Adding immunotherapy to first-line treatment of advanced and metastatic endometrial cancer.

BACKGROUND: Immunotherapy has transformed the endometrial cancer treatment landscape, particularly for those exhibiting mismatch repair deficiency [MMRd/microsatellite instability-hypermutated (MSI-H)]. A growing body of evidence supports the integration of immunotherapy with chemotherapy as a first-line treatment strategy. Recently, findings from ongoing trials such as RUBY (NCT03981796), NRG-GY018 (NCT03914612), AtTEnd (NCT03603184), and DUO-E (NCT04269200) have been disclosed. MATERIALS AND METHODS: This paper constitutes a review and meta-analysis of phase III trials investigating the role of immunotherapy in the first-line setting for advanced or recurrent endometrial cancer. RESULTS: The pooled data from 2320 patients across these trials substantiate the adoption of chemotherapy alongside immunotherapy, revealing a significant improvement in progression-free survival compared to chemotherapy alone [hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.62-0.79] across all patient groups. Progression-free survival benefits are more pronounced in MMRd/MSI-H tumors (n = 563; HR 0.33, 95% CI 0.23-0.43). This benefit, albeit less robust, persists in the MMR-proficient/microsatellite stable group (n = 1757; HR 0.74, 95% CI 0.60-0.91). Pooled data further indicate that chemotherapy plus immunotherapy enhances overall survival compared to chemotherapy alone in all patients (HR 0.75, 95% CI 0.63-0.89). However, overall survival data maturity remains low. CONCLUSIONS: The incorporation of immunotherapy into the initial treatment for advanced and metastatic endometrial cancer brings about a substantial improvement in oncologic outcomes, especially within the MMRd/MSI-H subset. This specific subgroup is currently a focal point of investigation for evaluating the potential of chemotherapy-free regimens. Ongoing exploratory analyses aim to identify non-responding patients eligible for inclusion in clinical trials.

A phase II trial of bevacizumab and rucaparib in recurrent carcinoma of the cervix or endometrium.

OBJECTIVE: The aim of this study was to examine the tolerability and efficacy of combination bevacizumab rucaparib therapy in patients with recurrent cervical or endometrial cancer. PATIENTS & METHODS: Thirty-three patients with recurrent cervical or endometrial cancer were enrolled. Patients were required to have tumor progression after first line treatment for metastatic, or recurrent disease. Rucaparib was given at 600 mg BID twice daily for each 21-day cycle. Bevacizumab was given at 15 mg/kg on day 1 of each 21-day cycle. The primary endpoint was efficacy as determined by objective response rate or 6-month progression free survival. RESULTS: Of the 33 patients enrolled, 28 were evaluable. Patients with endometrial cancer had a response rate of 17% while patients with cervical cancer had a response rate of 14%. Median progression free survival was 3.8 months (95% C·I 2.5 to 5.7 months), and median overall survival was 10.1 months (95% C·I 7.0 to 15.1 months). Patients with ARID1A mutations displayed a better response rate (33%) and 6-month progression free survival (PFS6) rate (67%) than the entire study population. Observed toxicity was similar to that of previous studies with bevacizumab and rucaparib. CONCLUSIONS: The combination of bevacizumab with rucaparib did not show significantly increased anti-tumor activity in all patients with recurrent cervical or endometrial cancer. However, patients with ARID1A mutations had a higher response rate and PFS6 suggesting this subgroup may benefit from the combination of bevacizumab and rucaparib. Further study is needed to confirm this observation. No new safety signals were seen.

Phase III, randomized trial of mirvetuximab soravtansine versus chemotherapy in patients with platinum-resistant ovarian cancer: primary analysis of FORWARD I.

BACKGROUND: Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate comprising a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. The randomized, open-label, phase III study FORWARD I compared MIRV and investigator's choice chemotherapy in patients with platinum-resistant epithelial ovarian cancer (EOC). PATIENTS AND METHODS: Eligible patients with 1-3 prior lines of therapy and whose tumors were positive for FRα expression were randomly assigned, in a 2 : 1 ratio, to receive MIRV (6 mg/kg, adjusted ideal body weight) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary endpoint was progression-free survival [PFS, Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, blinded independent central review] in the intention-to-treat (ITT) population and in the prespecified FRα high population. RESULTS: A total of 366 patients were randomized; 243 received MIRV and 109 received chemotherapy. The primary endpoint, PFS, did not reach statistical significance in either the ITT [hazard ratio (HR), 0.98, P = 0.897] or the FRα high population (HR, 0.69, P = 0.049). Superior outcomes for MIRV over chemotherapy were observed in all secondary endpoints in the FRα high population including improved objective response rate (24% versus 10%), CA-125 responses (53% versus 25%), and patient-reported outcomes (27% versus 13%). Fewer treatment-related grade 3 or higher adverse events (25.1% versus 44.0%), and fewer events leading to dose reduction (19.8% versus 30.3%) and treatment discontinuation (4.5% versus 8.3%) were seen with MIRV compared with chemotherapy. CONCLUSIONS: In patients with platinum-resistant EOC, MIRV did not result in a significant improvement in PFS compared with chemotherapy. Secondary endpoints consistently favored MIRV, particularly in patients with high FRα expression. MIRV showed a differentiated and more manageable safety profile than chemotherapy.

A phase Ib/II and pharmacokinetic study of EP0057 (formerly CRLX101) in combination with weekly paclitaxel in patients with recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

BACKGROUND: EP0057 (formerly CRLX101) is an investigational nanoparticle-drug conjugate (NDC) of a cyclodextrin-based polymer backbone plus camptothecin, a topoisomerase-1 inhibitor. Prior studies showed efficacy in recurrent or persistent, epithelial ovarian, fallopian tube or primary peritoneal cancer (EOC). METHODS: This phase Ib/2 trial assessed safety and efficacy of EP0057 Q2W plus weekly paclitaxel in patients with EOC. The recommended phase 2 dose (RP2D) was identified using a 3+3 design. The single-arm phase 2 assessed overall response (ORR) per RECIST 1.1 in patients previously treated with bevacizumab. Secondary objectives included progression free survival (PFS) and duration of response. RESULTS: The RP2D was established as 15 mg/m2 EP0057 Q2W plus 80 mg/m2 paclitaxel administered 3 weeks on/1 week off. Nine patients enrolled on phase 1b, with no DLTs; 21 additional patients enrolled on phase 2. All completed >1 cycle. Median age was 62 (44-76) years, 57% ≥3 prior therapies. For the primary analysis, 6/19 patients with prior bevacizumab had confirmed responses (ORR=31.6% (95% CI: 15.4% to 54.0%)) including one complete response (CR). Median PFS was 5.4 months. Most common grade 3/4 adverse events attributed to treatment were decreased neutrophil count (13, 43%) and anemia (3, 10%). CONCLUSIONS: Although the observed ORR was not statistically better than the historical control rate, EP0057 remains an interesting option for treatment of recurrent EOC. EP0057 exhibits high plasma drug retention, slow clearance, and controlled slow release of CPT from the polymer when administered alone and with paclitaxel. (NCT02389985) 242 words.

The forefront of ovarian cancer therapy: update on PARP inhibitors.

BACKGROUND: In recurrent ovarian cancer, poly(ADP-ribose) polymerase (PARP)-inhibiting agents have transformed the treatment of platinum-sensitive disease. New data support use of PARP inhibitors earlier in the treatment algorithm. DESIGN: We review results from recent phase III trials evaluating PARP inhibitors as treatment and/or maintenance therapy for patients with newly diagnosed ovarian cancer. We discuss the efficacy and safety of these agents in the all-comer and biomarker-selected populations studied in clinical trials, and compare the strengths and limitations of the various trial designs. We also consider priorities for future research, with a particular focus on patient selection and future regimens for populations with high unmet need. RESULTS: Four phase III trials (SOLO-1, PAOLA-1/ENGOT-OV25, PRIMA/ENGOT-OV26 and VELIA/GOG-3005) demonstrated remarkable improvements in progression-free survival with PARP inhibitor therapy (olaparib, niraparib or veliparib) for newly diagnosed ovarian cancer. Differences in trial design (treatment and/or maintenance setting; single agent or combination; bevacizumab or no bevacizumab), patient selection (surgical outcome, biomarker eligibility, prognosis) and primary analysis population (intention-to-treat, BRCA mutated or homologous recombination deficiency positive) affect the conclusions that can be drawn from these trials. Overall survival data are pending and there is limited experience regarding long-term safety. CONCLUSIONS: PARP inhibitors play a pivotal role in the management of newly diagnosed ovarian cancer, which will affect subsequent treatment choices. Refinement of testing for patient selection and identification of regimens to treat populations that appear to benefit less from PARP inhibitors are a priority.

A randomized phase II evaluation of weekly gemcitabine plus pazopanib versus weekly gemcitabine alone in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma.

OBJECTIVE: Angiogenesis inhibition is a valuable strategy for ovarian cancer (EOC). Pazopanib (paz) is a potent small molecular inhibitor of VEGF-1, -2, -3, PDGFR, c-kit, and has 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 EOC. METHODS: An open-label, randomized, multi-site, phase 2 trial was conducted (NCT01610206) including patients with platinum resistant or sensitive disease, ≤ 3 prior lines of chemotherapy, and measurable/evaluable disease. Patients were randomly assigned to weekly gem 1000 mg/m2 on days 1 and 8 of a 21 day cycle, with or without paz 800 mg QD, stratified by platinum sensitivity and number of prior lines (1 vs 2 or 3). The primary endpoint was PFS. RESULTS: 148 patients were enrolled 2012-2017. Median age was 63 years (30-82); 60% were platinum resistant; median surveillance was 13 months (0.4-54 months). Median PFS was 5.3 (95% CI, 4.2-5.8) vs 2.9 months (95% CI, 2.1-4.1) in the gem arm. The PFS effect was most pronounced in the platinum resistant group (5.32 vs 2.33 months Tarone-Ware p < 0.001). There was no difference in OS. Overall RR (PR 20% vs 11%, Chi-squre p = 0.02) and DCR (80% vs 60%, Chi-square p < 0.001) were higher in the combination. High grade AEs in the combination arm included ≥ Grade 3: hypertension (15%), neutropenia (35%), and thrombocytopenia (12%). CONCLUSIONS: The addition of paz to gem enhanced anti-tumor activity; those with platinum-resistant disease derived the most benefit from combination therapy, even in the setting of receiving prior bevacizumab.

Treatment of patients with recurrent epithelial ovarian cancer for whom platinum is still an option.

BACKGROUND: Ovarian cancer remains the most deadly gynecologic cancer with the majority of patients relapsing within 3 years of diagnosis. Traditional treatment paradigms linked to platinum sensitivity or resistance are currently being questioned in the setting of new diagnostic methods and treatment options. DESIGN: Authors carried out review of the literature on key topics in treatment of recurrent epithelial ovarian cancer (EOC) when platinum is still an option; including secondary surgical cytoreduction, chemotherapy, novel treatment options, and maintenance therapy. A treatment algorithm is proposed. RESULTS: Molecular characterization of EOC is critical to help guide treatment decisions. The role of secondary cytoreductive surgery is currently being evaluated with results from Gynecologic Oncology Group (GOG) 213 and anticipated results from DESKTOP III clinical trials. Chemotherapy backbone has remained relatively unchanged but utilizing non-platinum-based regimens is under investigation. In addition, maintenance therapy with anti-angiogenic therapy and Poly (ADP-ribose) Polymerase (PARP) inhibitors has emerged as the standard of care. Novel combinations, including immunotherapy and anti-angiogenesis agents, may further change the current landscape. CONCLUSIONS: The treatment of recurrent EOC is rapidly changing. Clinical trial design will need to continue to evolve as many novel therapies move to the upfront setting. Ultimately, the treatment of patients with recurrent EOC must incorporate individual patient and tumor factors.

Measurements of adiposity as prognostic biomarkers for survival with anti-angiogenic treatment in epithelial ovarian cancer: An NRG Oncology/Gynecologic Oncology Group ancillary data analysis of GOG 218.

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.

Anti-NaPi2b antibody-drug conjugate lifastuzumab vedotin (DNIB0600A) compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer in a randomized, open-label, phase II study.

Background: Lifastuzumab vedotin (LIFA) is a humanized anti-NaPi2b monoclonal antibody conjugated to a potent antimitotic agent, monomethyl auristatin E, which inhibits cell division by blocking the polymerization of tubulin. This study is the first to compare an antibody-drug conjugate (ADC) to standard-of-care in ovarian cancer (OC) patients. Patients and methods: Platinum-resistant OC patients were randomized to receive LIFA [2.4 mg/kg, intravenously, every 3 weeks (Q3W)] or pegylated liposomal doxorubicin (PLD) (40 mg/m2, intravenously, Q4W). NaPi2b expression and serum CA-125 and HE4 levels were assessed. The primary end point was progression-free survival (PFS) in intent-to-treat (ITT) and NaPi2b-high patients. Results: Ninety-five patients were randomized (47 LIFA; 48 PLD). The stratified PFS hazard ratio was 0.78 [95% confidence interval (95% CI), 0.46-1.31; P = 0.34] with a median PFS of 5.3 versus 3.1 months (LIFA versus PLD arm, respectively) in the ITT population, and 0.71 (95% CI, 0.40-1.26; P = 0.24) with a median PFS of 5.3 months versus 3.4 months (LIFA versus PLD arm, respectively) in NaPi2b-high patients. The objective response rate was 34% (95% CI, 22% to 49%, LIFA) versus 15% (95% CI, 7% to 28%, PLD) in the ITT population (P = 0.03), and 36% (95% CI, 22% to 52%, LIFA) versus 14% (95% CI, 6% to 27%, PLD) in NaPi2b-high patients (P = 0.02). Toxicities included grade ≥3 adverse events (AEs) (46% LIFA; 51% PLD), serious AEs (30% both arms), and AEs leading to discontinuation of drug (9% LIFA; 8% PLD). Five (11%) LIFA versus 2 (4%) PLD patients had grade ≥2 neuropathy. Conclusion: LIFA Q3W was well tolerated and improved objective response rate with a modest, nonstatistically significant improvement of PFS compared with PLD in platinum-resistant OC. While the response rate for the monomethyl auristatin E-containing ADC was promising, response durations were relatively short, thereby highlighting the importance of evaluating both response rates and duration of response when evaluating ADCs in OC. Clinical trials.gov: NCT01991210.

Phase I study of the checkpoint kinase 1 inhibitor GDC-0575 in combination with gemcitabine in patients with refractory solid tumors.

BACKGROUND: Checkpoint kinase 1 (Chk1) inhibition following chemotherapy-elicited DNA damage overrides cell cycle arrest and induces mitotic catastrophe and cell death. GDC-0575 is a highly-selective oral small-molecule Chk1 inhibitor that results in tumor shrinkage and growth delay in xenograft models. We evaluated the safety, tolerability, and pharmacokinetic properties of GDC-0575 alone and in combination with gemcitabine. Antitumor activity and Chk1 pathway modulation were assessed. PATIENTS AND METHODS: In this phase I open-label study, in the dose escalation stage, patients were enrolled in a GDC-0575 monotherapy Arm (1) or GDC-0575 combination with gemcitabine Arm (2) to determine the maximum tolerated dose. Patients in arm 2 received either i.v. gemcitabine 1000 mg/m2 (arm 2a) or 500 mg/m2 (arm 2b), followed by GDC-0575 (45 or 80 mg, respectively, as RP2D). Stage II enrolled disease-specific cohorts. RESULTS: Of 102 patients treated, 70% were female, the median age was 59 years (range 27-85), and 47% were Eastern Cooperative Oncology Group PS 0. The most common tumor type was breast (37%). The most frequent adverse events (all grades) related to GDC-0575 and/or gemcitabine were neutropenia (68%), anemia (48%), nausea (43%), fatigue (42%), and thrombocytopenia (35%). Maximum concentrations of GDC-0575 were achieved within 2 hours of dosing, and half-life was ∼23 hours. No pharmacokinetic drug-drug interaction was observed between GDC-0575 and gemcitabine. Among patients treated with GDC-0575 and gemcitabine, there were four confirmed partial responses, three occurring in patients with tumors harboring TP53 mutation. Pharmacodynamic data were consistent with GDC-0575 inhibition of gemcitabine-induced expression of pCDK1/2. CONCLUSION: GDC-0575 can be safely administered as a monotherapy and in combination with gemcitabine; however, overall tolerability with gemcitabine was modest. Hematological toxicities were frequent but manageable. Preliminary antitumor activity was observed but limited to a small number of patients with a variety of refractory solid tumors treated with GDC-0575 and gemcitabine. CLINICAL TRIAL NUMBER: NCT01564251.

Fifth Ovarian Cancer Consensus Conference: individualized therapy and patient factors.

This manuscript reports the consensus statements regarding the design and conduct of clinical trials in patients with newly diagnosed and recurrent epithelial ovarian cancer (EOC), following deliberation at the Fifth Ovarian Cancer Consensus Conference (OCCC), held in Tokyo in November 2015. Three important questions were identified for discussion prior to the meeting and achieved consensus during the meeting: (i) What are the most important factors to be evaluated prior to initial therapy? (ii) What are the most important factors to be evaluated specifically in recurrent disease? (iii) Are there specific considerations for special patient subpopulations? In addition, we report a list of important unmet needs compiled during the consensus process, which is intended to guide future research initiatives.

Phase I study of safety and pharmacokinetics of the anti-MUC16 antibody-drug conjugate DMUC5754A in patients with platinum-resistant ovarian cancer or unresectable pancreatic cancer.

BACKGROUND: MUC16 is a tumor-specific antigen overexpressed in ovarian (OC) and pancreatic (PC) cancers. The antibody-drug conjugate (ADC), DMUC5754A, contains the humanized anti-MUC16 monoclonal antibody conjugated to the microtubule-disrupting agent, monomethyl auristatin E (MMAE). PATIENTS AND METHODS: This phase I study evaluated safety, pharmacokinetics (PK), and pharmacodynamics of DMUC5754A given every 3 weeks (Q3W, 0.3-3.2 mg/kg) or weekly (Q1W, 0.8-1.6 mg/kg) to patients with advanced recurrent platinum-resistant OC or unresectable PC. Biomarker studies were also undertaken. RESULTS: Patients (66 OC, 11 PC) were treated with DMUC5754A (54 Q3W, 23 Q1W). Common related adverse events (AEs) in >20% of patients (all grades) over all dose levels were fatigue, peripheral neuropathy, nausea, decreased appetite, vomiting, diarrhea, alopecia, and pyrexia in Q3W patents, and nausea, vomiting, anemia, fatigue, neutropenia, alopecia, decreased appetite, diarrhea, and hypomagnesemia in Q1W patients. Grade ≥3-related AE in ≥5% of patients included neutropenia (9%) and fatigue (7%) in Q3W patients, and neutropenia (17%), diarrhea (9%), and hyponatremia (9%) in Q1W patients. Plasma antibody-conjugated MMAE (acMMAE) and serum total antibody exhibited non-linear PK across tested doses. Minimal accumulation of acMMAE, total antibody, or unconjugated MMAE was observed. Confirmed responses (1 CR, 6 PRs) occurred in OC patients whose tumors were MUC16-positive by IHC (2+ or 3+). Two OC patients had unconfirmed PRs; six OC patients had stable disease lasting >6 months. For CA125, a cut-off of ≥70% reduction was more suitable for monitoring treatment response due to the binding and clearance of serum CA125 by MUC16 ADC. We identified circulating HE4 as a potential novel surrogate biomarker for monitoring treatment response of MUC16 ADC and other anti-MUC16 therapies in OC. CONCLUSIONS: DMUC5754A has an acceptable safety profile and evidence of anti-tumor activity in patients with MUC16-expressing tumors. Objective responses were only observed in MUC16-high patients, although prospective validation is required. CLINICAL TRIAL NUMBER: NCT01335958.

The role of single nucleotide polymorphisms of the ERCC1 and MMS19 genes in predicting platinum-sensitivity, progression-free and overall survival in advanced epithelial ovarian cancer.

OBJECTIVE: This study aims to assess the role of polymorphisms in DNA repair genes, excision repair cross-complementation group 1 (ERCC1) and methyl-methanesulfonate sensitivity 19 (MMS19), in tumor response to platinum-based chemotherapy and survival in advanced epithelial ovarian cancer (EOC). METHODS: Single nucleotide polymorphism (SNP) analysis was performed on the paraffin-embedded tumor tissue of women with advanced EOC, treated with platinum-based chemotherapy at the University of Oklahoma Health Sciences Center. Polymorphisms from two ERCC1 (codon-118 and C8092A) and three MMS19 (rs2211243, rs2236575 and rs872106) gene loci were evaluated by real time PCR Allelic Discrimination Assay. RESULTS: Genotyping was performed in 107 patients, 45 platinum-sensitive and 62 platinum-resistant. ERCC1, codon-118 and C8092A genotyping was evaluable in 98 and 106 patients respectively and in all 107 patients for MMS19 polymorphisms. No differences were observed in genotype between platinum-sensitive and platinum-resistant patients. Polymorphisms in the ERCC1, codon-118 and MMS19 genes did not correlate with overall survival (OS), although a trend toward improved progression free survival (PFS) was observed in patients expressing the minor (GG) alleles of the rs872106 MMS19 gene. Women homozygous for the ERCC1-C8092A minor (AA) alleles had a significant increase in PFS compared to AC and CC patients and both AA and AC genotypes conferred improved survival over the major (CC) genotype. CONCLUSIONS: Polymorphisms in ERCC1, codon-118 and MMS19 genes are not associated with clinical response to platinum or survival. The ERCC1-C8092A genotypes containing an "A" allele were associated with significant improvement in PFS and OS strengthening the value of this specific genotype in survival.

Do uterine risk factors or lymph node metastasis more significantly affect recurrence in patients with endometrioid adenocarcinoma?

OBJECTIVES: Controversy continues over the importance of lymph node (LN) status in treating and predicting recurrence in endometrial cancer. Several predictive models are available which use uterine factors to stratify risk groups. Our objective was to determine how LN status affects recurrence and survival compared to uterine factors alone. METHODS: A retrospective review was performed of patients undergoing complete surgical staging for clinical stage 1 endometrioid adenocarcinoma of the uterus. Patients were assessed based on PORTEC 1 high intermediate risk (H-IR) criteria (2 factors : age>60, grade 3, >50% DOI), GOG-99 H-IR criteria (age >70+1 factor, age 50-70+2 factors, any age +3 factors: grade 2 or 3, LVSI, >50% DOI), and PORTEC 2 criteria. Rates of nodal involvement, recurrence rates, PFS, and OS were compared. RESULTS: We identified 352 clinical stage I patients with positive LN in 24% (87). 175 patients met PORTEC 1 eligibility and 66 met H-IR criteria. Rates of LN positivity were similar among groups (18.4% vs 19.7%, p=0.83) but recurrence rates were dissimilar (7.4% vs 27.3%, p=0.0004). Only 93 met PORTEC 2 criteria for treatment with no association between LN status, recurrence, and eligibility. 188 patients met H-IR eligibility criteria for GOG-99 with LN positive and recurrence rates higher in the H-IR group compared to GOG-99 eligible (34.6% vs 16.3%, p=0.0004, 28.3% vs. 10.6%, p=0.0002). CONCLUSIONS: Patients with H-IR disease based on uterine characteristics alone have substantial risk of nodal involvement. Knowledge of LN status may better define risk, prognosis, and postoperative treatment.

Malignant melanoma of the vulva: an extension of cutaneous melanoma?

OBJECTIVE: To determine the prognostic significance of the 2002 revisions of the American Joint Committee on Cancer (AJCC) Staging System for cutaneous melanoma in melanoma of the vulva and review the current surgical utilized for treatment of this neoplasm. METHODS: Demographic, surgical and outcomes data were obtained from the records of vulvar melanoma patients treated from 1990 to 2006 at five academic medical centers. The 2002 modifications of the AJCC staging system for cutaneous melanoma, Breslow thickness and Clark level, were applied to all subjects. Kaplan-Meier Modeling and Linear Regression analysis were utilized for data analysis. Statistics were performed with SAS v 9.1. RESULTS: Seventy-seven patients were identified with a median age of 62 years. 73% had Stage I/II disease. Surgical radicality did not impact recurrence rates or survival. Breslow thickness was associated with recurrence (p=0.002) but not survival. Only the 2002 modified AJCC staging criteria were predictive of overall survival (p=0.006) in patients with malignant melanoma of the vulva. CONCLUSIONS: In the largest multi-site series of vulvar melanoma, the AJCC-2002 staging system for cutaneous malignant melanoma appears to be applicable to primary vulvar melanoma. Moreover, surgical radicality was associated with significant morbidity but not with improvement in survival. Utilization of standard operative staging and resection principles in cutaneous melanoma should be used for all vulvar melanoma patients. Moreover, these patients should also be considered for enrollment in cutaneous melanoma clinical trials.