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e17545 Background: Indirect immunization with tumor specific antibody is an approach to triggering therapeutic immunity to cancer through activated immune cells. O is a monoclonal IgG1 specific to CA125 (MUC16). O is currently in phase III evaluation of front-line chemoimmunotherapy (CIT), having shown benefit relative to chemotherapy alone in a randomized phase II study (Brewer, Gyn Onc 2020). H is a TLR3 agonist used as a stimulatory immune adjuvant. The dosing phase of the protocol established safety and compatibility of this combination. The primary safety and response outcomes were reported at IGCS-2019. Immune parameters and long-term outcome associations are the focus of this final update. Methods: Pts with heavily treated RECIST evaluable platinum resistant ovarian cancer (median of 5 prior Rx) received 4 IV infusions with 2 mg O followed by 2mg H IM 30 min & 48 hrs post O at wks 0, 3, 6, 9. At wk 12 imaging was performed and elective salvage Rx allowed. A fifth O+H was optional at wk 16. Study endpoints included immune associations after O+H, after second-line chemotherapy, and survival outcomes. Results: 17 pts were enrolled at 2 centers; 15 patients were dosed and 13 completed the specified minimum 3 infusions. The treatment was well tolerated with local reactions and mild flu like symptoms (13/15 pts) as the only reported adverse events. There was no treatment related serious adverse events. Median survival was 15.0 m [95% CI:10.8m-NE] and 4 patients remained alive at data lock (median 26.5 m). H stimulated an early humoral antibody response to O at wk 6 in 7 of 9 pts (78%). Interval administration of second-line Rx (bevacizumab, paclitaxel, carboplatin, &/or doxorubicin) and O were associated with further antibody spikes. Baseline neutrophil monocyte to lymphocyte ratio (NMLR), a measure of myeloid-derived immune suppression was inversely associated with survival. PROC patients with baseline NMLR ≤4x (n = 8) had median OS 19.6m [15.0 m -NE] vs median OS 10.8m [3.6m-NE] HR 2.44 [0.73-8.15], ( p= 0.13) for pts with NMLR > 4.0 (n = 7). Conclusions: H is a viable immune adjuvant for combination with O suitable for further study in immune resistant settings. Immune responsiveness was similar to that observed in a prior study of same day schedule of carboplatin-paclitaxel front-line immunotherapy (Braly, JIT 2009; Battaglia, Cll, 2020). Patterns of immune response to O in the setting of recurrent ovarian cancer are influenced by concomitant anti-neoplastic therapy. Clinical outcomes appear sensitive to myeloid burden (NMLR > 4) which may be more prevalent in patients with treatment resistant disease than in chemotherapy naïve patients, as previously observed in front-line CIT trials. A phase III study to further evaluate these associations in the front-line setting is currently underway NCT04498117. Clinical trial information: NCT03162562.

Platinum and taxane-based chemotherapy after surgical cytoreduction remains the mainstay of treatment for advanced ovarian malignancies, with median progression-free survival (PFS) ranging from 17 to 30 months and median overall survival (OS) ranging from 36 to 65 months depending on the volume of postcytoreductive disease. Furthermore, adding additional cytotoxic agents to first-line therapy has not had an impact on outcome. Given the therapeutic limitations of conventional chemotherapy, recent investigations have explored molecularly guided therapies to target pathways of oncogenesis. Angiogenesis is recognized as a hallmark of several types of tumors, including ovarian cancer. One of the most important cytokines responsible for tumor-mediated angiogenesis is vascular endothelial growth factor (VEGF), which is secreted by tumor cells and binds to the VEGF receptor (VEGFR) that is present on normal endothelial cells, stimulating new blood vessel formation. Thus, efforts to block this pathway, either by inhibiting VEGF or its receptor, have emerged as attractive strategies for cancer treatment. Approaches to manipulation of the VEGF pathway include extracellular interference with VEGF itself, as well as intracytoplasmic inhibition of the tyrosine kinase domain of the VEGFR. The most investigated antiangiogenic agent to date is the humanized monoclonal antibody to VEGF, bevacizumab, which prevents binding of VEGF to its receptor and thereby inhibits angiogenesis. More recently, small-molecule tyrosine kinase inhibitors, which interact with the cytoplasmic domains of VEGFR, have been investigated clinically. Pazopanib is a multitargeted tyrosine kinase inhibitor that inhibits several tyrosine kinase receptors including VEGFR, platelet-derived growth factor receptor, and fibroblast growth factor receptor, all of which modulate signaling through angiogenic, proliferative, or cell survival pathways. Early clinical trials have demonstrated promising single-agent activity of pazopanib in recurrent ovarian cancer. To date, four phase III randomized clinical trials testing bevacizumab in ovarian cancer have been published. The first, Gynecologic Oncology Group (GOG) protocol 218, was a three-arm placebo-controlled study investigating the addition of bevacizumab 15 mg/kg to standard carboplatin and paclitaxel chemotherapy in first-line, adjuvant treatment of advanced-stage epithelial ovarian carcinoma (EOC). The 1,873 enrolled patients were treated either with standard chemotherapy alone, standard chemotherapy with concurrent bevacizumab followed by placebo maintenance, or standard chemotherapy with concurrent and maintenance bevacizumab every 21 days for up to 16 doses. Patients who were treated with concurrent and maintenance bevacizumab experienced a significantly prolonged PFS when compared with chemotherapy alone (14.1 v 10.3 months; hazard ratio [HR], 0.717; 95% CI, 0.625 to 0.824; P .001). Although the PFS advantage was encouraging, this benefit did not translate into an OS or quality of life (QOL) advantage. A substantial crossover to bevacizumab ( 40%) occurred during this trial, thereby confounding OS analysis. The second trial of first-line bevacizumab, International Cooperative Group for Ovarian Neoplasia study 7 (ICON-7), compared standard carboplatin and paclitaxel chemotherapy alone or the same chemotherapy with concurrent bevacizumab followed by 12 cycles of maintenance bevacizumab at 7.5 mg/kg in 1,528 patients with early-stage, high-risk (clear cell histology or grade 3) and stages IIB to IV EOC. As was observed with GOG 218, a statistically significant improvement in PFS was reported in the bevacizumab arm compared with standard chemotherapy (19 v 17.3 months; HR, 0.81; 95% CI, 0.70 to 0.94; P .0041). Unfortunately, this PFS advantage again did not translate into an OS benefit. Post hoc subgroup analysis in patients at high risk for recurrence (patients with suboptimally cytoreduced stage III and stage IV disease) demonstrated an even larger 5.4-month improvement in PFS and a 9.4-month median OS advantage (30.3 v 39.7 months; P .0072), which seems somewhat counterintuitive. Final analysis of the ICON-7 data was presented at the 2013 European Cancer Congress. In the poor-prognosis group, 332 of 502 patients died (174 in the control arm; 158 in the bevacizumab arm), with an improvement of 4.8 months in restricted mean survival time from 34.5 to 39.3 months (log-rank P .03; proportional hazards test 0.007). Two additional phase III trials were undertaken to assess the effects of bevacizumab in platinum-sensitive and platinumresistant recurrent EOC, respectively. The Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and AntiAngiogenic Therapy in Platinum-Sensitive Recurrent Disease (OCEANS), a phase III, randomized, placebo-controlled trial, evaluated bevacizumab in the treatment of 484 patients with platinum-sensitive recurrent disease, comparing gemcitabine and JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 30 OCTOBER 2

e22072Background: Studies describing patient factors associated with radiation toxicity in cervical cancer (CxCa) treatment predate advancements in the delivery of radiotherapy. This study identifi...

Purpose We evaluated the efficacy and safety of bevacizumab in patients with platinum-resistant epithelial ovarian carcinoma (EOC) or peritoneal serous carcinoma (PSC) who had experienced disease progression during, or within 3 months of discontinuing, topotecan or liposomal doxorubicin. Patients and Methods No more than three prior treatment regimens were allowed. Patients received single-agent bevacizumab 15 mg/kg intravenously every 3 weeks. Response was assessed by computed tomography (CT) scan every 6 weeks using Response Evaluation Criteria in Solid Tumors (RECIST). Results Of 44 patients treated, 83.7% were primarily platinum resistant, 59.1% had received liposomal doxorubicin, 25% topotecan, 15.9% both agents, and 47.7% had received three prior chemotherapy regimens. A median of five (range, two to 16) bevacizumab doses were administered. Partial responses were observed in seven patients (15.9%). Median progression-free survival was 4.4 months (95% CI, 3.1 to 5.5 months), with a median survival duration of 10.7 months at study termination. Bevacizumab-associated grade 3 to 4 events included hypertension (9.1%), proteinuria (15.9%), bleeding (2.3%), and wound-healing complications (2.3%). The incidence of GI perforation (GIP; 11.4%) was higher than reported in bevacizumab trials of other tumor types. GIP occurred in 23.8% of patients receiving three prior chemotherapy regimens, compared with 0% of patients receiving two prior chemotherapy regimens (P < .01). A trend toward higher risk of GIP was observed for patients with bowel wall thickening or bowel obstruction on CT scan. Arterial thromboembolic events occurred in three patients (6.8%). Three deaths were related to bevacizumab treatment. Conclusion Bevacizumab has single-agent activity in patients with platinum-resistant EOC or PSC. A higher than expected incidence of GIP was noted in these heavily pretreated patients.

Purpose: The purpose of this study was to determine whether amifostine (WR-2721) prevents or ameliorates clinically significant (grade 2 to 4) neurotoxicity associated with cisplatin and 3-hour paclitaxel chemotherapy. Materials and Methods: The chemotherapy program consisted of intravenous paclitaxel 175 mg/m2 over 3 hours followed by amifostine 740 mg/m2 and cisplatin 75 mg/m2 administered over 90 minutes beginning 15 minutes after amifostine administration. At baseline, before each treatment cycle, and for 3 months after completing chemotherapy, patients were evaluated for evidence of neurotoxicity and other treatment-related adverse effects using three methods: standard clinical evaluation (National Cancer Institute common toxicity criteria [CTC] grading), a neurotoxicity questionnaire to assess symptoms and limitations imposed by peripheral neuropathy, and vibration perception threshold (VPT) testing. Results: Four of 27 assessable patients developed grade 2 to 4 neurotoxicity based on clinical assessments and CTC grading. This number of neuropathic events exceeded the predetermined threshold level for a second stage of accrual and the study was closed. Conclusion: Amifostine’s level of activity in this trial was insufficient to warrant further study in a phase III trial. Based on the receiver operating characteristic analysis, it would appear that VPT measurements are less sensitive to the development of peripheral neuropathy than the neurotoxicity questionnaire. The questionnaire, referred to as the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity, may be used instead of VPT measurements in future studies of chemotherapy-induced peripheral neuropathy.

5532 Background: Inhibition of angiogenesis is a valuable treatment strategy for ovarian cancer. Pazopanib (paz) is a potent angiogenic small molecular inhibitor of the tyrosine kinases VEGRF-1, -2, -3, PDGFR, c-kit and has shown activity as a single agent in ovarian cancer. We designed a trial to assess the benefit of adding paz to gemcitabine (gem) in patients with recurrent, advanced ovarian cancer. Methods: An open-label, randomized, multi-site, phase 2 trial was conducted (NCT01610206) including patients with platinum resistant or sensitive ovarian cancer with up to 3 prior lines of chemotherapy, and measurable or evaluable disease. Patients were randomly assigned (1:1) to receive weekly gem 1000 mg/m2 with or without paz 800 mg QD and stratified according to platinum sensitivity and number of prior lines (1 vs 2 or 3). The primary endpoint was PFS. Intent-to-treat was defined as all eligible patients who receive any protocol treatment with analysis based on randomized arm. Results: As of 3/2017, we randomized 148 and treated 146 patients (target sample size 148 eligible patients who receive any protocol treatment). 75 (46 platinum resistant, 61%) were randomly assigned to receive gem/paz and 71 (41 platinum resistant, 58%) to receive gem only. 110 patients (75%) had received 2 or 3 prior lines. There were no unexpected toxicities or deaths. Adverse events were more common in the gem/paz group. The most common grade 3–4 AEs (gem/paz vs gem) were: neutropenia (25 [33%] vs 15 [21%]), fatigue (7 [10%] vs 1 [2%]), hypertension (11 [15%] vs 1 [1%]), elevated alanine aminotransferase (8 [11%] vs 0), thrombocytopenia (9 [12%] vs 12[3%]) and anemia (7 [9%] vs 2 [3%]). There were 2 GI perforations in the paz arm. Median time on therapy was 12 weeks (range 1-55 weeks). Of the 138 patients off study to date, 30 (22%) were for AE’s (23 on gem/paz arm). Conclusions: The gem/paz combination is tolerable in this population, with patients tolerating multiple cycles with manageable toxicity. Median follow-up and PFS data will be presented after 122 events (progression or death) have occurred per protocol (currently 117 events). Clinical trial information: NCT01610206.

PURPOSE: The primary objective of this phase I trial was to determine the feasibility of administering a combination of paclitaxel, cisplatin, and doxorubicin with or without granulocyte colony-stimulating factor (G-CSF) in patients with advanced endometrial and other gynecologic cancers. PATIENTS AND METHODS: Patients were chemotherapy-naive. Doxorubicin was administered as a brief infusion, paclitaxel for 3 hours, and cisplatin for 60 minutes. Treatments were repeated every 3 weeks. For most dose levels, the cisplatin and doxorubicin were fixed at 60 mg/m2 and 45 mg/m2, whereas the paclitaxel was escalated in successive cohorts from 90 to 250 mg/m2. Patients who had received previous radiotherapy to the whole pelvis were escalated separately from those who had not. RESULTS: Eighty patients received 320 cycles of therapy. When G-CSF was not used, myelosuppression prevented escalation beyond the starting dose for patients with or without previous pelvic radiotherapy. When G-CSF was added, neurotoxicity became dose-limiting for both groups. Ten patients were removed from the study for asymptomatic declines in ejection fraction, but no symptomatic congestive heart failure was observed. Major antitumor responses occurred in 46% of patients (six of 13) with measurable endometrial carcinoma and 50% of patients (eight of 16) with measurable cervical carcinoma. CONCLUSION: The combination of paclitaxel, doxorubicin, and cisplatin at relevant single-agent doses is active and feasible with the addition of G-CSF. A regimen of cisplatin 60 mg/m2, doxorubicin 45 mg/m2, and paclitaxel 160 mg/m2 with G-CSF support is recommended for further testing.

Untreated and minimally pretreated solid tumor patients received alternating sequences of taxol and cisplatin. Sequential dose escalation of each agent using taxol doses of 110 or 135 mg/m2 and cisplatin doses of 50 or 75 mg/m2 resulted in four dosage permutations that induced grades 3 and 4 neutropenia in 72% to 84% and 50% to 53% of courses, respectively. Neutropenia was brief, and hospitalization for neutropenia and fever was required in 13% to 24% of courses. However, further escalation of taxol to 170 or 200 mg/m2 induced grade 4 neutropenia in 79% to 82% of courses. At the highest taxol-cisplatin dose level (200 mg/m2 to 75 mg/m2), the mean neutrophil count nadir was 98/microL, and hospitalization for neutropenia and fever was required in 64% of courses. The sequence of cisplatin before taxol, which has less antitumor activity in vitro, induced more profound neutropenia than the alternate sequence. Pharmacologic studies indicated that this difference was probably due to 25% lower taxol clearance rates when cisplatin preceded taxol. Although neurotoxicity was initially thought to be a potentially serious effect of the combination, mild to modest neurotoxicity occurred in only 27% of patients. Adverse effects also included myalgias, alopecia, vomiting, diarrhea, bradycardia, and asymptomatic ventricular tachycardia. Objective responses were noted in melanoma, as well as non-small-cell lung, ovarian, breast, head and neck, colon, and pancreatic carcinomas. Based on these results, the sequence of taxol before cisplatin at doses of 135 and 75 mg/m2, respectively, is recommended for phase II/III trials, with escalation of taxol to 170 mg/m2 if treatment is well tolerated.

PURPOSE To test the hypothesis that prolonged infusion of paclitaxel (96 hours) might overcome resistance to shorter infusion schedules (3 or 24 hours) in ovarian cancer. PATIENTS AND METHODS A total of 30 patients with advanced ovarian cancer (24 patients), primary carcinoma of the peritoneum (four patients), or fallopian tube cancer (two patients) who previously had received paclitaxel administered on either a 3-hour or 24-hour schedule were treated with the agent delivered as a 96-hour infusion (30 to 35 mg/m2/d x 4 days) on an every 3-week program. RESULTS Although the regimen generally was well tolerated, no objective responses were observed. CONCLUSION In patients with ovarian cancer who have shown resistance to shorter paclitaxel infusion schedules, ninety-six hour infusional paclitaxel is an inactive treatment strategy. This makes it less likely that protracted infusion of paclitaxel will improve outcome when used as part of primary therapy of ovarian cancer. An ongoing randomized study will answer that question.

5559 Background: Folate Receptor Alpha (FRa) (aka Folate Binding protein (FBP)) is an immunogenic protein that is over-expressed in breast, lung, endometrial (EC) and ovarian cancers (OC). In fact,...

Biomarkers can be useful in risk stratification of a disease or as a surrogate end point in determining the effectiveness of treatment. CA-125 has been proposed as a surrogate for response in ovarian cancer, and in most clinical trials, clinical complete response is defined as radiographic disappearance of all disease, resolution of all disease-related symptoms, and normalization of the CA-125 if it was elevated at therapy initiation. Less well accepted is assignment of complete response in a patient whose only evidence of disease is an elevated tumor marker that subsequently normalizes on therapy. It is possible that this type of serologic definition of complete response is as good as or better than conventional radiographic imaging in patients with advanced ovarian cancer. CA-125 has also been shown to be an accurate marker to define progression of ovarian cancer, and becomes elevated on an average of 3 to 4 months (range, 1 to 15 months) before clinically assessable (symptomatic, palpable, or visible by imaging) disease in 70% of patients. Furthermore, an increasing CA-125 serum level alone is sometimes being used to initiate cytotoxic systemic therapy for recurrence in the absence of clinically demonstrable disease, despite the lack of evidence demonstrating a survival advantage for this approach. Many investigators have attempted to codify what degree of CA-125 elevation can predict progression of ovarian cancer with acceptable specificity and sensitivity. Although this serologic approach to assess disease progression may eventually prove useful in the conduct of clinical trials, it may not demand routine treatment initiation, given that there is wide variability in lead time between biochemical and clinical progression. Furthermore, there is significant variation among investigators in terms of when to initiate treatment for recurrent disease based on personal bias and patient preference. The Gynecologic Cancer Intergroup (GCIG) defines progressive disease after a complete response to primary therapy based on CA-125 criteria: the date of first elevation of CA-125 to two-fold the upper limit of normal (documented on two occasions at least a week apart). For those with persistently elevated CA-125 levels, progression of disease is defined as the first date of CA-125 2 the nadir value documented on two occasions no less than a week apart. A number of ongoing and planned clinical trials incorporated these existing GCIG criteria in conjunction with the standard Response Evaluation Criteria in Solid Tumors Group (RECIST) classifications in an attempt to validate the use of serum CA-125 levels as surrogate markers for defining disease progression in ovarian cancer. Recently, the GCIG criteria of progression were validated using data from an Intergroup trial that randomly assigned patients to frontline combination chemotherapy with cisplatin and paclitaxel compared with cisplatin and cyclophosphamide. The analysis using GCIC criteria showed that the magnitude of therapeutic benefit was similar using either CA-125 or RECIST criteria. From an economic point of view, use of a biomarker seems preferable to more expensive radiographic testing that is often used to determine response and progression in the context of clinical trials. However, outside of a clinical trial, what should one do when the marker signals progression but the patient’s review of systems is negative and the imaging study of choice is within normal limits? In such a situation the false-positive rate of the marker signal becomes paramount because this type of information could lead to inappropriate treatment. In addition, even if clinical recurrence is predicted by the marker signal, there are no data demonstrating a survival or quality-of-life benefit for the patient treated before clinical progression. In the validation trial by Rustin et al, the false-positive rate was 2%. The only two clinical trials addressing immediate versus delayed therapy at the time of biochemical progression are the Medical Research Council (MRC) 05 study combined with the European Organization for the Research and Treatment of Cancer (EORTC) study 55955, and Gynecologic Oncology Group (GOG) trial 198. The first trial simply randomly assigns notification or lack thereof of the patient when there is biochemical evidence of recurrence. Therapy is not controlled. In GOG 198, patients with biochemical recurrence are randomly assigned to receive either tamoxifen or thalidomide until clinical progression, with progression-free survival (PFS) as the end point. What might this new and potentially more sensitive indicator of recurrence do? First, it will shorten the PFS of the prior therapy. Second, it may alter the definition of platinum resistance, given that currently, platinum-free intervals are based largely on intervals between discontinuation of primary therapy and presentation with clinical recurrence. Third, it will lead to inappropriate therapy in those patients with false-positive results and possibly also in those patients where there is a long lead time between biochemical and clinical progression. These changes in definitions are largely surmountable because clinical trials typically are randomized JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 24 AUGUST 2

This issue of the Journal of Clinical Oncology is dedicated to recent advances in the management of gynecologic cancers, with special reference to epithelial ovarian cancer. Improvement in the survival of patients with ovarian cancer has been slow but steady over the past three decades. Although the combination of intravenous (IV) taxane and platinum chemotherapy has improved survival in newly diagnosed patients with advanced disease, most are still not cured. More recently, three randomized trials have demonstrated that intraperitoneal (IP) administration of cisplatin confers an additional survival advantage compared with systemic chemotherapy in newly diagnosed patients with optimally debulked, stage III epithelial ovarian cancer. One of these studies used a regimen of IV paclitaxel on day 1, IP cisplatin on day 2, and IP paclitaxel on day 8, yielding a 16-month prolongation of median overall survival compared with the control arm of IV paclitaxel and cisplatin therapy. However, a substantial number of patients (58%) could not complete this regimen due to toxicities including catheter infection and blockage, febrile neutropenia, and neuropathy. The article by Rao et al discusses IP therapy in detail and reviews strategies to reduce the toxicity and further improve the efficacy of this approach. In this regard, the use of IP carboplatin instead of cisplatin, the use of lower doses of IP cisplatin, and the inclusion of bevacizumab into first-line IP therapy are approaches that are currently being investigated. Although IP therapy has now been embraced by many physicians as a reasonable strategy in the management of selected patients with newly diagnosed epithelial ovarian cancer, we must be careful not to extrapolate to populations in which efficacy has not been demonstrated. Such patients include those with stage IV disease, those with suboptimally debulked stage III tumors, those with high-risk early-stage disease, or those with recurrent disease. Furthermore, some patients with optimally debulked, stage III disease might be poor candidates for IP therapy due to comorbid conditions such as pre-existing neuropathy, renal disease, or extensive bowel adhesions. The treatment of patients with newly diagnosed ovarian cancer involves both surgical debulking and chemotherapy administration. Our gynecologic oncology colleagues have contributed a great deal to the initial treatment of patients with this disease, as discussed in the review by Fader et al. Achieving an optimal cytoreduction, currently defined as having no residual lesions larger than 1 cm in diameter, is associated with improved survival. Whether the ability to debulk simply selects for patients who are more responsive to postoperative chemotherapy, or whether debulking itself is therapeutically useful, is a question that will most likely never be answered. Fader et al discusses the important role of surgery in this disease and also reviews the proper place for secondary cytoreductive procedures in the management of recurrence. It is likely that further improvements in the outcome of patients with advanced ovarian cancer will not be based solely on traditional cytotoxic chemotherapy approaches. The recent demonstration that triple-drug combinations are no better than the paclitaxel and carboplatin doublet is a case in point. In recognition of this fact, we present three articles in this issue discussing immunologic approaches and novel strategies designed to target the angiogenesis pathway. These authors discuss exciting developments in their respective areas, including randomized trials such as Gynecologic Oncology Group (GOG) 218, which is designed to explore the role of bevacizumab in the first-line and maintenance setting. Single-agent bevacizumab has also been shown to induce responses in patients with recurrent ovarian cancer, although enthusiasm for this approach has been tempered by the recent demonstration of an 11% incidence of bowel perforation with this agent. It has been suggested that the number of prior cytotoxic regimens and the presence of bowel obstruction might predispose to this complication, although our ability to identify high-risk patients requires further investigation. In addition to antiangiogenic drugs, inhibitors of novel targets such as poly-ADP ribose polymerase hold a great deal of promise in patients with relapsed disease who harbor either BRCA-1 or BRCA-2 germline mutations. Not all ovarian cancers are associated with a poor prognosis. Within the epithelial category, early-stage disease is often curable with surgery alone, or with surgery followed by adjuvant chemotherapy. Trope et al discuss the management of early-stage disease and the selection of appropriate patients for adjuvant chemotherapy. Prevention of malignant transformation is the most definitive strategy for managing epithelial ovarian cancer, and Kauff et al review the role of risk reduction salpingooophorectomy in patients with BRCA-1 or BRCA-2 germline mutations. Borderline ovarian tumors are an interesting category of epithelial ovarian tumors that do not invade, are typically early stage and chemotherapy resistant, and generally have a good prognosis. These neoplasms are reviewed by Cadron et al, 16 and a case is made for more conservative surgery in selected young women who wish to preserve fertility. It is important to note that a subset of borderline tumors can behave aggressively, with a higher chance of relapse and transformation into low grade invasive serous carcinoma. Such borderline tumors are often characterized by the presJOURNAL OF CLINICAL ONCOLOGY O V E R V I E W VOLUME 25 NUMBER 20 JULY 1

e15540 Background: To assess antitumor activity and toxicity of a weekly topotecan schedule in patients with recurrent platinum- sensitive/resistant ovarian, tubal or primary peritoneal cancer. Met...

2006 Background: Docetaxel exhibits wide interindividual variation in drug clearance (CL). Reduction in CL by ≥25% is associated with increased neutropenia. Docetaxel is metabolized by cytochrome P...

5018 Background: Novel agents to prolong remission in ovarian cancer are needed. ACA-125 is a murine anti-idiotypic mAb which mimics the tumor associated antigen CA-125. A prior phase I/II study associated longer survival with an immune response to vaccination (C Ca Res 7:1154–62, 2001) prompting the need to evaluate the optimal dose and administration route for prospective study. Methods: Three institution, open label, phase I study evaluating two doses and routes: Four subcutaneous (SC) versus intramuscular (IM) injections at 2.0 mg or 0.2 mg administered every two weeks, and then monthly for two additional doses. Eligible patients had epithelial ovarian, fallopian tube, or peritoneal cancer who relapsed; and had completed cytotoxic therapy for recurrence with partial or complete response. Planned evaluation included interval physical examination and routine laboratory studies, with immune assessments including HLA-typing, HAMA, ELISA and ELISPOT. Primary endpoints were: 1) safety and 2) immunogenicity ...

PURPOSE: To assess CA-125 as a measure of response in patients treated with paclitaxel. PATIENTS AND METHODS: One hundred forty-four patients treated with paclitaxel derived from four different trials and 625 patients treated with platinum from two trials were analyzed using precisely defined 50% and 75% reductions in CA-125. The standard and CA-125 response rates to paclitaxel and platinum were compared. In addition, we analyzed individual patient groups in which there was a difference in response according to the two response criteria. RESULTS: Patients with stable disease as determined by standard criteria who were treated with platinum and responded according to CA-125 criteria have an improved median progression-free survival compared with patients with stable disease who did not respond according to CA-125 criteria (10.6 v 4.8 months; P < .001). Standard and CA-125 response rates for patients treated with platinum (58.93% v 61.31%, respectively) and paclitaxel (30.65% v 31.67%, respectively) were very similar, as were rates of false-positive prediction of response by CA-125 (platinum 2.2% and paclitaxel 2.9%). Responders to paclitaxel had a significantly improved progression-free survival compared with nonresponders by both standard criteria (median progression-free survival, 6.8 v 2.5 months; P < .001) and CA-125 criteria (median progression-free survival, 6.8 v 3.4 months; P < .001). CONCLUSION: For assessing activity of therapy for ovarian cancer, these data show that precise 50% or 75% CA-125 response criteria are as sensitive as standard response criteria. We propose that they may be used as a measure of response in lieu of or in addition to standard response criteria in clinical trials involving epithelial ovarian cancer. Sensitivity is maintained whether patients are treated with platinum or paclitaxel.