Laparoscopic intraperitoneal port placement for optimally cytoreduced advanced ovarian cancer.

STUDY OBJECTIVE: To evaluate complications of intraperitoneal ports placed laparoscopically as a separate procedure after initial debulking surgery for ovarian, fallopian tube, or primary peritoneal cancer. DESIGN: A retrospective case series (Canadian Task Force Classification III). SETTING: Inpatient, academic teaching institution. PATIENTS: Female patients of any age, at a single institution, undergoing laparoscopically-assisted intraperitoneal port placement after initial surgery for ovarian, fallopian tube, or primary peritoneal cancer from January 2001 through December 2009. INTERVENTIONS: Laparoscopically assisted intra-peritoneal port placement. MEASUREMENTS/MAIN RESULTS: Thirty-three ports were successfully placed, with no conversions to laparotomy. Only 2 patients were unable to receive intraperitoneal chemotherapy, and there was 1 major complication (enterotomy) related to port placement. There were 6 cases of port dysfunction (17%); however, in 3 cases the port was replaced and subsequently functioned well. There were 2 cases of port infection necessitating port removal. The majority (81.8%) of patients were able to complete all planned cycles of intraperitoneal chemotherapy. CONCLUSION: Based on the data from our institution, laparoscopic placement of an intraperitoneal port may be safely performed as a second procedure after initial surgery for stage III ovarian, fallopian tube, or primary peritoneal cancer and provides access for post-operative therapy.

Advanced Epithelial Ovarian Cancer: Do More Options Mean Greater Benefits?

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A healthy 51-year-old woman presented with increasing abdominal and pelvic pain. Computed tomography imaging of the abdomen and pelvis showed an 11.6-cm pelvic mass, retroperitoneal lymphadenopathy, right hydronephrosis, and mesenteric tumor deposits ( Fig 1A ). A serum CA-125 was elevated at 1,149 U/mL. She underwent primary surgical cytoreduction including hysterectomy, bilateral salpingo-oophorectomy, appendectomy, resection of pelvic tumor, omentectomy, and low anterior resection with colorectal anastomosis. Intraoperatively, she was noted to have bilateral ovarian masses, pelvic and para-aortic lymphadenopathy, and a 4-cm omental tumor; in addition, both the uterus and rectosigmoid colon had adherent tumor deposits. All gross tumor was resected during the procedure. Final pathology confirmed high-grade serous carcinoma of ovarian origin ( Fig 1B ) that was determined to be stage IIIC as a result of upper abdominal involvement with greater than 2-cm tumor deposits, as well as retroperitoneal lymph node involvement. She underwent germline genetic testing, which did not identify a mutation in the BRCA1, BRCA2, BRIP1, RAD51C, or RAD51D genes. She presented for adjuvant chemotherapy after an optimal (R0) resection.

When Should Tumor Genomic Profiling Prompt Consideration of Germline Testing?

Somatic genomic testing is rapidly becoming an integral part of care for patients with metastatic cancer. Extrapolation of these results beyond personalized cancer therapy is a skill being demanded of practicing oncologists without prior specialty in genetics. Up to 12% of tumor genomic profiling reports will reveal a germline pathogenic variant. Recognition of these germline variants is essential not only for optimal care of the patient with cancer but also to initiate cascade genetic testing in at-risk family members who also may carry the familial mutation. This article provides a concise and methodical, evidence-based strategy to guide oncology providers about how to identify genes associated with an inherited predisposition for cancer, determine the pathogenicity of variants reported within those genes, and understand the likelihood that these variants are of germline origin in a particular patient with cancer. Case examples are provided to illustrate clinical scenarios and facilitate application of the proposed approach.

Assessment of Combined Nivolumab and Bevacizumab in Relapsed Ovarian Cancer: A Phase 2 Clinical Trial.

Importance: To date, single-agent programmed cell death 1 protein 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint blockade has shown limited activity in recurrent epithelial ovarian cancer. Combination strategies of PD-1/PD-L1 inhibition with antiangiogenic therapy have the potential for synergistic activity through modulation of the microenvironment and represent a potential therapeutic opportunity in this disease. Objective: To evaluate the activity of combined nivolumab and bevacizumab in women with relapsed ovarian cancer. Design, Setting, and Participants: A single-arm, phase 2 study enrolled patients between February 8, 2017, and December 29, 2017, at 2 sites in the United States; the primary data analysis was completed July 27, 2018. Thirty-eight women with relapsed epithelial ovarian cancer were enrolled in this study. Participants had disease recurrence within 12 months of their last platinum-based therapy and had received between 1 and 3 lines of prior therapy. Interventions: Participants received intravenous nivolumab and intravenous bevacizumab once every 2 weeks. Main Outcome and Measures: The primary end point was objective response rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors 1.1. Secondary end points included evaluation of the ORR by platinum sensitivity, assessment of progression-free survival, assessment of safety data, and investigation of the association of tumor PD-L1 with response to therapy. Results: Of the 38 women enrolled, 18 had platinum-resistant and 20 had platinum-sensitive disease; mean (SD) age was 63.0 (9.1) years. Eleven patients experienced a confirmed response to nivolumab with bevacizumab (ORR, 28.9%; 95% exact binomial CI, 15.4%-45.9%), with 1 additional unconfirmed response. The ORR was 40.0% (19.1%-64.0%) in platinum-sensitive and 16.7% (95% CI 3.6%-41.4%) in platinum-resistant participants. Thirty-four participants (89.5%) experienced at least 1 treatment-related adverse event; 9 participants (23.7%) experienced a grade 3 or higher treatment-related adverse event. Median progression-free survival was 8.1 months (95% CI, 6.3-14.7 months). In 36 histologic samples for which PD-L1 testing could be performed, 22 samples (61.1%) had a PD-L1 tumoral percentage less than 1, and 14 samples (38.9%) had a PD-L1 tumoral percentage of 1 or greater. Ten responses occurred in patients with PD-L1 tumor percentage less than 1, and 2 in patients with PD-L1 tumor percentages of 1 or greater. Conclusions and Relevance: The nivolumab with bevacizumab combination appeared to show activity in patients with relapsed ovarian cancer, with greater activity in the platinum-sensitive setting. Alternative combinational strategies may be necessary in the platinum-resistant setting.

Phase II Study of Avelumab in Patients With Mismatch Repair Deficient and Mismatch Repair Proficient Recurrent/Persistent Endometrial Cancer.

PURPOSE: Despite the tissue-agnostic approval of pembrolizumab in mismatch repair deficient (MMRD) solid tumors, important unanswered questions remain about the role of immune checkpoint blockade in mismatch repair-proficient (MMRP) and -deficient endometrial cancer (EC). METHODS: This phase II study evaluated the PD-L1 inhibitor avelumab in two cohorts of patients with EC: (1) MMRD/POLE (polymerase ε) cohort, as defined by immunohistochemical (IHC) loss of expression of one or more mismatch repair (MMR) proteins and/or documented mutation in the exonuclease domain of POLE; and (2) MMRP cohort with normal IHC expression of all MMR proteins. Coprimary end points were objective response (OR) and progression-free survival at 6 months (PFS6). Avelumab 10 mg/kg intravenously was administered every 2 weeks until progression or unacceptable toxicity. RESULTS: Thirty-three patients were enrolled. No patient with POLE-mutated tumor was enrolled in the MMRD cohort, and all MMRP tumors were not POLE-mutated. The MMRP cohort was closed at the first stage because of futility: Only one of 16 patients exhibited both OR and PFS6 responses. The MMRD cohort met the predefined primary end point of four ORs after accrual of only 17 patients; of 15 patients who initiated avelumab, four exhibited OR (one complete response, three partial responses; OR rate, 26.7%; 95% CI, 7.8% to 55.1%) and six (including all four ORs) PFS6 responses (PFS6, 40.0%; 95% CI, 16.3% to 66.7%), four of which are ongoing as of data cutoff date. Responses were observed in the absence of PD-L1 expression. IHC captured all cases of MMRD subsequently determined by polymerase chain reaction or genomically via targeted sequencing. CONCLUSION: Avelumab exhibited promising activity in MMRD EC regardless of PD-L1 status. IHC for MMR assessment is a useful tool for patient selection. The activity of avelumab in MMRP/non-POLE-mutated ECs was low.

Gene-expression profiling in epithelial ovarian cancer.

DNA-microarray technology has made it possible to simultaneously analyze the expression of thousands of genes in a small sample of tumor tissue. In epithelial ovarian cancer, gene-expression profiling has been used to provide prognostic information, to predict response to first-line platinum-based chemotherapy, and to discriminate between different histologic subtypes. Furthermore, DNA-microarray technology might permit identification of novel markers for early detection of disease and provide insights into the mechanisms of cancer growth and chemotherapy resistance. In this Review, we summarize the contributions of gene-expression profiling to the diagnosis and management of epithelial ovarian cancer and discuss ways in which this technique could become a useful tool in clinical management.

IGF axis gene expression patterns are prognostic of survival in epithelial ovarian cancer.

The IGF axis has documented growth-promoting effects in various malignancies, but its role in epithelial ovarian cancer (EOC) has not been adequately examined. We studied the expression of the IGF axis genes in relation to outcome in EOC. Microarray expression profiles from 64 patients with advanced-stage EOC were used. Two multi-gene subsets were chosen, one upstream of the IGF receptor ('IGF family') and the other downstream of the IGF receptor ('IGF signaling pathway'), and analyzed in relation to survival. In addition, expression patterns of the two gene subsets were analyzed in relation to favorable and unfavorable prognosis categories identified in a previous study by whole-genome expression profiling. In a gene-by-gene analysis, IGF binding protein 4 and IGF-II receptor gene expression was inversely associated with survival. Using hierarchical clustering, the two multi-gene subsets separated the patient cohort into two groups with different median survival (IGF family: 33 vs 63 months, P=0.02 and IGF signaling pathway: 41 vs 63 months, P=0.05). Furthermore, the two multi-gene subsets were differentially expressed between the previously defined favorable and unfavorable prognosis tumors (Kolmogorov-Smirnov permutation: P=0.0005 and 0.003 for the IGF family and signaling pathway respectively), and individual genes (including IGF-I, IGF-I receptor, and several genes downstream of the receptor) were overexpressed in unfavorable prognosis tumors (permutation P<0.05). The expression patterns of several genes in the IGF axis are associated with survival in EOC, and expression changes of these genes may be underlying previously proposed microarray-derived clinical prognostic models. Future studies are needed to more precisely determine the diagnostic and potential therapeutic significance of these findings.

Unique gene expression profile based on pathologic response in epithelial ovarian cancer.

PURPOSE: We investigated whether tumor tissue obtained at diagnosis expresses a specific gene profile that is predictive of findings at second-look surgery in patients with epithelial ovarian cancer (EOC). PATIENTS AND METHODS: Tumor tissue obtained at the time of diagnosis was profiled with oligonucleotide microarrays. Class prediction analysis was performed in a training set of 24 patients who had undergone a second-look procedure. The resultant predictive signature was then tested on an independent validation set comprised of 36 patients. RESULTS: A 93-gene signature referred to as the Chemotherapy Response Profile (CRP) was identified through its association with pathologic complete response. When applied to a separate validation set, the CRP distinguished between patients with unfavorable versus favorable overall survival (median 41 months v not yet reached, respectively, log-rank P = .007), with a median follow-up of 52 months. The signature maintained independent prognostic value in multivariate analysis, controlling for other known prognostic factors such as age, stage, grade, and debulking status. There was no genetic overlap between the CRP and our previously described Ovarian Cancer Prognostic Profile (OCPP), which demonstrated similar prognostic value. The combination of the CRP and OCPP yielded better prognostic discrimination then either profile alone. Genes present in the CRP include BAX, a proapoptotic protein previously associated with chemotherapy response in ovarian cancer. CONCLUSION: Identification of a gene expression profile based on pathologic response in EOC provides independent prognostic information and offers potential insights into the mechanism of drug resistance. Efforts to identify a more tailored profile using selected genes from both the CRP and OCPP are underway.

Granulosa cell tumor of the ovary.

Adult granulosa cell tumor (GCT) of the ovary is oftentimes a hormonally active, stromal cell neoplasm that is distinguished by its ability to secrete sex steroids such as estrogen. Patients may present with vaginal bleeding caused by endometrial hyperplasia or uterine cancer as a result of prolonged exposure to tumor-derived estrogen. In addition, GCT is a vascular tumor that may occasionally rupture and result in abdominal pain, hemoperitoneum, and hypotension, mimicking an ectopic pregnancy in younger patients. GCT is usually associated with a mass on pelvic examination that is subsequently confirmed on ultrasonography. Surgery is required for definitive tissue diagnosis, staging, and tumor debulking. In older women, a total abdominal hysterectomy and bilateral salpingooophorectomy are typically performed. In women of childbearing age, a more conservative unilateral salpingo-oophorectomy may be performed, assuming that careful staging reveals that the disease has not extended outside of the involved ovary and that a concomitant uterine cancer has been excluded. Survival of patients with GCT is generally excellent because most patients present with early-stage disease, although certain high-risk patient groups may be identified. Stage is the most important prognostic factor, with a higher risk of relapse being associated with stages II through IV disease. In addition, patients with stage I disease associated with features such as large tumor size, high mitotic index, or tumor rupture may also be at higher risk in some series. The value of postoperative adjuvant therapy for high-risk patients has not been investigated by prospective randomized trials, which are difficult to perform because of the rarity of this tumor. Nonetheless, the use of adjuvant chemotherapy or radiation has sometimes been associated with prolonged disease-free survival in patients with high-risk features. Because of the propensity of GCT to recur years after initial diagnosis, prolonged surveillance with serial physical examination and serum tumor markers such as estradiol and inhibin is reasonable.

Gene expression signature with independent prognostic significance in epithelial ovarian cancer.

PURPOSE: Currently available clinical and molecular prognostic factors provide an imperfect assessment of prognosis for patients with epithelial ovarian cancer (EOC). In this study, we investigated whether tumor transcription profiling could be used as a prognostic tool in this disease. METHODS: Tumor tissue from 68 patients was profiled with oligonucleotide microarrays. Samples were randomly split into training and validation sets. A three-step training procedure was used to discover a statistically significant Kaplan-Meier split in the training set. The resultant prognostic signature was then tested on an independent validation set for confirmation. RESULTS: In the training set, a 115-gene signature referred to as the Ovarian Cancer Prognostic Profile (OCPP) was identified. When applied to the validation set, the OCPP distinguished between patients with unfavorable and favorable overall survival (median, 30 months v not yet reached, respectively; log-rank P = .004). The signature maintained independent prognostic value in multivariate analysis, controlling for other known prognostic factors such as age, stage, grade, and debulking status. The hazard ratio for death in the unfavorable OCPP group was 4.8 (P = .021 by Cox proportional hazards analysis). CONCLUSION: The OCPP is an independent prognostic determinant of outcome in EOC. The use of gene profiling may ultimately permit identification of EOC patients appropriate for investigational treatment approaches, based on a low likelihood of achieving prolonged survival with standard first-line platinum-based therapy.

Advances in the management of epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy in adult women. The most easily identifiable riskfactor is a strong family history of either ovarian or breast cancer; that may indicate the presence of an inherited germ-line mutation in either BRCA-1 or BRCA-2. Common symptoms, such as abdominal bloating and early satiety, indicate more advanced disease, involving the upper abdomen and present in approximately 70% of patients at the time of diagnosis. Physical examination often reveals the presence of a pelvic mass, which is best evaluated by transvaginal ultrasound (TVU) for confirmation. Exploratory laparotomy is required for histologic confirmation, staging and tumor debulking and should be performed by a surgeon trained in these aspects of ovarian cancer management. Patients with early-stage disease, limited to the ovary or pelvis (stages I and II, respectively), have survival in the 80-95% range, whereas the survival of patients with disease involving the upper abdomen or beyond (stages III and IV, respectively) is 10-30%. Because of the propensity of EOC to spread beyond the confines of the ovary, the majority of patients will require postoperative chemotherapy in an attempt to eradicate residual disease. For selected patients with early-stage disease, confined to the ovary, such as those with well-differentiated, completely encapsulated tumors (e.g., stage IA, grade 1), no further treatment is necessary in view of excellent survival after surgery alone. For patients with higher-risk early-stage disease (e.g., those with pelvic extension, capsular rupture or involvement, positive washings, ascites or high-grade lesions) and for patients with advanced-stage disease (stages III and IV), postoperative combination chemotherapy with a taxane and platinum combination is the standard of care. Such treatment is capable of inducing responses in > 70% of patients with residual EOC and is also capable of prolonging both disease-free and overall survival. Unfortunately, despite an initial response to chemotherapy in the majority of patients, relapse is afrequent problem and is often detected by a rise in the serum tumor marker CA-125 in the absence of symptoms or signs of disease by physical examination or radiographic studies. In such cases, a hormonal maneuver is oftentimes considered in order to avoid the toxic effects of chemotherapy when the patient is asymptomatic and the goal of treatment is largely palliation, although eventually the development of clinical progression mandates the institution of second-line chemotherapy. If the treatment-free interval is > 6 months from the completion of first-line treatment, rechallenge with platinum-based chemotherapy is a reasonable first step. For those patients who develop resistance to second-line platinum or who have difficulty tolerating this agent, multiple other options are available for relapse management, including liposomal doxorubicin, topotecan, gemcitabine and etoposide per os. Eventually the disease becomes resistant to multiple chemotherapy agents, and reorienting management toward supportive care and pain control is necessary. Ongoing efforts to identify more effective multiagent first-line regimens, to develop more effective strategies for early detection and to incorporate agents with novel mechanisms of action, such as antiangiogenesis compounds, hold promise.