Search

With expanded use of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi), there is a potential impact of PARPi resistance on platinum resistance. A post-hoc analysis of SOLO2 demonstrated a reduction in response to subsequent platinum-based therapy among patients who received prior olaparib but not placebo. The present multicentre, retrospective, observational study was conducted to determine the effects of olaparib on subsequent therapy for recurrent epithelial ovarian cancer (EOC).Data on EOC patients with BRCA1/2-mutated tumours who received second-line platinum-based chemotherapy between January 2012 and June 2020, at three South Korean institutions (n = 197) were collected. Patients who received olaparib as maintenance therapy after second-line chemotherapy were assigned to the olaparib group (n = 105), and subjects who did not receive olaparib maintenance therapy were assigned to the control group (n = 92). The primary endpoint was time intervals from the date of second disease progression (PFS1) to the date of third disease progression (PFS2), expressed as PFS2 - PFS1.As expected, PFS1 in the olaparib group was longer than the control group. However, PFS2 - PFS1 in the olaparib group was significantly shorter than that of the control group (median 7.9 vs. 13.6 m; p = 0.0005). Even when the third-line PARPi maintenance (cross-over) patients were excluded from the control group, the response to subsequent therapy in the olaparib group remained poor (median 7.7 vs. 11.5; p = 0.0422).Patients with platinum-sensitive BRCA1/2 mutated tumours who progressed during olaparib maintenance after second-line chemotherapy were less likely to respond to third-line chemotherapy compared to controls who did not receive olaparib, suggesting that resistance to olaparib may contribute to chemotherapy resistance.

OBJECTIVE: In the phase 3 VELIA/GOG-3005 trial, veliparib added to carboplatin-paclitaxel and continued as maintenance improved progression-free survival (PFS) compared to carboplatin-paclitaxel alone in patients with newly diagnosed ovarian carcinoma. Primary analysis of PFS was by investigator (INV) assessment, with a supplemental analysis of PFS by blinded independent central review (BICR).METHODS: Patients received veliparib or placebo with carboplatin-paclitaxel (6 cycles) and as maintenance (30 additional cycles). The primary analysis compared PFS in the veliparib-throughout arm to the carboplatin-paclitaxel only arm in the BRCA mutation (BRCAm), homologous recombination deficiency (HRD), and intention-to-treat (ITT) populations. Exploratory analyses of PFS in BRCA wildtype (BRCAwt), homologous recombination proficient (HRP), and HRD + BRCAwt populations were also performed. PFS per BICR and overall concordance rates between INV and BICR assessments were analyzed.RESULTS: Hazard ratios for PFS by INV and BICR were consistent in each of the primary analysis and exploratory populations. In the ITT population, median PFS per INV was 23.5 months in the veliparib-throughout arm versus 17.3 months in the control arm (hazard ratio [HR] 0.683, 95% confidence interval [CI] 0.562-0.831; P CONCLUSIONS: Hazard ratios for PFS per BICR and per INV were consistent, with no suggestion of investigator bias. These findings support the reliability of PFS by INV in ovarian cancer trials.

Objective GAS6 and AXL are expressed in high-grade serous ovarian cancer but not in normal ovarian tissue. AVB-500, a novel high affinity Fc-sAXL fusion protein, binds GAS6 preventing AXL signaling. This Phase 1b study ( NCT03639246 ) evaluated safety, efficacy, and exploratory predictive markers of AVB-500 combined with paclitaxel (PAC) or pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant ovarian cancer (PROC), and used a model informed drug development (MIDD) approach for identification of the recommended phase 2 dose (RP2D). Methods Eligible patients received AVB-500 at 10, 15, or 20 mg/kg IV q2wk combined with PAC (n = 23) or PLD (n = 30). Patients were treated until progression or unacceptable toxicity. All were followed for survival. Results No dose limiting toxicities were observed and serum GAS6 was completely suppressed across the three dose levels evaluated. AVB-500 + PAC yielded better clinical activity than AVB-500 + PLD with an ORR of 34.8% (8/23, 2 complete responses) and median DoR, PFS, and OS of 7.0, 3.1, and 10.3 months, respectively. Subgroup analyses showed AVB-500 + PAC patients who had no prior bevacizumab or whose AVB-500 trough levels were >13.8 mg/L exhibited the best clinical response. The ORR and median PFS and OS in patients with these characteristics were ≥50%, ≥7.5 months, and ≥19 months, respectively. Given AVB-500 nor the combination with chemotherapy was expected to cause DLTs, the RP2D of AVB-500 was 15 mg/kg identified using an MIDD approach. Conclusion AVB-500 was well-tolerated in combination with PAC or PLD and contributed to the clinical activity of PAC in PROC patients. Subgroup analyses identified a population of PROC patients who may benefit the most from AVB-500 treatment, which will be further assessed in an ongoing Phase 3 PROC trial.

Objective Adiposity has been hypothesized to interfere with the activity of bevacizumab (BEV), an anti-angiogenic agent. Measurements of adiposity, BMI, surface fat area (SFA), and visceral fat area (VFA) were investigated as prognostic of oncologic outcomes among patients treated with chemotherapy, with or without BEV, on GOG 218, a prospective phase III trial. Method Pretreatment computed tomography (CT) for 1538 GOG 218 participants were analyzed. Proportional hazards models assessed association between adiposity and overall survival (OS) adjusted for other prognostic factors. The predictive value of adiposity as a function of BEV treatment was assessed in 1019 patients randomized to either chemotherapy (CT) + placebo (P) → P or CT + BEV → BEV. Results After adjusting for prognostic factors, SFA was not associated with the overall hazard of death (p = 0.981). There was a non-significant 0.1% (p = 0.062) increase in hazard of death associated with a unit increase in VFA. When comparing the treatment HRs for patients who did and did not receive BEV, there was no association with SFA (p = 0.890) or VFA (p = 0.106). A non-significant 0.8% increase in the hazard of death with unit increase in BMI (p = 0.086) was observed. BMI values were not predictive of a longer survival for patients with BEV vs placebo (p = 0.606). Conclusion Measures of adiposity strongly correlated to one another but were not predictive of efficacy for BEV. VFA is a weak prognostic factor.

PurposeTo compare patient/tumor characteristics and outcomes of Asians to Caucasian patients with epithelial ovarian cancer.MethodsAncillary data were pooled and analyzed from ten prospective randomized front-line Gynecologic Oncology Group clinical trials from 1996 to 2011. Demographic, clinicopathologic features, disease-specific and all-cause survival were analyzed.ResultsOf 7914 patients, 7641 were Caucasian and 273 Asian. When compared to Caucasians, Asians were younger at trial enrollment, had a better performance status, earlier-stage cancers (17.2% vs. 8.1% with stage I; p

Objectives: AVB-500 is a first-in-class Fc fusion protein that binds the GAS6 ligand thereby inhibiting AXL signaling. Both GAS6 and AXL are highly expressed in high-grade serous ovarian cancer (HSGOC). The purpose of this study was to evaluate safety, tolerability, and preliminary efficacy of AVB-500 in combination with pegylated liposomal doxorubicin (PLD) and paclitaxel (Pac) and determine the RP2D. Methods: Patients were enrolled in escalating dose cohorts of AVB-500 10mg/kg to 20mg/kg at q2 weeks in combination with weekly Pac 80mg/m2D1, 8, 15 q28 days or PLD 40mg/m2D1 q28 days and assessed for safety, pharmacokinetics, pharmacodynamics, and response (via RECIST v1.1, assessed by investigator). A safety review committee reviewed each cohort prior to escalation to the next higher dose level. Results: A total of 53 patients with platinum-resistant HGSOC ovarian adenocarcinoma (PROC) were enrolled. A total of 23 patients received Pac + AVB-500 and 30 patients received PLD + AVB-500. No patients experienced a dose-limiting toxicity (DLT). A total of 53% (28/53)of patients experienced a grade 3-4 adverse event. No grade 5 events were observed. The majority of events were related to known chemotherapy side effects. No subject discontinued study therapy due to an adverse event. Confirmed ORR with Pac+AVB-500 was 35% (8/23) and 15% (4/26) in the PLD+AVB-500 subgroup. ORR in the Pac subgroup after 1-2 prior lines was 40% with a platinum-free interval (PFI) ≥3 months, and 60% with a PFI of 13.8mg/L as the minimal efficacious concentration (MEC). Among the Pac treated subgroup, the ORR was 39% vs 22% and median overall survival (OS) was 10.3 months vs 6.7 months in the MEC-high and MEC-low groups, respectively (Figure 1). Additionally, serum soluble AXL/GAS6 ratio was measured at baseline as an indicator of pathway activation. Among the Pac treated subgroup, the ORR was 42.9% vs 0% for those with ratios >0.773 compared to those with ratios ≤0.773. Download : Download high-res image (103KB) Download : Download full-size image Conclusions: AVB-500 is a novel Fc fusion protein that binds the GAS6 ligand and targets GAS6/AXL pathway. AVB-500was found to be safe and tolerable in this Ph1B trial in combination with Paclitaxel or PLD. The RP2D was based upon PK/PD parameters. This Ph1B trial suggesteda higher ORR in the Pac treated subgroup, particularlywith C1D15 trough levels >13.8mg/L (most consistently achieved at the 15mg/kg dose level). Exploratory analysis also suggested that improved response rates may be observed in patients who have not been exposed to bevacizumab. The serum soluble AXL/GAS6 ratio may serve as a potential biomarker of pathway activation and identify patients who most benefit from Pac+AVB-500. Further development of AVB-500 15 mg/kg Q2W in combination with Pac is warranted in PROC.

Objectives: Genomically unstable tumors, characterized by BRCA1/2 alterations and homologous recombination deficiency (HRD), are hypothesized to be more mutated and potentially more sensitive to immune checkpoint inhibitors. To explore this hypothesis we analyzed outcomes in the IMagyn050 trial according to BRCA1/2, HRD, and PD-L1 status [Moore, ESMO 2020]. Methods: IMagyn050 (NCT03038100) is a double-blind randomized phase III trial evaluating the efficacy and safety of adding atezolizumab/placebo to carboplatin, paclitaxel, and bevacizumab (CPB) followed by maintenance bevacizumab plus atezolizumab/placebo. PD-L1 status was determined centrally using VENTANA SP142 (PD-L1+ defined as ≥1% tumor-infiltrating immune cells expressing PD-L1). Deleterious tumor germline/somatic BRCA1/2 alterations (BRCA1/2m), genomic loss of heterozygosity (gLOH), tumor mutation burden (TMB), and microsatellite instability (MSI) were evaluated using the FoundationOne assay (Foundation Medicine, Inc., Cambridge, MA). HRD and homologous recombination proficiency (HRP) were defined as gLOH ≥16% and Results: Among 1301 randomized patients, samples from 1050 were evaluable for BRCA1/2 (22% were BRCA1/2m, 78% BRCA1/2 nonmutant) and 980 were evaluable for gLOH (46% were HRD, 54% HRP). Median TMB was similarly low in BRCA1/2m and BRCA1/2 nonmutant (3.78 vs 2.52 Mut/Mb, respectively), and HRD and HRP (3.78 vs 2.52 Mut/Mb, respectively) tumors. Only 3% (29/1024) of evaluable tumors had TMB ≥10 Mut/Mb and 0.3% (3/1022) were MSI-high (1 mixed, 1 undifferentiated, 1 other). All high-grade serous cases were MS-stable. PFS prognosis (assessed in the placebo + CPB arm) was improved in patients with BRCA1/2m (hazard ratio [HR] 0.62, 95% CI 0.46–0.84) and HRD (HR 0.63, 95% CI 0.49–0.80) tumors. There was a suggested association between PD-L1+ and HRD (HRD prevalence: 40% vs 25% in PD-L1+ vs PD-L1– subgroups, respectively; exploratory Fisher's exact test p=0.0001) but not with BRCA1/2m (BRCA1/2m prevalence: 21% vs 14%, respectively; exploratory Fisher exact test p=0.064). Adding atezolizumab to CPB did not improve PFS, irrespective of BRCA1/2 or HRD status (table). In the PD-L1+ population, HRs were similar in BRCA1/2m and BRCA1/2 nonmutant subgroups, and in HRD and HRP subgroups. In the PD-L1– population, atezolizumab did not improve PFS. Download : Download high-res image (172KB) Download : Download full-size image Conclusions: We showed that the majority of ovarian tumors have low TMB scores regardless of BRCA1/2 or HRD. Neither BRCA1/2m nor HRD was associated with greater clinical benefit from adding atezolizumab to CPB. PD-L1 status was more reliably associated with numerically longer PFS with atezolizumab + CPB. This is the first randomized double-blind trial in ovarian cancer to demonstrate that genomic instability triggered by BRCA1/2m or HRD does not improve sensitivity to immune checkpoint inhibitors.

Objectives: Although primary results from the IMagyn050 trial showed no statistically significant improvement in progression-free survival (PFS) with atezo added to carboplatin/paclitaxel/bevacizumab (CPB) [Moore, ESMO 2020], the impact of this regimen on selected patient (pt)-reported ovarian cancer symptoms, function, and health-related quality of life (HRQoL) is unknown and the focus of this study. Methods: IMagyn050 is a double-blind randomized phase 3 trial evaluating the efficacy and safety of adding atezo/placebo to CPB followed by maintenance bevacizumab + atezo/placebo. The trial includes two cohorts: neoadjuvant chemotherapy (NACT) and primary surgery (PS). Pts complete EORTC QLQ-C30, QLQ-OV28, and FACT-G single-item GP5 at baseline (BL) and at regular intervals during treatment and follow-up. In NACT pts, prespecified responder analyses (using a ≥10-point cutoff for clinically meaningful change) assessed improvement in abdominal pain (OV28 item 31) and bloating (OV28 item 32) at week 9, comparing treatment arms by Cochran-Mantel-Haenszel (CMH) testing. Additional secondary objectives in the NACT and PS cohorts were assessments of function (physical, role, emotional, social) and HRQoL, as measured by QLQ-C30 functional and global health status/quality of life scales. Exploratory endpoints included mean change from BL in symptoms (QLQ-C30 and OV28) and treatment side-effect bother (FACT-G GP5) in both cohorts. Results: Of 1301 randomized pts, completion rates for each of the 3 questionnaires were 83-100% at BL and >85% on treatment. In NACT pts, mean BL scores were similar in the atezo vs placebo arms for abdominal pain (40.2 vs 44.8) and bloating (50.4 vs 56.3). At week 9, there was no difference between treatments in the proportion of NACT pts with ≥10-point improvement in either symptom (abdominal pain: 69/136 [51%] with atezo vs 77/142 [54%] with placebo, CMH p=0.56; bloating: 74 [54%] vs 89 [63%], CMH p=0.14). Results were consistent when restricted to NACT pts with sufficient BL symptoms to show ≥10-point improvement. There was no difference between treatments in the proportion of NACT pts with improvement in function or HRQoL at week 9. In the PS cohort, similar proportions of pts in each arm showed on-treatment improvement, stabilization, or deterioration in function and HRQoL. In both cohorts, neither arm showed meaningful changes from BL in treatment-related symptoms and similar proportions of pts in both arms reported being ‘a little bit’ or ‘somewhat’ bothered by treatment side effects while on therapy. Conclusions: Consistent with PFS results, there were no differences between arms in the proportion of NACT pts with a clinically meaningful improvement in abdominal pain and bloating after 3 cycles of bevacizumab-containing therapy. Pt-reported outcome analyses in both cohorts showed that adding atezo to CPB did not increase treatment burden for pts, thereby demonstrating the tolerability of this 4-drug regimen and providing further insight on the benefit-risk assessment of atezo.

Purpose To determine the relationship between chemotherapy dose modification (dose adjustment or treatment delay), overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma (PPC) who receive carboplatin and paclitaxel. Methods Women with stages III and IV EOC and PPC treated on the Gynecologic Oncology Group phase III trial, protocol 182, who completed eight cycles of carboplatin with paclitaxel were evaluated in this study. The patients were grouped per dose modification and use of granulocyte colony stimulating factor (G-CSF). The primary end point was OS; Hazard ratios (HR) for PFS and OS were calculated for patients who completed eight cycles of chemotherapy. Patients without dose modification were the referent group. All statistical analyses were performed using the R programming language and environment. Results A total of 738 patients were included in this study; 229 (31%) required dose modification, 509 did not. The two groups were well-balanced for demographic and prognostic factors. The adjusted hazard ratios (HR) for disease progression and death among dose-modified patients were: 1.43 (95% CI, 1.19–1.72, P Conclusion Dose-modified patients were at a higher risk of disease progression and death. The need for chemotherapy dose modification may identify patients at greater risk for adverse outcomes in advanced stage EOC and PPC.

To identify clinicopathologic factors associated with 10-year overall survival in epithelial ovarian cancer (EOC) and primary peritoneal cancer (PPC), and to develop a predictive model identifying long-term survivors.Demographic, surgical, and clinicopathologic data were abstracted from GOG 182 records. The association between clinical variables and long-term survival (LTS) (10years) was assessed using multivariable regression analysis. Bootstrap methods were used to develop predictive models from known prognostic clinical factors and predictive accuracy was quantified using optimism-adjusted area under the receiver operating characteristic curve (AUC).The analysis dataset included 3010 evaluable patients, of whom 195 survived greater than ten years. These patients were more likely to have better performance status, endometrioid histology, stage III (rather than stage IV) disease, absence of ascites, less extensive preoperative disease distribution, microscopic disease residual following cyoreduction (R0), and decreased complexity of surgery (p0.01). Multivariable regression analysis revealed that lower CA-125 levels, absence of ascites, stage, and R0 were significant independent predictors of LTS. A predictive model created using these variables had an AUC=0.729, which outperformed any of the individual predictors.The absence of ascites, a low CA-125, stage, and R0 at the time of cytoreduction are factors associated with LTS when controlling for other confounders. An extensively annotated clinicopathologic prediction model for LTS fell short of clinical utility suggesting that prognostic molecular profiles are needed to better predict which patients are likely to be long-term survivors.

We examined disparities in prognosis between patients with ovarian clear cell carcinoma (OCCC) and serous epithelial ovarian cancer (SOC).We reviewed data from FIGO stage I-IV epithelial ovarian cancer patients who participated in 12 prospective randomized GOG protocols. Proportional hazards models were used to compare progression-free survival (PFS) and overall survival (OS) by cell type (clear cell versus serous).There were 10,803 patients enrolled, 9531 were eligible, evaluable and treated with platinum, of whom 544 (6%) had OCCC, 7054 (74%) had SOC, and 1933 (20%) had other histologies and are not included further. In early stage (I-II) patients, PFS was significantly better in OCCC than in SOC patients. For late stage (III, IV) patients, OCCC had worse PFS and OS compared to SOC, OS HR=1.66 (1.43, 1.91; p0.001). After adjusting for age and stratifying by protocol and treatment arm, stage, performance status, and race, OCCC had a significantly decreased OS, HR=1.53 (1.33, 1.76; p0.001). In early stage cases, there was a significantly decreased treatment effect on PFS for consolidative therapy with weekly Paclitaxel versus observation in OCCC compared to SOC (p=0.048).This is one of the largest analyses to date of OCCC treated on multiple cooperative group trials. OCCC histology is more common than SOC in early stage disease. When adjusted for prognostic factors, in early stage patients, PFS was better for OCCC than for SOC; however, in late-stage patients, OCCC was significantly associated with decreased OS. Finally, treatment effect was influenced by histology.

Objective This study evaluated single nucleotide polymorphisms (SNPs) associated with progression free (PFS) and overall survival (OS) in patients with advanced stage serous EOC. Methods Patients enrolled in GOG-172 and 182 who provided specimens for translational research and consent were included. Germline DNA was evaluated with the Illumina's HumanOMNI1-Quad beadchips and scanned using Illumina's iScan optical imaging system. SNPs with allele frequency>0.05 and genotyping rate>0.98 were included. Analysis of SNPs for PFS and OS was done using Cox regression. Statistical significance was determined using Bonferroni corrected p -values with genomic control adjustment. Results The initial GWAS analysis included 1,124,677 markers in 396 patients. To obtain the final data set, quality control checks were performed and limited to serous tumors and self-identified Caucasian race. In total 636,555 SNPs and 289 patients passed all the filters. The pre-specified statistical level of significance was 7.855e −08 . No SNPs met this criteria for PFS or OS, however, two SNPs were close to significance (rs10899426 p -2.144e − 08 ) (rs6256 p -9.774e −07 ) for PFS and 2 different SNPs were identified (rs295315 p -7.536e − 07 ; rs17693104 p -7.734e − 07 ) which were close to significance for OS. Conclusions Using the pre-specified level of significance of 1×10 −08 , we did not identify any SNPs of statistical significance for OS or PFS, however several were close. The SNP's identified in this GWAS study will require validation and these preliminary findings may lead to identification of novel pathways and biomarkers.

Objectives: To determine safety, efficacy, and biomarkers of response to neoadjuvant therapy (NACT) with atezolizumab (atezo), weekly paclitaxel and carboplatin (wPC) followed by maintenance (maint) atezo±bevacizumab (bev) in women with advanced epithelial ovarian, tubal, and peritoneal cancer (EOC). Methods: Patients (pts) with high-grade EOC were eligible. Pts underwent pretreatment biopsy, received paclitaxel 80 mg/m2 IV D1/8/15 + carboplatin AUC6 IV D1 + atezo 1200 mg D1 every 3 weeks x 3 cycles followed by interval cytoreductive surgery (ICS). Post-surgery, pts received adjuvant atezo, wPC±bev followed by maint atezo±bev. Primary objective was to assess safety of the combination when given prior to ICS. Early stopping rules were built around the primary safety endpoint if patients were unable to proceed to planned ICS within the specified timeframe (≤6 weeks from last dose of NACT) due to atezo-related toxicities. Safety was assessed in all treated pts using frequency and severity of adverse events (AE). Objective response rate (ORR), pathologic complete response rate (pCR) at ICS, and progression free survival (PFS) were determined. Planned exploratory objectives included quantitation of changes in PD-L1 expression, tumor-infiltrating lymphocyte subpopulations, immune checkpoint receptor profile, and immune blood-based markers. Results: A total of 18 pts enrolled and received therapy between 05/15/2018 - 07/14/2020. Median age was 69 years (range 46-87). Key disease characteristics: 18 (100%) pts had high-grade serous EOC; 13 (72%) pts had Stage III and 5 (28%) had stage IV disease; BRCA status: 5 (28%) mutations, 13 (72%) wildtype. Grade (G) 3/4 atezo-related AEs included 1 (6%) G3 anemia, 2 (11%) G3 thrombocytopenia, 2 (11%) G4 hypokalemia, 2 (11%) G3 rash, 1 (6%) thrombotic event. Other AEs of special interest included pneumonitis (n=3, 2 G2, 1 G1), blurred vision (n=1, G1), and myositis (n=1, G1). A total of 3 pts withdrew prior to ICS; 1 to change to every 3 weeks therapy locally, 1 due to non-atezo related AEs, and 1 due to negative results of IMAGYN050. These 3 pts are not included in the response-evaluable population (n=15). Nine (60%) pts had a partial response (PR) after 3 cycles and 6 (40%) had stable disease. All 15 pts underwent ICS; 1 had delayed cytoreduction due to pulmonary embolism, possibly atezo-related. Cytoreduction status was optimal in 86% pts [R0 8 (53%), R1 (33%)], and suboptimal in 2 (13%) pts; no pCRs were observed. All response-evaluable pts completed chemotherapy. Pts opted for maint therapy as follows: 6 (40%) adjuvant/maint atezo+bev; 4 (27%) atezo alone; and 5 (33%) withdrew for PARP inhibitor maint. A total of 2 (20%) of 10 receiving atezo maint discontinued due to recurrence. Blood-based and tumor biomarker results will be presented. Download : Download high-res image (90KB) Download : Download full-size image Conclusions: NACT with atezo + wPC followed by maint atezo±bev was feasible with no new safety signals. Biomarker analysis is ongoing to identify potential candidates who may benefit from atezo front-line therapy.

To understand the relationship between primary platinum-free interval (PFI), BRCA mutation status, and overall survival (OS) in patients with recurrent ovarian cancer receiving multiple lines of therapy in a multicenter, community-based, retrospective observational cohort study of adult patients with stage III-IV high-grade ovarian cancer.Data were retrospectively obtained from the electronic health record (EHR) of a US community oncology network, including patient characteristics, subsequent treatments, primary PFI, and BRCA status. OS was analyzed by the Kaplan-Meier method, stratified by primary PFI and BRCA status.750 patient charts were reviewed. BRCA testing status was known in 267 patients (16% BRCA mutation). Among patients with identified recurrent disease, 41% had a primary PFI6months and 59% had a primary PFI ≥6months. Of second-line patients, 59% received third-line therapy, and 60% of third-line patients received fourth-line therapy within the period of observation. Median OS from the start of primary treatment for the entire population was 41.4months (95% CI, 39.0-48.3months). Median OS was significantly increased in patients with primary PFI ≥6months at second-line and third-line (P0.0001 and P=0.002, respectively). Survival was observed to be increased among patients with BRCA mutations across multiple treatment lines, although this was not statistically significant.Patients with a primary PFI ≥6months demonstrated improved outcomes over multiple lines of therapy. BRCA status was known in 36% of patients, and those patients with a BRCA mutation demonstrated a trend toward delayed primary recurrence and improved clinical outcomes.

To examine the utility of upper abdominal procedures (UAPs) performed in a cohort of optimally cytoreduced patients with advanced stage epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC) and identify potential areas where aggressive surgery may impact survival.We reviewed 2655 patients enrolled in Gynecologic Oncology Group (GOG) 182 who had complete resection (CR) or minimal residual (MR) disease1cm. Demographic, pathologic, surgical, and outcome data were collected. UAPs included diaphragm stripping or resection, liver resection, splenectomy, pancreatectomy, and porta hepatis surgery. Effect of UAP and CR on PFS/OS was assessed by Kaplan-Meier and proportional hazards methods.Four-hundred eighty-two patients (18.1%) underwent a total of 590 UAPs. There were 351 (13.1%) diaphragm surgeries, 112 (4.2%) liver surgeries, 108 (4%) splenectomies, 12 (0.5%) pancreatectomies, and 7 (0.2%) porta hepatis surgeries. Comparing patients who did not have UAPs to patients who had UAPs, the PFS was 18.2 months (mos) and 14.8 mos (p0.01) and OS was 49.8 mos v. 43.7 mos (p = 0.01), respectively. However, in the multivariable analysis this survival benefit did not remain (PFS HR = 1.03, 95% CI 0.91-1.15; OS HR=0.92, 95%CI 0.81-1.04). The OS of the 141 patients who had an UAP and achieved CR compared to the 341 patients who had an UAP with MR was 54.6 compared to 40.4 mos (p=0.0005).UAP procedures should only be performed when CR is attainable. A significant proportion of patients with MR were left with diaphragmatic disease that could potentially be completely resected.

Purpose Efflux transporters of the ATP-binding cassette (ABC) family are major determinants of chemoresistance in tumor cells. This study examined associations between functional variants in ABCB1 , ABCC2 and ABCG2 genes and clinical outcomes in patients with epithelial ovarian/primary peritoneal cancer (EOC/PPC) following platinum and taxane-based chemotherapy. Methods Sequenom iPLEXTMGOLD Assay and MALDI-TOF platform were used to genotype the non-synonymous G2677T/A (rs2032582; encoding Ala893Ser/Thr) and synonymous C3435T (rs1045642; encoding Ile1145Ile) variants in ABCB1 , the non-synonymous G1249A variant in ABCC2 (rs2273697; encoding Val417Ile), and the non-synonymous C421A variant in ABCG2 (rs2231142; encoding Q141K, Gln141Lys) in normal DNA from up to 511 women in Gynecologic Oncology Group (GOG) phase III trials, GOG-172 or GOG-182. Progression-free survival (PFS) and overall survival (OS) were analyzed in relation to genetic polymorphisms using Kaplan-Meier and Cox proportional hazards model. Results The C421A variant (CA+AA versus CC) in ABCG2 was associated with a 6-month longer median PFS (22.7 versus 16.8months, p=0.041). In multivariate analysis, patients with variant genotypes were at a reduced risk of disease progression (hazard ratio [HR]=0.75, 95% confidence interval [CI]=0.59-0.96, p=0.022). The association between C421A and OS was not statistically significant (HR=0.88, 95% CI=0.67-1.15, p=0.356). None of the other variants measured in either ABCB1 or ABCC2 was associated with PFS or OS. Conclusion The C421A variant in ABCG2 , previously shown to be associated with enhanced protein degradation and drug sensitivity, was associated with longer PFS in advanced stage EOC/PPC patents treated with platinum+taxane-based chemotherapy. This finding requires further validation.

Objective This study evaluated common polymorphisms in excision repair cross-complementation group 1 (ERCC1) involved in repair of platinum-induced DNA damage in advanced-stage, epithelial ovarian/peritoneal/tubal cancer (EOC/PPC/FTC) patients treated with intravenous carboplatin- and paclitaxel-based chemotherapy. Methods Pyrosequencing was performed to examine single nucleotide polymorphisms (SNPs) in codon 118 and C8092A in ERCC1 in leukocyte DNA from the Gynecologic Oncology Group phase III protocol, GOG-182. Kaplan–Meier method and adjusted Cox regression modeling were used to examine associations between ERCC1 polymorphisms and progression-free survival (PFS) and overall survival (OS). Results The genotype distribution at codon 118 ( n =278) in ERCC1 for CC, CT, and TT was 23%, 45% and 32%, and the median OS was 32, 47 and 43months, respectively. Patients with the CT+TT versus CC genotype in codon 118 in ERCC1 were at a reduced risk of death (hazard ratio [HR]=0.68, 95% confidence interval [CI]=0.49–0.95, p=0.025). The genotype distribution for C8092A in ERCC1 ( N =280) was 50%, 42% and 8%, and the median OS was 45, 40 or 30months for CC, CA and AA, respectively. Women with the CA+AA versus CC genotype in C8092A in ERCC1 had a trend suggesting an increased risk of death (HR=1.29, 95% CI=0.97–1.72, p =0.077). Conclusions The polymorphism in codon 118 in the DNA repair gene ERCC1 was an independent predictor for better survival in EOC/PPC/FTC patients treated with intravenous carboplatin- and paclitaxel-based chemotherapy. The relationship between the C8092A polymorphisms in ERCC1 and survival was modest with an effect size that was not always statistically significant.

Objectives To determine the maximum tolerated dose (MTD) and feasibility of weekly cisplatin and paclitaxel chemotherapy administered concurrently with whole abdominal radiation therapy (WART) in women with high-risk endometrial cancer. Methods Following surgery, patients with stage III–IV endometrial cancer (any histology) or with stage I–II serous or clear cell histology, and with largest residual disease ≤2 cm were eligible for this phase I feasibility trial. Six weekly cycles of chemotherapy were administered with WART in dose level (DL) cohorts of 3 patients in a 3+3 design. Once the MTD was defined, a second, feasibility portion of the trial was conducted to assess for chronic toxicity. All patients were to be treated with 25 Gy to the abdomen and 50.2 Gy to the pelvis. Results Thirty-five patients were enrolled in the study, including 21 in the dose finding portion, and 14 in the feasibility portion of the trial. The initial DL tested was paclitaxel 10 mg/m 2 and cisplatin 20 mg/m 2 . The MTD identified was at DL3 using paclitaxel 20 mg/m 2 and cisplatin 25 mg/m 2 . The most common acute dose-limiting toxicities (DLT) were gastrointestinal and hematologic. The prescribed radiation therapy was successfully delivered to 32/35 patients. Twenty patients (6 phase I, 14 feasibility) were assessed at the MTD. No acute grade 4 toxicities, and two grade 3–4 chronic toxicities were observed in these patients. Treatment contributed to the deaths of 2 patients. Conclusion A regimen of cisplatin 25 mg/m 2 and paclitaxel 20 mg/m 2 weekly with WART was determined to be feasible, but is associated with moderate acute and chronic gastrointestinal toxicity.

Objectives. To determine a recommended dose level (RDL) of paclitaxel, cisplatin and topotecan in women with previously untreated epithelial ovarian or peritoneal cancer as a possible experimental arm in a future Gynecologic Oncology Group phase III study. Methods. Patients with newly diagnosed stage III or IV disease were treated with paclitaxel 175 mg/m 2 /3 h, followed 2 h later by cisplatin 50 mg/m 2 on day 1. Topotecan was administered on consecutive days as a 30-minute infusion, beginning after cisplatin on day 1, receiving either 5 days beginning at 0.3 mg/m 2 (cohort 1), or 3 days beginning at 0.5 mg/m 2 (cohort 2). Treatment was given every 21 days for a maximum of 8 cycles. Results. Forty-five evaluable patients were enrolled in the two cohorts. Thrombocytopenia and prolonged neutropenia were the major dose-limiting toxicities. Dose-limiting neutropenia was seen at the first dose level, thus all subsequent dose escalations included Filgrastim. The RDL of cohort 1 was paclitaxel 175 mg/m 2 /3 h, cisplatin 50 mg/m 2 and topotecan 0.5 mg/m 2 daily×5 with Filgrastim. The RDL of cohort 2 was paclitaxel 175 mg/m 2 /3 h, cisplatin 50 mg/m 2 and topotecan 0.75 mg/m 2 daily×3 with Filgrastim. Conclusion. In women with previously untreated epithelial ovarian or peritoneal cancer the combination of paclitaxel, cisplatin and topotecan is feasible. However, this treatment requires the use of Filgrastim and attenuated dosing of topotecan in both a 5-day and 3-day topotecan infusion schedule.

Predictive factors for efficacy of bevacizumab in advanced ovarian cancer have remained elusive. We investigated ascites both as a prognostic factor and as a predictor of efficacy for bevacizumab.Using data from GOG 0218, patients receiving cytotoxic therapy plus concurrent and maintenance bevacizumab were compared to those receiving cytotoxic therapy plus placebo. The presence of ascites was determined prospectively. Chi-square and Wilcoxon-Mann-Whitney tests compared baseline variables between subgroups. Survival was estimated by Kaplan-Meier method, and Cox proportional hazard models were used to evaluate independent prognostic factors and estimate their covariate-adjusted effects on survival.Treatment arms were balanced with respect to ascites and other prognostic factors. Overall, 886 (80%) women had ascites, 221 (20%) did not. Those with ascites were more likely to have: poorer performance status (p0.001); serous histology (p=0.012); higher baseline CA125 (p0.001); and suboptimal cytoreduction (p=0.004). In multivariate survival analysis, ascites was prognostic of poor OS (Adjusted HR 1.22, 95% CI 1.00-1.48, p=0.045), but not PFS. In predictive analysis, patients without ascites treated with bevacizumab had no significant improvement in either PFS (AHR 0.81, 95% CI 0.59-1.10, p=0.18) or OS (AHR 0.94, 95% CI 0.65-1.36, p=0.76). Patients with ascites treated with bevacizumab had significantly improved PFS (AHR 0.71, 95% CI 0.62-0.81, p0.001) and OS (AHR 0.82, 95% CI 0.70-0.96, p=0.014).Ascites in women with advanced ovarian cancer is prognostic of poor overall survival. Ascites may predict the population of women more likely to derive long-term benefit from bevacizumab.

Ovarian cancer is the leading cause of gynecologic cancer deaths in the U.S. The concept of intraperitoneal drug delivery for therapy of intraperitoneal cancers, such as ovarian cancer, arose in the 1960s. The field of intraperitoneal cisplatin therapy for ovarian cancer was initiated in the late 1970s and early 1980s. The markedly improved survival data resulting from a third phase III trial of intraperitoneal cisplatin for ovarian cancer in early 2006 led to an NCI Clinical Announcement and a Gynecologic Oncology Group-sponsored workshop on Intraperitoneal Therapy in January, 2006, in San Diego, California. The proceedings of this workshop summarize both research trial results and practical implementation issues associated with intraperitoneal therapy discussed at this workshop.

Purpose . To determine the feasibility of administering a minimum of four cycles of carboplatin, paclitaxel, and gemcitabine (CPG) every 21 days without excessive dose modification or cycle delay in patients with previously untreated epithelial ovarian cancer or primary peritoneal cancer. Methods . Paclitaxel 175 mg/m 2 was given over 3 h followed by carboplatin concentration time curve (AUC) 5 (day 1) and gemcitabine 1 g/m 2 (days 1 and 8) in the first cohort. A second cohort received paclitaxel 135 mg/m 2 over 3 h followed by carboplatin AUC 5 (day 1) and gemcitabine 800 mg/m 2 (days 1 and 8). A maximum of eight cycles was administered. Results . Fourteen patients received 89 cycles during the first cohort. Seven patients experienced 19 hematologic dose-limiting events (DLEs) within the first four cycles, including grade 4 thrombocytopenia ( n = 9), febrile neutropenia ( n = 3), and omission of gemcitabine on day 8 ( n = 7). This exceeded the threshold for nonfeasibility. In the second, less intense regimen, 36 patients were entered. Thirty-one evaluable patients received a total of 200 and median of 6 (range: 2–8) cycles. Thirteen of the thirty-one had 27 DLEs within the first four cycles including grade 4 thrombocytopenia ( n = 5), prolonged grade 4 neutropenia ( n = 2), febrile neutropenia ( n = 2), and omission of day 8 gemcitabine ( n = 18). There was one patient death secondary to a wound abscess and febrile neutropenia. Myelosuppression as expected was the dose-limiting toxicity. Conclusion . The schedule of paclitaxel 135 mg/m 2 (day 1, 3 h), carboplatin AUC 5 (day 1), and gemcitabine 800 mg/m 2 (days 1 and 8) is feasible, with an acceptable toxicity profile.

Objective To examine whether clinical outcomes varied with intraperitoneal (IP) and/or retroperitoneal (RP) involvement in stage IIIC epithelial ovarian cancer (EOC) patients with microscopic residual disease after cytoreduction. Methods Retrospective review was performed for EOC patients enrolled in Gynecologic Oncology Group (GOG)-182 who underwent primary cytoreduction to microscopic residual disease. Patients were divided into 3 groups: stage IIIC by lymphadenopathy with 2cm IP spread and negative nodes (IP/RP−); and >2cm IP dissemination and positive lymphadenopathy (IP/RP+). Product-limit and multivariate proportional hazards modeling were used. Results Analyses included 417 stage IIIC women who underwent primary cytoreduction with lymphadenectomy to microscopic residual. There were 203, 123, and 91 in the RP, IP/RP−, and IP/RP+ groups, respectively. IP/RP+ and IP/RP− were associated with worse progression-free survival (PFS) (Hazard Ratio (HR) 1.68, 95% confidence interval (CI) 1.23–2.30; HR 1.38, 95% CI 1.04–1.84) vs. RP only. IP/RP+ was associated with worse overall survival (OS) (HR 1.79, 95% CI 1.24–2.57) while IP/RP− trended towards worse OS (HR 1.21, 95% CI 0.85–1.73) vs. RP only. Median PFS for IP/RP+ and IP/RP− groups was 21 and 29months, respectively, vs. 48months in the RP group (p=0.0007) and median OS of 63 and 79months vs. "not reached," respectively (p=0.0038). Conclusions Among EOC patients surgically cytoreduced to microscopic residual disease, those upstaged to IIIC by retroperitoneal involvement demonstrated significant improvement in PFS and OS compared to patients with intraperitoneal tumor, suggesting that these women may represent a unique subset of FIGO stage IIIC patients.

The success of platinum-based chemotherapy in the initial management of advanced-stage ovarian cancer has been challenged by the emergence of drug-resistant tumors in the majority of patients. Even taxol, which can achieve clinical responses in one-third of patients with platinum-resistant tumors, may fail to substantially alter long-term survival for many patients with refractory disease. Thus, there continues to be a need for alternative therapeutic strategies. Specific roles for primary or adjunctive biologic therapy in the management of refractory ovarian cancer have not yet been defined. For example, a variety of conjugated monoclonal antibodies have been evaluated for over 10 years, but have not yet been shown to be effective with acceptable levels of host toxicity. The closest candidate for standardized biologic therapy is intraperitoneal interferon for treatment of microscopic residual disease. Adjunctive hematopoietic colony stimulating factors are widely used with taxol to achieve greater dose intensity and cumulative drug delivery, although they have not yet been shown to improve response or survival. Appreciation of the complex pathways regulated by growth factors and cytokines will provide a more challenging framework for continued development of biological therapeutics in the future.

Purpose We investigated whether tumor response rate (TRR), disease control rate (DCR), or progression-free survival (PFS) was a valid surrogate for overall survival (OS) in phase II trials of second-line therapies for patients with platinum-resistant ovarian carcinoma (PROC). Methods We retrospectively evaluated data from 11 second-line phase II trials conducted for PROC by the Gynecologic Oncology Group (GOG). TRR included complete response and partial response (CR/PR) and DCR was defined as either tumor response or stable disease (CR/PR+SD). Survival by tumor response was analyzed using a landmark approach. Correlations of OS with TRR, DCR, and PFS were estimated. Results Among 407 patients analyzed the TRR was 13.8% (56/407) and DCR was 38.8% (158/407). Median OS was 10.2months while median PFS was only 2.4months. Median OS among patients with a best response of CR/PR, SD, and progressive disease (PD) was 13.3, 12.1 and 5.7months, respectively, showing no difference between CR/PR and SD. From a protocol level, DCR correlated better with OS (Pearson r =0.748; Tau-b r =0.514) compared to TRR (Pearson r =0.564; Tau-b r =0.404). PFS rate at 6months (Pearson r =0.661; Tau-b r =0.514) also correlated strongly with OS. Conclusions This study demonstrates the limitations of the use of response rate alone in PROC. Clinical benefit, as defined by OS, appeared similar for patients with an objective response and those with SD. The DCR, by including tumor response and SD may have utility as a surrogate endpoint for survival in phase II therapeutic trials in PROC.

To estimate the maximum tolerated dose (MTD) of paclitaxel poliglumex (PPX) in combination with carboplatin in patients with chemotherapy-naive ovarian, primary peritoneal or fallopian tube cancer, and to assess the feasibility of administering multiple cycles of this regimen.The first 11 patients were treated in a standard 3 + 3 dose-seeking design, with carboplatin held constant at area under the curve (AUC) of 6 and PPX at 225, 175 or 135 mg/m(2). Pharmacokinetics of PPX and carboplatin were evaluated during this dose-seeking component of the trial. MTD was defined by acute dose-limiting toxicities (DLT) in the first cycle. Twenty additional evaluable patients were treated at the estimated MTD to assess the feasibility of this regimen overor=4cycles.PPX at 225 mg/m(2) resulted in DLT in 2/3 patients, and was de-escalated first to 175 mg/m(2) and then to 135 mg/m(2). PPX slowly hydrolyzed to paclitaxel and did not alter the pharmacokinetics of carboplatin. DLT within the first 4-cycles were observed in 3 patients (15%) treated at the MTD: neutropenia2weeks (2), febrile neutropenia (1). Nineteen patients (95%) experienced grade 4 neutropenia. Sixteen patients (80%) had at least one episode of grade 3 thrombocytopenia. Three patients (15%) had grade 2 and one had grade 3 peripheral neuropathy. Complete response by CA-125 was 75%.The recommended dose of PPX of 135 mg/m(2) with carboplatin (AUC = 6) in newly diagnosed ovarian cancer was feasible for multiple cycles, but hematologic toxicity was greater compared with standard carboplatin and 3-hour paclitaxel.

surgery. QI #7 & 8: A total of 119/121 (98.3%) patients received prophylactic parenteral antibiotics within 60 min of cytoreduction and these were discontinued in 120/121 (99.2%) cases. Conclusions: These data can help establish benchmark criteria for integrating ovarian indicators into actual practice. The surprisingly low percentage of “completely staged” patients deserves additional exploration as to whether this is a flaw in reporting or a lack of compliance. The study not only identifies areas for improvement but also demonstrates the importance of documentation when medical reasons prevent indicators from being met. Further validation requires prospective evaluation of these indicators and their correlation to patient outcomes, such as survival.

Purpose. Selection of a feasible sequence and schedule of carboplatin in combination with topotecan for evaluation in advanced epithelial ovarian cancer (EOC). Patients and methods. Women with stages III–IV EOC or primary peritoneal carcinoma without prior chemotherapy were assigned to consecutive cohorts evaluating a "forward" (carboplatin day 1, topotecan days 1–3), "reverse" (carboplatin day 3, topotecan days 1–3), or "extended reverse" sequence (carboplatin day 5, topotecan days 1–5). Patients received 4 cycles carboplatin–topotecan followed by 4 cycles carboplatin–paclitaxel. Feasibility was defined according to the cumulative proportion of patients with dose-limiting events (DLEs) during the first four cycles. Results. Sixty-eight patients were enrolled across 5 cohorts. The forward sequence demonstrated unacceptable hematologic DLEs at the lowest topotecan dose (0.75 mg/m 2 /day×3 days). The reverse sequence was feasible at 1.25 mg/m 2 /day×3 days, with only 1/15 patients experiencing a DLE within 4 cycles, and 14/15 patients were able to receive 4 subsequent cycles of carboplatin–paclitaxel. The extended reverse sequence was associated with excessive DLEs at 1.00 mg/m 2 /day×5 days. Prophylactic hematopoietic growth factors were not required. Conclusion. Higher doses of topotecan could be safely administered with reduced toxicity over multiple cycles using the reverse sequence, which was selected for phase III evaluation. The relative efficacy of the forward and reverse sequence is unknown.

Objectives The current standard of chemotherapy for previously untreated patients with stage III/IV ovarian cancer who have undergone optimal or suboptimal cytoreductive surgery leaves room for improvement in terms of response rate and both progression-free and overall survival. Gynecologic Oncology Group (GOG) 182-ICON5 is a five-arm international collaborative study designed to improve on the efficacy of standard platinum/taxane therapy by incorporating newer cytotoxic agents in sequential doublet and triplet combinations. Methods The evolution of a standard regimen for treating advanced ovarian cancer is reviewed, and the reasons for selecting carboplatin and paclitaxel for the control arm of the study are presented. Among the newer agents available for the experimental treatment arms, three stood out—gemcitabine, polyethylene-glycol (PEG)–liposomal doxorubicin, and topotecan—based on evidence of their activity demonstrated in previous phase I and II trials and, with appropriate dosage modifications, manageable toxicity when used in combination with platinum. Results GOG 182-ICON5 is now in its second year of accrual. Patient recruitment, which is anticipated to grow to between 3400 and 4000 patients by the time the study is closed, is meeting expectations, and no problems have been encountered, except for the initial slow pace of recruitment outside of the United States. Conclusions Combination chemotherapy using newer cytotoxic agents with demonstrated activity in treating advanced-stage ovarian cancer and the ability to enhance platinum-based therapies appears to offer hope of prolonging life and reducing mortality from this disease.

Objectives. Acridine compounds are believed to exhibit anti-cancer cytotoxic effects because of interactions with both DNA and RNA. Pyrazoloacridine (PZA) (NSC No. 366140) is a 9-methoxyacridine compound that has demonstrated activity in some patients with solid tumors. The Gynecologic Oncology Group (GOG) performed a phase II trial of PZA to determine the response rate of this agent in patients with recurrent platinum-sensitive ovarian cancer. Methods. Patients with recurrent ovarian cancer who experienced a progression-free interval of greater than 6 months after response to platinum-based chemotherapy are defined as platinum sensitive by the GOG and were eligible for this trial. PZA was administered at a dose of 750 mg/m 2 intravenously over 3 h every 3 weeks. Results. Among 42 evaluable patients, there was 1 (2.4%) complete response and 9 (21.5%) partial responses, including 1 patient who had a partial response after 10 courses of treatment. The major toxicity was neutropenia; severe thrombocytopenia was infrequent. Conclusion. PZA demonstrates moderate activity in this chemotherapy-sensitive population, with manageable hematologic toxicity. Due to its unique mechanism of action and preclinical activity against hypoxic and noncycling cells, PZA should be considered for evaluation in combination with other active agents.

Purpose. The activity and toxicity of topotecan were evaluated in a multicenter Phase II study for patients with previously treated squamous cell carcinoma of the uterine cervix. Patients and methods. Histologic confirmation of the primary diagnosis was required, as well as adequate performance status and vital organ function and the presence of measurable disease. Patients were allowed one prior regimen of systemic therapy, usually platinum-based. A two-stage accrual design was utilized with early stopping criteria and monitoring of toxicity. Topotecan was administered at 1.5 mg/m 2 per day for 5 consecutive days on a 21-day cycle with modifications based on hematologic toxicity. Results. Forty-five patients were entered. Two patients were ineligible (incorrect tumor type) and 2 were inevaluable (never received therapy). One additional patient was not evaluable for response (nonmeasurable disease). A median of 2 cycles was administered to each patient (range: 1–17 cycles) with grade 4 neutropenia in 68% and grade 4 thrombocytopenia in 39% of patients, but without treatment-related deaths. Nonhematologic toxicity was generally mild and not dose-limiting. The overall (complete and partial) response rate among evaluable patients with measurable disease was 12.5% with stable disease in an additional 37.5%. Median progression-free survival was 2.1 months. Conclusions. As a single agent topotecan shows modest antitumor activity, with manageable hematologic and nonhematologic toxicity, in patients with previously treated squamous cell carcinoma of the cervix. Further evaluation in chemotherapy-naive patients or in combination with cisplatin and/or radiation may be indicated.