Long-term safety in patients with recurrent ovarian cancer treated with niraparib versus placebo: Results from the phase III ENGOT-OV16/NOVA trial.

OBJECTIVE: Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved for use in heavily pretreated patients and as maintenance treatment in patients with newly-diagnosed or recurrent ovarian cancer following a response to platinum-based chemotherapy. We present long-term safety data for niraparib from the ENGOT-OV16/NOVA trial. METHODS: This multicenter, double-blind, randomized, controlled phase III trial evaluated the efficacy and safety of niraparib for the treatment of recurrent ovarian cancer. Patients were randomly assigned 2:1 to receive either once-daily niraparib 300 mg or placebo. Two independent cohorts were enrolled based on germline BRCA mutation status. The primary endpoint was progression-free survival, reported previously. Long-term safety data were from the most recent data cutoff (September 2017). RESULTS: Overall, 367 patients received niraparib 300 mg once daily. Dose reductions due to TEAEs were highest in month 1 (34%) and declined every month thereafter. Incidence of any-grade and grade ≥ 3 hematologic and symptomatic TEAEs was also highest in month 1 and subsequently declined. Incidence of grade ≥ 3 thrombocytopenia decreased from 28% (month 1) to 9% and 5% (months 2 and 3, respectively), with protocol-directed dose interruptions and/or reductions. Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) were reported in 2 and 6 niraparib-treated patients, respectively, and in 1 placebo patient each. Treatment discontinuations due to TEAEs were <5% in each month and time interval measured. CONCLUSION: These data demonstrate the importance of appropriate dose reduction according to toxicity criteria and support the safe long-term use of niraparib for maintenance treatment in patients with recurrent ovarian cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01847274.

Progression-free and overall survival in ovarian cancer patients treated with CVac, a mucin 1 dendritic cell therapy in a randomized phase 2 trial.

BACKGROUND: CAN-003 was a randomized, open-label, Phase 2 trial evaluating the safety, efficacy and immune outcomes of CVac, a mucin 1 targeted-dendritic cell (DC) treatment as a maintenance therapy to patients with epithelial ovarian cancer (EOC). METHODS: Patients (n = 56) in first (CR1) or second clinical remission (CR2) were randomized (1:1) to standard of care (SOC) observation or CVac maintenance treatment. Ten doses were administered over 56 weeks. Both groups were followed for progression-free survival (PFS) and overall survival (OS). RESULTS: Fifty-six patients were randomized: 27 to SOC and 29 to CVac. Therapy was safe with only seven patients with Grade 3-4 treatment-emergent adverse events. A variable but measurable mucin 1 T cell-specific response was induced in all CVac-treated and some standard of care (SOC) patients. Progression free survival (PFS) was not significantly longer in the treated group compared to SOC group (13 vs. 9 months, p = 0.36, hazard ratio [HR] = 0.73). Analysis by remission status showed in the CR1 subgroup a median PFS of 18 months (SOC) vs. 13 months (CVac); p = 0.69 (HR = 1.18; CI 0.52-2.71). However CR2 patients showed a longer median PFS in the CVac-treated group (median PFS not yet reached, >13 vs. 5 months; p = 0.04, HR = 0.32 CI). OS for CR2 patients at 42 months of follow-up showed a difference of 26 months for SOC vs. > 42 months for CVac-treated (as median OS had not been reached; HR = 0.17 (CI 0.02-1.4) with a p = 0.07). CONCLUSIONS: CVac, a mucin 1-dendritic cell maintenance treatment was safe and well tolerated in ovarian cancer patients. A variable but observed CVac-derived, mucin 1-specific T cell response was measured. Notably, CR2 patients showed an improved PFS and lengthened OS. Further studies in CR2 ovarian cancer patients are warranted (NCT01068509). TRIAL REGISTRATION: NCT01068509. Study Initiation Date (first patient screened): 20 July 2010. Study Completion Date (last patient observation): 20 August 2013, the last patient observation for progression-free survival; 29 April 2015, the last patient was documented regarding overall survival.

A phase I study of weekly topotecan and Paclitaxel in previously treated epithelial ovarian carcinoma patients.

OBJECTIVE: We have previously reported on the feasibility of weekly topotecan as single-agent therapy in previously treated patients with ovarian cancer. The objective of this study was to assess the maximum tolerated dose (MTD) of weekly bolus intravenous (IV) topotecan combined with weekly paclitaxel in a comparable patient population. METHODS: Previously treated ovarian cancer patients with measurable disease and/or elevated cancer antigen 125 (CA-125) received (as second-line or third-line therapy) weekly 30-min bolus IV topotecan starting at 2 mg/m(2) combined with weekly paclitaxel starting at a dose of 60 mg/m(2). In this intrapatient dose-escalation study, topotecan and paclitaxel were escalated in parallel until the MTD was reached, defined as the first dose level at which >or= 2 of 6 patients experienced dose-limiting toxicity. RESULTS: Twenty-one of 26 patients were evaluable for toxicity and received a total of 306 weeks of therapy (median, 13 weeks; range, 5 to 33 weeks). No significant dose-limiting toxicity was observed up to a weekly bolus IV topotecan dose of 3 mg/m(2) and a concurrent paclitaxel dose of 80 mg/m(2). The MTD was topotecan 3.5 mg/m(2) plus 90 mg/m(2) paclitaxel. The dose-limiting toxicities included anemia and fatigue, with 10 of 21 patients receiving epoetin alfa for grade 3 or 4 anemia; only 1 patient required a blood transfusion. Two patients had a treatment delay of at least 1 week and only 1 patient required a dose reduction to maintain the weekly schedule. CONCLUSIONS: Based on the results of this study, the recommended initial dose for this novel regimen is topotecan 3 mg/m(2) and paclitaxel 80 mg/m(2). Further investigation of the efficacy of weekly topotecan plus paclitaxel in less heavily pretreated patients is warranted.

The role of laparoscopy in the management of gynecologic malignancy.

With the advent of minimally invasive laparoscopic techniques, most gynecologic procedures for benign conditions can be performed in an outpatient setting. However, the role of such techniques in gynecologic oncology is not well defined. By reviewing the literature and presenting some new data, we attempt to elucidate the applications of operative videolaparoscopy in gynecologic oncology. Advanced laparoscopic techniques are utilized for the management of cervical cancer as well as the staging and treatment of endometrial and ovarian cancers. Such techniques are used in performing radical hysterectomy for early stage cervical cancer, pelvic and paraaortic lymphadenectomy, and second look laparoscopy following chemotherapy for ovarian cancer. Even though preliminary data are encouraging, large prospective controlled studies with long-term follow-up are necessary to better define the role and limitations of laparoscopy in the treatment of gynecologic malignancies.

Four ovarian cancers diagnosed during laparoscopic management of 1011 women with adnexal masses.

OBJECTIVES: This study was conducted to assess the value of laparoscopic management of adnexal masses. Two concerns we wish to address are the failure to diagnose early ovarian cancer at laparoscopy and worsening the prognosis of stage I cancer by spilling fluid during surgery. STUDY DESIGN: The setting is a predominantly referral-based, private subspecialty practice. All operations were preformed in the outpatient surgical suite of a large suburban hospital. After extensive patient screenings, which included history and physical examination, preoperative serum CA 125 levels (since 1988), and pelvic ultrasonography, 1209 adnexal masses were managed laparoscopically. RESULTS: Of 1011 patients with surgical management, ovarian cancer was discovered intraoperatively in four. CONCLUSIONS: Our findings indicate that with consistent use of frozen sections of all cyst walls and suspicious tissue, laparoscopic management did not alter the prognosis. Neither CA 125 level, pelvic ultrasonography, nor peritoneal cytologic testing had sufficient diagnostic specificity to predict malignancy. Experienced surgeons using intraoperative histologic sampling may safely evaluate adnexal mass laparoscopically.

Laparoscopic radical hysterectomy with paraaortic and pelvic node dissection.

We report the first case of a laparoscopic radical hysterectomy and paraaortic and pelvic lymphadenectomy to treat a stage IA2 carcinoma of the cervix. To our knowledge, a laparoscopic radical hysterectomy with laparoscopic paraaortic lymphadenectomy has not been previously described.

Results of a multicenter comparative study of single-dose cefotetan and multiple-dose cefoxitin as prophylaxis in patients undergoing cesarean section.

A study to compare the prophylactic efficacy of a single 2 g dose of cefotetan with multiple 2 g doses of cefoxitin in reducing the incidence of postcesarean section infection was evaluated in a multicenter trial of 269 women. No significant differences in clinical or bacteriologic response were detected between the two groups. A successful clinical response rate was achieved in 139 of 162 of the evaluable subjects given cefotetan (86 percent) and in 71 of 79 patients (90 percent) given cefoxitin. The respective satisfactory bacteriologic response rates were 91 percent (135 of 148 patients) and 93 percent (68 of 73 patients). The incidences of endometritis for cefotetan and cefoxitin (12 percent and 5 percent, respectively) and of postoperative wound infection (3 percent and 5 percent, respectively) were also not significantly different. Bactericidal levels of cefotetan were maintained in plasma in the immediate postpartum period. Both drugs were well tolerated. Single-dose prophylaxis with cefotetan was comparable to multiple doses of cefoxitin in reducing infectious morbidity in women undergoing cesarean section.

Comparison of cefotetan and cefoxitin prophylaxis for abdominal and vaginal hysterectomy.

The safety and efficacy of parenteral prophylaxis with either cefotetan or cefoxitin were evaluated in a prospective, randomized study of 355 subjects undergoing abdominal or vaginal hysterectomy. Each subject received either a single 1 gm dose of cefotetan intravenously 30 to 60 minutes before operation or three 2 gm doses of cefoxitin, the first 30 to 60 minutes before operation and subsequent doses 6 and 12 hours later. Prophylaxis was successful in 69 of 70 (98.6%) receiving cefotetan and 32 of 33 (97.0%) receiving cefoxitin who underwent vaginal hysterectomy. Prophylaxis was successful in 160 of 169 (94.7%) receiving cefotetan and in 79 of 83 (95.2%) receiving cefoxitin who underwent abdominal hysterectomy. Both drugs were well tolerated and without serious side effects or complications. On the basis of these findings, we conclude that a single 1 gm dose of cefotetan given before operation is as safe and effective as a multiple-dosing regimen of cefoxitin in subjects undergoing vaginal hysterectomy and in those undergoing abdominal hysterectomy at institutions where prophylaxis is indicated.

A comparison of piperacillin, cephalothin and cefoxitin in the prevention of postoperative infections in patients undergoing vaginal hysterectomy.

A randomized, double-blind, multicenter trial was initiated to compare the safety and efficacy of piperacillin, cephalothin and cefoxitin in the prophylactic treatment of patients undergoing vaginal hysterectomy. The total dose of each antibiotic was 6 grams given in three equally divided doses. A satisfactory prophylactic response was obtained in 143 of 151 (95 per cent) patients treated with piperacillin, in 82 of 87 (94 per cent) patients treated with cephalothin and in 57 of 60 (95 per cent) patients treated with cefoxitin. The pooled data indicated that the piperacillin treatment group did not differ from the combined cephalosporin treatment groups with respect to prophylactic response, presence of febrile morbidity, fever index, duration of postoperative hospitalization and incidence of reported adverse experiences.

A double-blind, controlled comparison of piperacillin and cefoxitin in the prevention of postoperative infection in patients undergoing cesarean section.

Data are presented from a randomized, double-blind multicenter trial (six study sites, involving 346 patients) in which piperacillin was compared with cefoxitin as a prophylactic agent for patients undergoing cesarean section. One hundred and sixty-nine patients received piperacillin and 177 received cefoxitin; in each instance, the total dosage was 6 grams. Strict criteria were used to evaluate safety and efficacy. The courses of all of the patients were evaluable for safety and 183 courses were evaluable for efficacy (136 efficacy-evaluable courses were from patients treated with piperacillin and 147, from those treated with cefoxitin). Postoperative infection was prevented in 89 per cent of the patients treated with piperacillin and in 93 per cent of the those treated with cefoxitin. The difference was not statistically significant. The data from each of the individual study sites, as well as the pooled data, indicated that the short term perioperative administration of piperacillin in patients undergoing a cesarean section was as safe and effective as cefoxitin with regard to prophylactic response, duration of hospitalization and the usage of other systemic antibiotics.

Cigarette smoking and dysplasia and carcinoma in situ of the uterine cervix.

We conducted a case-control study of cigarette smoking and dysplasia and carcinoma in situ of the uterine cervix. Cases were black women 17 to 55 years of age who were attending a dysplasia clinic and had biopsy-confirmed cervical pathologic conditions. Controls were women who were attending the family planning clinic at the same hospital and who had at least two normal Papanicolaou smears. Results were adjusted for age, number of sexual partners, age at first intercourse, socioeconomic status, and oral contraceptive use. Cigarette smoking was significantly associated with carcinoma in situ, severe dysplasia, and mild-moderate dysplasia (relative risks, 3.6, 3.3, and 2.4, respectively). Cumulative exposure to cigarette smoking (as measured by pack-years smoked) was strongly related to the risk of these conditions; women with 12 or more pack-years of exposure had relative risks of 12.7, 10.2, and 4.3, respectively, for the three conditions. There was some evidence that the risk was greatest in women who began smoking in their early teenage years. A reduction in the risk of cervical cancer appears to be another inducement for young women not to smoke.

Diagnostic endometrial aspiration with the Karman cannula.

Endometrial aspiration with the Karman cannula can be used to detect endometrial pathology. To document the feasibility and accuracy of endometrial aspiration with this cannula, 49 women were evaluated by this technique prior to diagnostic dilation and curettage (D&C). Completion rates for both endometrial aspiration and D&C were 96%. Endometrial aspiration yielded tissue adequate for histologic evaluation in 82% of cases as compared with 76% of D&C cases. Three cases of cancer (two endometrial and one endocervical) were identified by both techniques. A majority of patients expressed a preference for endometrial aspiration over D&C. Endometrial aspiration with the Karman cannula appears to be a convenient, accurate and acceptable method of detecting endometrial pathology.

Medical and surgical management of the pelvic abscess.

A pelvic abscess is the end stage in the progression of a genital tract infection and is frequently an unnecessary complication. Intensive medical management including the use of broad-spectrum antibiotics, posterior colpotomy, and major surgery involving a hysterectomy and bilateral salpingo-oophorectomy, all have their place in the management of this condition. Such surgery, however necessary, is associated with profound physical and emotional effects in addition to the economic consequences associated with such therapy. It is hoped that with a better understanding of the epidemiology of PID and with the advent of improved diagnostic and therapeutic modalities for early genital tract infection, a pelvic abscess will eventually become a great rarity on gynecology services.

PIP: A pelvic abscess is the end stage in the progression of a genital tract infection and is frequently preventable. The abscess may fill the pelvis and occasionally the lower abdomen, and is usually posterior to the uterus and bound by the sigmoid colon, loops of small bowel, cul-de-sac, and sidewalls of the pelvis. A tubo-ovarian abscess may occur in the acute stage of pelvic inflammatory disease (PID) but is more common with chronic or subacute PID. An abscess occurs when pus from the fallopian tube spills onto the ovary and infects it at the site of follicular rupture or by direct penetration. Pelvic and abdominal pain which is bilateral and aggravated by motion and intercourse, and fever possibly exceeding 103 degrees fahrenheit with leucocytosis, tachycardia, and prostration are the most common symptoms of pelvic abscess. The pelvic examination may reveal all gradations of pathology, but because of the degree of guarding and tenderness it elicits, the abscess may elude the examiner. The rectal examination, computerized tomography, and ultrasonography are useful in diagnosis. Other disorders such as acute appendicitis and ecoptic pregnancy may be mistaken for abscess. Patients with pelvic abscesses should be immediately admitted to hospital regardless of the size of the abscess because the broad-spectrum anerobic antibiotic coverage needed is most effectively provided there. Preservation of normal tubal function is rarely possible in patients developing tubal abscesses. Bed rest, fluid and electrolyte replacement, nasogastric suction when indicated, and antibiotics are the basis of medical treatment. Controversy exists regarding appropriate antibiotic therapy, but the probable presence of anaerobic organisms should be kept in mind. Patients with pelvic abscesses are frequently given a triple antibiotic regimen including clindamycin, gentamicin, and aqueous penicillin. Guidelines for the failure of medical management in patients with a pelvic abscess include persistent fever, increase in size of abscess, persistent ileus, suspicion of rupture, septic shock, and uncertainty of the diagnosis. A posterior colpotomy is preferable to a laparotomy if surgical treatment is necessary, but it is only suitable for selected patients. Removal of a pelvic abscess frequently involves a total abdominal hysterectomy. Operating instructions and diagrams are included. Rupture of a pelvic abscess is life threatening and requires immediate surgery.

The microbiology and therapy of acute pelvic inflammatory disease in hospitalized patients.

We examined microbial isolates from the endocervical and peritoneal cavity of 30 women hospitalized with acute PID. Patients were randomly assigned to one of two antibiotic regimens: amoxicillin, 6 gm by mouth every 24 hours, or aqueous penicillin G, 30 million units and gentamicin, 180 to 240 mg intravenously every 24 hours. We measured response by quantifying physical examination findings. Neisseria gonorrhoeae was isolated from the cervix of 24 patients (80%) and from the peritoneal cavity of 10 (33%). Other peritoneal isolates included Enterobacteriaceae in five patients, Ureaplasma urealyticum in five, Mycoplasma hominis in six, and Chlamydia trachomatis in three. Bacteroides melaninogenicus, the most frequent anaerobe, was isolated in 11 cases. Bacteroides fragillis was not isolated from any specimen. The cure rates were the same for both regimens: three patients failed on each. Four women required total abdominal hysterectomy and unilateral or bilateral salpingo-oophorectomy.

Rosette formation and inhibition in cervical dysplasia and carcinoma in situ.

Total and early rosettes and rosette inhibition were measured in patients with cervical dysplasia and carcinoma in situ. Both total and early rosettes were significantly depressed in patients with carcinoma in situ; early rosettes were also significantly lower than were controls in women with severe dysplasia. Rosette inhibition titers were increased in most patients with moderate dysplasia and in all patients with either severe dysplasia or carcinoma in situ. Thus, the Rosette inhivition test may be useful in detecting, in a precancerous state, patients at risk for cancer.

The residual adnexa--asset or liability?

Nine hundred and twenty-two patients who had one or both adnexa conserved at the time of abdominal hysterectomy for benign diseases are presented. Thirteen patients (1.4%) have required subsequent re-exploration for adnexal pathology. Corpus luteum cysts were found in 10 (77%) of these patients. The primary pathology was found in the Fallopian tube in five patients (38%). No patient was found to have an ovarian malignancy in the short period of follow-up. Conservation of ovarian function is recommended in patients who have not undergone menopause.