Phase I and Randomized Phase II Study of Ruxolitinib With Frontline Neoadjuvant Therapy in Advanced Ovarian Cancer: An NRG Oncology Group Study.

PURPOSE: The interleukin-6/Janus kinase (JAK)/signal transducers and activators of transcription 3 axis is a reported driver of chemotherapy resistance. We hypothesized that adding the JAK1/2 inhibitor ruxolitinib to standard chemotherapy would be tolerable and improve progression-free survival (PFS) in patients with ovarian cancer in the upfront setting. MATERIALS AND METHODS: Patients with ovarian/fallopian tube/primary peritoneal carcinoma recommended for neoadjuvant chemotherapy were eligible. In phase I, treatment was initiated with dose-dense paclitaxel (P) 70 mg/m2 once daily on days 1, 8, and 15; carboplatin AUC 5 intravenously day 1; and ruxolitinib 15 mg orally (PO) twice a day, every 21 days (dose level 1). Interval debulking surgery (IDS) was required after cycle 3. Patients then received three additional cycles of chemotherapy/ruxolitinib, followed by maintenance ruxolitinib. In the randomized phase II, patients were randomly assigned to paclitaxel/carboplatin with or without ruxolitinib at 15 mg PO twice a day for three cycles, IDS, followed by another three cycles of chemotherapy/ruxolitinib, without further maintenance ruxolitinib. The primary phase II end point was PFS. RESULTS: Seventeen patients were enrolled in phase I. The maximum tolerated dose and recommended phase II dose were established to be dose level 1. One hundred thirty patients were enrolled in phase II with a median follow-up of 24 months. The regimen was well tolerated, with a trend toward higher grade 3 to 4 anemia (64% v 27%), grade 3 to 4 neutropenia (53% v 37%), and thromboembolic events (12.6% v 2.4%) in the experimental arm. In the randomized phase II, the median PFS in the reference arm was 11.6 versus 14.6 in the experimental, hazard ratio (HR) for PFS was 0.702 (log-rank P = .059). The overall survival HR was 0.785 (P = .24). CONCLUSION: Ruxolitinib 15 mg PO twice a day was well tolerated with acceptable toxicity in combination with paclitaxel/carboplatin chemotherapy. The primary end point of prolongation of PFS was achieved in the experimental arm, warranting further investigation.

Genomic characterization of vulvar squamous cell carcinoma reveals differential gene expression based on clinical outcome.

OBJECTIVE: The greatest challenge in the management of vulvar squamous cell carcinoma (VSCC) is treatment of recurrent disease where options for surgery and radiation have been exhausted, or treatment of disease where distant metastasis is present. Identification of mutations differentially expressed between tumor from patients who died of aggressive disease and tumor from patients with an indolent course could reveal novel prognostic indicators and guide development of therapeutic drugs. METHODS: From 202 consecutive patients with VSCC, patients who recurred and died of disease (group A) were identified and matched by age, tumor size, depth of invasion and nodal status with those whose disease did not recur (group B). Tumors from 21 patients were subjected to whole exome sequencing of DNA and RNA, immunohistochemistry (IHC) antibodies of PD-L1 and P16, and in-situ hybridization (ISH) for high-risk HPV. RESULTS: Analysis of DNA and RNA revealed six genes that were strongly differentially expressed between group A and B: TGM3, ACVR2A, ROS1, NFEL2, CCND1 and BCL6. Clinically relevant DNA mutations were significantly greater in group A versus B: 7 vs 2.3 mutations per patient. The most common genomic alterations were mutations in TP53 and the promoter region of TERT. Other common genomic events include alterations of FAT1, CDKN2A, PIK3CA, CCND1, and LRP1B. All samples were MSI stable and tumor mutational burden (TMB) was similar in groups A and B. Most VSCC specimens (81%) were positive for PD-L1. CONCLUSIONS: ACVR2A and TGM3 are significantly under-expressed in tumors with poor outcome, suggesting they may play a role in tumor suppression. Clinical outcome of VSCC appears independent of MSI, TMB, or PD-L1 status.

Impact of Screening for Sexual Trauma in a Gynecologic Oncology Setting.

OBJECTIVES: Sexual trauma poses a significant concern and is associated with heightened stress, negative health repercussions, and adverse economic effects. A history of abuse may increase a woman's risk of developing cancer, in particular cervical cancer. We analyzed the impact of screening for sexual abuse in a gynecologic oncology population. METHODS: Patients were screened for sexual trauma in a gynecologic oncology clinic over 5 and a half years (April 1, 2011, to September 30, 2016) in this cohort study. The screening questions were selected by behavioral oncology physicians and integrated into the gynecologic history component of the new patient assessment. Patients who screened positive for a history of sexual abuse or intimate partner violence were offered a behavioral oncology referral. Providers were also questioned about the effect of screening on their practice. RESULTS: Of the 1,423 consecutive patients screened for sexual trauma, a total of 164 patients (12%) disclosed a history of sexual abuse. Of the 133 patients who specified their age at the sexual trauma, the majority (107 [80%]) responded that they were a young child or early teen. Most patients (92%) declined counseling. Among individuals presenting with cancer, the distribution of cancer type was statistically different between those patients with and without a sexual trauma history (p = 0.0001). CONCLUSION: Screening for sexual trauma in a gynecologic oncologic population serves as a valuable opportunity to uncover a history of abuse that may increase a woman's susceptibility to cancer. This study demonstrates that screening for sexual abuse in a gynecologic oncology setting may be integrated into new patient interviews with minimal disruption. Identification of an undisclosed sexual trauma history allows for an opportunity to offer counseling and minimize the emotional distress that may be precipitated by treatment and exams.

Pembrolizumab in Recurrent Squamous Cell Carcinoma of the Vulva: Case Report and Review of the Literature.

Advanced vulvar cancer is associated with a very poor prognosis. Surgical resection is the mainstay of treatment, with radiation indicated for areas at high risk for recurrence. When surgical and radiation options have been exhausted, the effectiveness of systemic chemotherapy is poor. No biologic or targeted agents have been approved for the management of advanced or recurrent vulvar cancer. Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), has been successfully used as a target of tumor immune therapy in small cell lung cancer and melanoma. We present the first case in the literature of a patient with recurrent vulvar cancer who was treated successfully with pembrolizumab. Caris next-generation testing revealed a PD-L1 and PD-1 mutation (PD-L1 positive, 2+, 100%). She attained a complete clinical remission after 2 cycles, and a CT scan after 6 cycles revealed a significant response by RECIST criteria. After completing 10 cycles, treatment was stopped due to complications of severe malnutrition related to narcotic abuse. A CT scan 10 weeks after the final treatment revealed no adenopathy. Pembrolizumab is a safe and effective chemotherapeutic agent to treat recurrent vulvar carcinoma.

Laparoscopic surgery for endometrial cancer: increasing body mass index does not impact postoperative complications.

OBJECTIVE: To determine the effect of body mass index on postoperative complications and the performance of lymph node dissection in women undergoing laparoscopy or laparotomy for endometrial cancer. METHODS: Retrospective chart review of all patients undergoing surgery for endometrial cancer between 8/2004 and 12/2008. Complications graded and analyzed using Common Toxicity Criteria for Adverse Events ver. 4.03 classification. RESULTS: 168 women underwent surgery: laparoscopy n=65, laparotomy n=103. Overall median body mass index 36.2 (range, 18.1 to 72.7) with similar distributions for age, body mass index and performance of lymph node dissection between groups. Following laparoscopy vs. laparotomy the percent rate of overall complications 53.8:73.8 (p=0.01), grade ≥3 complications 9.2:34.0 (p<0.01), ≥3 wound complications 3.1:22.3 (p<0.01) and ≥3 wound infection 3.1:20.4 (p=0.01) were significantly lower after laparoscopy. In a logistic model there was no effect of body mass index (≥36 and<36) on complications after laparoscopy in contrast to laparotomy. Para-aortic lymph node dissection was performed by laparoscopy 19/65 (29%): by laparotomy 34/103 (33%) p=0.61 and pelvic lymph node dissection by laparoscopy 21/65 (32.3%): by laparotomy 46/103 (44.7%) p=0.11. Logistic regression analysis revealed that for patients undergoing laparoscopy for stage I disease there was an inverse relationship between the performance of both para-aortic lymph node dissection and pelvic lymph node dissection and increasing body mass index (p=0.03 and p<0.01 respectively) in contrast to the laparotomy group where there was a trend only (p=0.09 and 0.05). CONCLUSION: For patients undergoing laparoscopy, increasing body mass index did not impact postoperative complications but did influence the decision to perform lymph node dissection.

Oral thalidomide as palliative chemotherapy in women with advanced ovarian cancer.

OBJECTIVE: We prospectively evaluated thalidomide, an oral agent with antiangiogenic and immunomodulatory properties, in patients with recurrent ovarian cancer, comparing the drug to standard intravenous chemotherapy and treatment holiday in terms of both progression-free interval and quality of life. METHODS: Eligible patients had recurrent ovarian or primary peritoneal cancer and had received a minimum of two prior therapeutic regimens. Patients were offered one of three arms: (Arm A) any standard intravenous single-agent chemotherapy; (Arm B) oral thalidomide 200 mg daily; (Arm C) treatment holiday. Computed tomography (CT) scans were performed every two cycles until disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. CA-125 was measured monthly as was quality of life using the Functional Assessment of Cancer Therapy (FACT-O) questionnaire. RESULTS: Forty patients participated: 18 on Arm A; 18 on Arm B; and 4 on Arm C. The groups were comparable in terms of number of prior regimens and cycles of chemotherapy. The progression- free intervals were similar in Arm A and Arm B (3.7 versus 3.8 months). The PR/SD rate was 6.7%/60% for Arm A, and 7.7%/53.8% in Arm B. Of those treated with thalidomide, 53% had a drop in CA-125 greater than 50%, compared to 13% receiving intravenous chemotherapy. FACT-O scores at baseline and throughout treatment were equivalent. CONCLUSION: The oral chemotherapeutic agent thalidomide appears to be comparable in response and quality of life, compared to single agent intravenous chemotherapy, in our population of heavily pretreated patients with ovarian cancer.

Hyperthermic intraperitoneal chemotherapy in conjunction with surgery for the treatment of recurrent ovarian carcinoma.

OBJECTIVES: To review experience of secondary surgical cytoreduction (SSC) with hyperthermic intraperitoneal chemotherapy (IPHC). METHODS: Eligible patients with ovarian cancer in whom pre-operative evaluation indicated that there was a good possibility that disease could be resected to < or = 5 mm underwent surgery followed by intraperitoneal perfusion of cisplatin (100 mg/m2) or mitomycin C (30-40 mg total dose) heated to 41-43 degrees C (105.8-109.4 degrees F) for 90 min. Data for analysis were extracted from retrospective chart review. RESULTS: Eighteen patients underwent surgery and IPHC between 9/02 and 3/05. Characteristics were median age 64 (37-77) years, mean prior laparotomies 1.4 (0-3), mean chemotherapy regimens 3.2 (0-7), mean time from initial therapy to IPHC 30.6 (1-88) months. Original histology: papillary serous 12, poorly differentiated adenocarcinoma 1, serous low malignant potential 2, mucinous 1 and mixed subtypes 2. 13 had recurrent disease and 5 had persistent disease following front-line therapy. 15 received cisplatin and 3 mitomycin C. The mean duration of surgery was 9.8 (5-16) h. The maximum dimension of residual lesions at the end of surgery prior to IPHC was nil (n=11), < or = 2 mm (n=4), < or = 5 mm (n=2) and < or = 10 mm (n=1). Mean time to return of bowel function was 7 (5-20) days and mean time to hospital discharge 11.5 (5-49) days. All patients developed CTEP grade 1 or 2 metabolic or hematologic toxicities. CTEP grade 3 or 4 metabolic toxicity occurred in 72% and a hematologic toxicity in 28%. There was one peri-operative death due to pulmonary embolus. Median progression-free interval was 10 months and median overall survival was 31 months. Improved outcome was significantly related to the size of residual disease prior to IPHC and postoperative chemotherapy. CONCLUSIONS: IPHC is a relatively well-tolerated procedure with the majority of the morbidity being related to associated surgery. When combined with SSC it has the potential to extend quality life in some patients with recurrent ovarian cancer and warrants continued research. Randomized studies are needed earlier in the course of the disease.

The effect of total parenteral nutrition on the survival of terminally ill ovarian cancer patients.

OBJECTIVES: Total parenteral nutrition (TPN) for terminal ovarian cancer patients remains controversial. In this study, we compared survival from time of terminal intestinal obstruction (TIO) diagnosis in patients who received TPN versus those who did not. METHODS: A historical cohort of 55 patients with stage IIIC/IV epithelial ovarian cancer hospitalized for TIO between 1994 and 2002 was studied. All patients were previously treated with paclitaxel/platinum following cytoreductive surgery. Exposure was administration of TPN after TIO. The primary outcome was survival from TIO diagnosis to death. Number of chemotherapy cycles completed after TIO diagnosis, major complications of TPN, and demographics were measured. Survival analysis was performed using Kaplan-Meier methods. RESULTS: The median survival from time of TIO diagnosis was 72 days (range 16-485) for patients receiving TPN and 41.0 days (range 4-133) for those not receiving TPN (P = 0.05), but no difference in survival was observed when adjusting for chemotherapy. Overall survival [median 23 (range 6-67) vs. 35 months (range 8-67), P = 0.03] was shorter for the TPN group. Demographic data were similar in both groups. Patients receiving TPN after obstruction were more likely to undergo concurrent chemotherapy (64 vs. 26%, P = 0.004). One major TPN-related complication was found. CONCLUSIONS: Ovarian cancer patients with TIO receiving TPN had a median survival benefit of 4 weeks. This benefit decreased when patients were treated with concurrent chemotherapy. Issues of cost, quality of life, and human values need to be investigated to assess the full impact of TPN in this patient population.

Elevated body mass index does not increase the risk of palmar-plantar erythrodysesthesia in patients receiving pegylated liposomal doxorubicin.

OBJECTIVES: The dose-limiting toxicity of pegylated liposomal doxorubicin (PLD) is palmar-plantar erythrodysesthesia (PPE). Some physicians are reluctant to use this drug in overweight patients, postulating that larger size increases the likelihood of PPE. We sought to determine whether a correlation exists between body mass index (BMI) and the frequency or severity of skin reactions during PLD chemotherapy. METHODS: The records of all patients receiving PLD chemotherapy for gynecologic malignancy at our institution were reviewed for chemotherapy history, BMI at start of treatment, dose, infusion time, and adverse outcomes. Skin reaction sites, grade, and treatments were recorded. Possible predisposing factors were extracted, as well as the reason for drug discontinuation. RESULTS: Over 7 years, 103 patients were treated with PLD for gynecologic malignancies. 429 cycles were given, and PPE occurred in 36% of patients treated. Of those with PPE, reactions were grades 1, 2, or 3 in 54%, 32%, and 14% of patients, respectively. The BMI of patients with PPE (29.0) was not significantly different from that of patients without PPE (28.8). Analysis using finer subsets of weight also revealed no association. Finally, logistic regression revealed no relationship between BMI and rash grade. CONCLUSIONS: Elevated BMI does not appear to correlate with occurrence of PPE in our population. Of interest, among patients discontinuing PLD due to skin toxicity, 25% had clinical evidence of response. The identification of predisposing risk factors may help guide treatment decisions; however, elevated BMI does not appear to be such a risk factor.

Cross-sensitivity between paclitaxel and docetaxel in a women's cancers program.

PURPOSE: With the use of steroid premedication, the incidence of severe hypersensitivity reactions (S-HSR) to paclitaxel is estimated to be 2%. For those who develop a S-HSR to paclitaxel, docetaxel has been employed as an alternative agent though the presence of cross-sensitivity has not been established. We sought to define the incidence of S-HSR to docetaxel following a paclitaxel S-HSR in an academic women's cancer program. METHODS: Patients treated with either paclitaxel (P) or docetaxel (D) between 11/1999 and 8/2004 were identified through our pharmacy database. Records were reviewed and data collected on those patients who had a S-HSR, defined as symptoms for which drug was discontinued, to P, D, or both. RESULTS: 718 patients received P and 93 received D. 59 received D following treatment with P. The presence of S-HSR for P was 2.2% (16/718 patients) and for D was 9.7% (9/93 patients). 10 patients with S-HSR to P crossed over to D and all nine patients reacting to D had a prior reaction to T for a cross-sensitivity rate of 90% (9/10 patients). CONCLUSIONS: Cross-sensitivity of D after P was 90% at our institution. Given the different vehicles used in P and D, it is likely attributed to the taxane moiety. Caution is required with re-challenge of patients with docetaxel if they have previously reacted to paclitaxel.

Two for good measure: six versus eight cycles of carboplatin and paclitaxel as adjuvant treatment for epithelial ovarian cancer.

INTRODUCTION: Although the standard of care for advanced epithelial ovarian cancer (EOC) is six cycles (6C) of platinum-taxane (PT), there have been no studies on the optimal duration of treatment in the era of adjuvant taxanes. At our center, some women receive eight cycles (8C) of PT, based on physician judgment. We were interested in evaluating the outcomes of women treated with 8C of PT for EOC as compared to a cohort who received 6C. METHODS: We retrospectively identified women with Stage III or IV EOC between 1998 and 2003 who received 6C or 8C of PT. The endpoints were disease-free (DFS) and overall survival (OS). CA-125 response was defined as a decrease in CA-125 of 50% in four serial samples or of 75% over three samples. RESULTS: One hundred and twenty-two women met criteria for inclusion; 84 received 6C, and 38 received 8C. Comparing the cohorts receiving 6C versus 8C, 71% versus 26% were optimally debulked (P < 0.01). 79 patients were evaluable by CA-125 (52 6C/27 8C), and all responded. 88% receiving 6C and 81% receiving 8C normalized their CA-125 at end of treatment (P = 0.20). The proportion with a normal CA-125 at Cycle 2 was 29% versus 12%, respectively (P = 0.15) and, at Cycle 4, was 88% versus 36%, respectively (P < 0.01). DFS was 13 months with 6C and 8 months with 8C (P = 0.01). OS was 31 versus 23.5 months (P = 0.02), respectively. When the survival analysis is restricted to suboptimal debulked patients only, the DFS is 12.5 versus 8 months (P = 0.02), and OS is 32 versus 26.5 months (P = 0.15), respectively. CONCLUSIONS: Two further cycles of PT did not improve DFS or OS for patients with advanced EOC. Patients who do not achieve remission after 6C are unlikely to benefit from additional chemotherapy using the same agents and should be considered for clinical trials involving novel agents with different mechanisms of action.

Adnexal masses in pregnancy: surgery compared with observation.

OBJECTIVE: To estimate whether the delay of surgery impacts the risk of adverse maternal and fetal outcomes in patients diagnosed with an adnexal mass during pregnancy. METHODS: A review was performed of pregnant patients diagnosed with an adnexal mass 5 cm or greater in diameter. Data collected included age, gravity/parity, gestational age at diagnosis, and presenting symptoms. Ultrasound examinations were evaluated for mass size and complexity. Pregnancy outcome, complications, and surgical pathology were reviewed. RESULTS: Between 1990 and 2003, 127,177 deliveries were performed at our institution. An adnexal mass 5 cm in diameter or greater was diagnosed in 63 (0.05%) patients. Pathologic diagnosis was available for 59 (94%) patients. The remaining 4 patients were lost to follow-up and excluded from the analysis. Antepartum surgery was performed in 17 patients (29%): 13 because of ultrasound findings that suggested malignancy and 4 secondary to ovarian torsion. The remaining patients were observed, with surgery performed in the postpartum period or at time of cesarean delivery. The majority of masses were dermoid cysts (42%). Four patients were diagnosed with ovarian cancer (6.8% of masses, 0.0032% of deliveries), and one patient (1.7%) had a tumor of low malignant potential. Antepartum surgery due to ultrasound findings that caused concern was performed on all 5 women diagnosed with a malignancy or borderline tumor, compared with 12 (22%) of the patients with benign tumors (P < .01). CONCLUSION: In select cases, close observation is a reasonable alternative to antepartum surgery in patients with an adnexal mass during pregnancy.

Dyspnea during thalidomide treatment for advanced ovarian cancer.

OBJECTIVE: To detail the dyspnea encountered in women receiving thalidomide as therapy for advanced ovarian cancer. CASE SUMMARIES: Eight of 18 (44%) patients with recurrent ovarian cancer developed dyspnea while receiving thalidomide 200 mg daily as part of a prospective Phase II study. Dyspnea was evaluated with pulse oximetry, chest X-ray and, if indicated, spiral computed tomography scan. Four patients had abnormal chest X-ray findings (1 pleural effusion, 1 pneumonia, 2 mild congestive heart failure), and one of these patients also had a pulmonary embolus. The other 4 patients had no objective test findings to explain their dyspnea. Five patients had resolution of symptoms when thalidomide was discontinued and, when the drug was resumed at a 50% dose reduction, experienced no further shortness of breath. DISCUSSION: While dyspnea in association with thalidomide has not previously been reported as a common adverse event, it was a frequent complaint of patients receiving this drug as part of a Phase II study. Comorbid conditions causing dyspnea were evaluated since they are common in this patient population; however, half of our patients had no objective evidence of such conditions. The Naranjo probability scale indicated a probable relationship between dyspnea and thalidomide therapy in the patients with no objective evidence of comorbidity. We advocate discontinuation of thalidomide until symptoms have resolved, at which time reintroduction of thalidomide at a reduced dose may be considered. CONCLUSIONS: Patients receiving thalidomide may develop dyspnea as an adverse effect of the drug. In selected patients, thalidomide may be safely reintroduced once symptoms resolve.

Groin recurrence in patients with vulvar cancer with negative nodes on superficial inguinal lymphadenectomy.

OBJECTIVE: The objective of this study was to investigate the cause of groin recurrence in patients with vulvar cancer who had negative nodes in their superficial inguinal lymphadenectomy (SIL) specimens. METHODS: The records of patients with vulvar cancer treated at M. D. Anderson Cancer Center between 1986 and 1997 were reviewed to identify patients with squamous histology, clinical and surgical stage I or II, depth of invasion greater than 1 mm, and primary treatment consisting of radical wide excision and SIL. One hundred four patients met these criteria. Among these, nine experienced recurrent disease that involved one or both of the groins. All of the original hematoxylin and eosin (H&E)-stained slides were reviewed by one pathologist (AM). Then, each paraffin block containing nodal tissue was recut at 40 microm intervals to obtain five sections for H&E staining and two unstained sections to be used for cytokeratin immunostaining if necessary. RESULTS: The median age at diagnosis and primary surgery was 65 years and the median depth of invasion was 4 mm. Seven patients underwent bilateral, and two underwent unilateral, groin dissections. The median number of lymph nodes removed per groin was seven. The median time to recurrence was 22 months. A total of 785 additional H&E-stained slides were prepared and examined at 100x and 400x magnification. No micrometastases were identified, and there were no other suspicious findings. Therefore, immunohistochemical staining was not performed. At recurrence, one patient had a biopsy only, and eight had attempted surgical resection. In two patients, tumor was identified in fibroadipose tissue only; no lymph nodes were identified. Among the other six patients, the median number of lymph nodes resected at the time of the recurrence was five (range 1 to 10). At last report, six patients had died and three were alive and free of disease. Median follow-up for survivors was 63 months (range 42 to 71). CONCLUSION: These data strongly suggest that groin relapse in patients with negative nodes on SIL is caused by metastatic disease in unresected inguinal nodes. SIL as performed on the patients in this study did not eliminate all sites of nodal metastasis.