that the question was not applicable. Most respondents (60%) in 2012 performed at least 11 procedures per month, whereas most respondents (45%) in 2007 performed 6 to 10 procedures per month (P = 0.005). All respondents at institutions where robotic surgery was used were allowed to operate at the robotic console, and 63% of respondents reported that in robotic-assisted surgery cases when a fellow sat at the robot, the fellow performed more than 50% of the case at the console. Conclusions These findings indicate that MIS in gynecologic oncology is here to stay. Fellowship programs should develop a systematic approach to training in MIS and in individual MIS platforms as they become more prevalent. Fellowship programs should also develop and apply an objective assessment of minimum proficiency in MIS to ensure that programs are adequately preparing trainees.