Safety and efficacy of topical artesunate for the treatment of vulvar intraepithelial neoplasia 2/3.

OBJECTIVE: To evaluate the safety, tolerability, and efficacy of topical artesunate ointment for treatment of biopsy-confirmed Human papillomavirus (HPV)-associated Vulvar intraepithelial neoplasia (VIN) 2/3. METHODS: Participants were enrolled on a prospective, IRB-approved, dose-escalation phase I trial testing either 1, 2 or 3 treatment cycles (5 days), every other week, as applicable. Clinical assessments were completed prior to each dose cycle and included exam and review of adverse event (AE) diary cards. HPV testing and colposcopy was completed at 15 and 28 weeks. AEs were assessed according to CTCAE 4.0 criteria. Complete responders (CR) underwent biopsy of the treated site at the 28-weeks while partial (PR) and non (NR)-responders underwent surgical resection or biopsy and ablation. RESULTS: Fifteen patients consented to and began treatment. Per-protocol assessments were completed in 100% at 15- and 80% at 28-weeks. All patients completed prescribed cycles with no grade 3 or 4 AEs. Vulvovaginal burning/ was the most common AE occurring in 93.3%. AEs were grade 2 in 23.7% and included vulvovaginal pruritus (n = 3), swelling (n = 3) and candidiasis (n = 2). The highest ORR was in the 3-cycle group (88.9% with 55.6% CR). HPV-16 was detected either alone (46.7%) or with other subtypes (33.3%) in 80% of lesions and 5 of 8 (62.5%) with CR had complete viral clearance. CONCLUSIONS: Topical artesunate for treatment of high-grade VIN shows high tolerability, low toxicity and evidence for clinical response in this initial small series. The safety and observed responses support further study in a Phase II trial.

Abdominopelvic MR to CT registration using a synthetic CT intermediate.

Accurate coregistration of computed tomography (CT) and magnetic resonance (MR) imaging can provide clinically relevant and complementary information and can serve to facilitate multiple clinical tasks including surgical and radiation treatment planning, and generating a virtual Positron Emission Tomography (PET)/MR for the sites that do not have a PET/MR system available. Despite the long-standing interest in multimodality co-registration, a robust, routine clinical solution remains an unmet need. Part of the challenge may be the use of mutual information (MI) maximization and local phase difference (LPD) as similarity metrics, which have limited robustness, efficiency, and are difficult to optimize. Accordingly, we propose registering MR to CT by mapping the MR to a synthetic CT intermediate (sCT) and further using it in a sCT-CT deformable image registration (DIR) that minimizes the sum of squared differences. The resultant deformation field of a sCT-CT DIR is applied to the MRI to register it with the CT. Twenty-five sets of abdominopelvic imaging data are used for evaluation. The proposed method is compared to standard MI- and LPD-based methods, and the multimodality DIR provided by a state of the art, commercially available FDA-cleared clinical software package. The results are compared using global similarity metrics, Modified Hausdorff Distance, and Dice Similarity Index on six structures. Further, four physicians visually assessed and scored registered images for their registration accuracy. As evident from both quantitative and qualitative evaluation, the proposed method achieved registration accuracy superior to LPD- and MI-based methods and can refine the results of the commercial package DIR when using its results as a starting point. Supported by these, this manuscript concludes the proposed registration method is more robust, accurate, and efficient than the MI- and LPD-based methods.

Beyond Sedlis-A novel histology-specific nomogram for predicting cervical cancer recurrence risk: An NRG/GOG ancillary analysis.

PURPOSE: The Sedlis criteria define risk factors for recurrence warranting post-hysterectomy radiation for early-stage cervical cancer; however, these factors were defined for squamous cell carcinoma (SCC) at an estimated recurrence risk of ≥30%. Our study evaluates and compares risk factors for recurrence for cervical SCC compared with adenocarcinoma (AC) and develops histology-specific nomograms to estimate risk of recurrence and guide adjuvant treatment. METHODS: We performed an ancillary analysis of GOG 49, 92, and 141, and included stage I patients who were surgically managed and received no neoadjuvant/adjuvant therapy. Multivariable Cox proportional hazards models were used to evaluate independent risk factors for recurrence by histology and to generate prognostic histology-specific nomograms for 3-year recurrence risk. RESULTS: We identified 715 patients with SCC and 105 with AC; 20% with SCC and 17% with AC recurred. For SCC, lymphvascular space invasion (LVSI: HR 1.58, CI 1.12-2.22), tumor size (TS ≥4 cm: HR 2.67, CI 1.67-4.29), and depth of invasion (DOI; middle 1/3, HR 4.31, CI 1.81-10.26; deep 1/3, HR 7.05, CI 2.99-16.64) were associated with recurrence. For AC, only TS ≥4 cm, was associated with recurrence (HR 4.69, CI 1.25-17.63). For both histologies, there was an interaction effect between TS and LVSI. For those with SCC, DOI was most associated with recurrence (16% risk); for AC, TS conferred a 15% risk with negative LVSI versus a 25% risk with positive LVSI. CONCLUSIONS: Current treatment standards are based on the Sedlis criteria, specifically derived from data on SCC. However, risk factors for recurrence differ for squamous cell and adenocarcinoma of the cervix. Histology-specific nomograms accurately and linearly represent risk of recurrence for both SCC and AC tumors and may provide a more contemporary and tailored tool for clinicians to base adjuvant treatment recommendations to their patients with cervical cancer.

Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240).

BACKGROUND: On Aug 14, 2014, the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial. In this study, we report the prespecified final analysis of the primary objectives, OS and adverse events. METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited patients with metastatic, persistent, or recurrent cervical carcinoma from 81 centres in the USA, Canada, and Spain. Inclusion criteria included a GOG performance status score of 0 or 1; adequate renal, hepatic, and bone marrow function; adequately anticoagulated thromboembolism; a urine protein to creatinine ratio of less than 1; and measurable disease. Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible. We randomly allocated patients 1:1:1:1 (blocking used; block size of four) to intravenous chemotherapy of either cisplatin (50 mg/m2 on day 1 or 2) plus paclitaxel (135 mg/m2 or 175 mg/m2 on day 1) or topotecan (0·75 mg/m2 on days 1-3) plus paclitaxel (175 mg/m2 on day 1) with or without intravenous bevacizumab (15 mg/kg on day 1) in 21 day cycles until disease progression, unacceptable toxic effects, voluntary withdrawal by the patient, or complete response. We stratified randomisation by GOG performance status (0 vs 1), previous radiosensitising platinum-based chemotherapy, and disease status (recurrent or persistent vs metastatic). We gave treatment open label. Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information), assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board. The cutoff for final analysis was 450 patients with 346 deaths. This trial is registered with ClinicalTrials.gov, number NCT00803062. FINDINGS: Between April 6, 2009, and Jan 3, 2012, we enrolled 452 patients (225 [50%] in the two chemotherapy-alone groups and 227 [50%] in the two chemotherapy plus bevacizumab groups). By March 7, 2014, 348 deaths had occurred, meeting the prespecified cutoff for final analysis. The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups: 16·8 months in the chemotherapy plus bevacizumab groups versus 13·3 months in the chemotherapy-alone groups (hazard ratio 0·77 [95% CI 0·62-0·95]; p=0·007). Final OS among patients not receiving previous pelvic radiotherapy was 24·5 months versus 16·8 months (0·64 [0·37-1·10]; p=0·11). Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8·4 months) and chemotherapy-alone groups (7·1 months; 0·83 [0·66-1·05]; p=0·06). Fistula (any grade) occurred in 32 (15%) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1%) of 220 in the chemotherapy-alone groups (all previously irradiated). Grade 3 fistula developed in 13 (6%) versus one (<1%). No fistulas resulted in surgical emergencies, sepsis, or death. INTERPRETATION: The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated. After progression while receiving bevacizumab, we did not observe a negative rebound effect (ie, shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped). These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer. FUNDING: National Cancer Institute.

A phase I study of IV doxorubicin plus intraperitoneal (IP) paclitaxel and IV or IP cisplatin in endometrial cancer patients at high risk for peritoneal failure (GOG 9920): an NRG Oncology/Gynecologic Oncology Group study.

OBJECTIVE: To determine the maximum tolerated dose (MTD) of a modified paclitaxel/doxorubicin/cisplatin (TAP) regimen which incorporated intraperitoneal (IP) paclitaxel or IP paclitaxel/cisplatin in advanced endometrial cancer. METHODS: Patients (pts) with FIGO (1998) Stage IIIA/IIIC with positive cytologic washings/ascites, adnexa, or serosa or Stage IV (intraperitoneal disease spread), histologically confirmed endometrial cancer were eligible. The study was designed as a phase I, 3+3 dose escalation study evaluating 5 dose levels (DL). All pts received cycles 1-2 with IV TAP, and cycles 3-6 with IV/IP therapy, on a 21day schedule. Adverse events were evaluated on cycles 3-4 for dose limiting toxicity (DLT) and dose escalation decisions. RESULTS: Twenty-one pts were enrolled, of which 17 were evaluable for DLT. Most pts had Stage IV disease (76%) and serous/clear cell histology (59%). The MTD was determined to be DL 3 (cycles 3-6 including paclitaxel 90mg/m(2) IP, doxorubicin 45mg/m(2) IV, cisplatin 50mg/m(2)). Three DLT events occurred and were related to grades 3-4 metabolic toxicities. There was one grade 2 sensory neuropathy event and myelosupression was tolerable without the use of G-CSF. 88% of evaluable pts completed 6cycles of therapy. With a median follow-up of 22months, 46% of patients remain progression-free at 2years. CONCLUSION: We described an IV/IP based modification of a standard TAP regimen in endometrial cancer. Based on the high rate of completing 6cycles of therapy, low rates of neuropathy, and promising PFS, further study of IP therapy in endometrial cancer is warranted.

A phase I study with an expanded cohort to assess feasibility of intravenous docetaxel, intraperitoneal carboplatin and intraperitoneal paclitaxel in patients with previously untreated ovarian, fallopian tube or primary peritoneal carcinoma: a Gynecologic Oncology Group study.

OBJECTIVE: To define the maximum tolerated dose (MTD) and assess the feasibility of intravenous (IV) docetaxel, intraperitoneal (IP) carboplatin and IP paclitaxel in women with stage II-IV untreated ovarian, fallopian tube or primary peritoneal carcinoma. METHODS: Patients received docetaxel (55-75 mg/m(2)) IV and carboplatin (AUC 5-7) IP on day 1 and paclitaxel 60 mg/m(2) IP on day 8. A standard 3+3 design was used in the dose escalation phase. A 2-stage group sequential design with 20 patients at the MTD was used in the feasibility phase. RESULTS: The MTD determined during the dose escalation phase was day 1 docetaxel 75 mg/m(2) IV, carboplatin AUC 6 IP and day 8 IP paclitaxel 60 mg/m(2). Forty-six patients were enrolled in the feasibility portion at this dose level. Six were unevaluable. Fifteen evaluable patients had dose-limiting toxicities (DLTs) within the first four cycles. These DLTs were prolonged neutropenia (2), neutropenic fever (7), grade 4 thrombocytopenia (1), grade 4 dehydration (1), grade 3 infection (2), grade 3 oral mucositis (1) and pulmonary embolism (1). CONCLUSIONS: Docetaxel 75 mg/m(2) IV, carboplatin AUC 6 IP administered on day 1, and paclitaxel 60 mg/m(2) IP administered on day 8, is the MTD when considering one cycle of treatment but was not feasible over four cycles due to bone marrow toxicity. We recommend reduction of carboplatin to AUC 5 should this regimen be considered for treatment in women with newly diagnosed advanced ovarian cancer.

Toxicity of weekly oral topotecan in relation to dosage for gynecologic malignancies: a phase I study.

The aim of this study was to determine the dose of weekly oral topotecan that allows safe administration and to evaluate the pharmacokinetics of this dose in patients with recurrent gynecologic malignancies. The first cohort of patients received oral topotecan 6 mg/week administered orally on days 1, 8, and 15 of a 28-day regimen. A standard 3+3 dose-escalating phase design was used for dose levels II-V (8, 10, 12 and 14 mg/week). Toxicity was scored according to the Common Terminology Criteria for Adverse Events. Cumulative toxicity was summarized in the 6-12 mg/week combined cohort and 14 mg/week cohort separately. Pharmacokinetic samples were obtained for day 1, cycle 1 only in the expansion cohort (dose level V). Twenty-five patients received a total of 88 cycles of therapy. Hematologic toxicities of grade 3 (6-12 mg dose) were neutropenia (25%) and anemia (8.3%). Gastrointestinal toxicities of grade 3 were diarrhea (16.7%) and obstruction (8.3%, disease-related). Grade 3 or 4 (14 mg/week) hematologic toxicities consisted of neutropenia (38.5%), platelets (15.4%), anemia (15.4%), infection with neutropenia (7.7%), and thrombosis (7.7%). Gastrointestinal toxicities of grade 3 were diarrhea (7.7%), obstruction (7.7%), and vomiting (7.7%). One patient died secondary to neutropenic sepsis. One patient (4%; 95% confidence interval: 2.1, 22.3) showed a partial response and five patients (20%; 95% confidence interval: 7.6, 41.3) had stable disease. An oral topotecan dose of 14 mg/week for 3 consecutive weeks out of 4 is mostly associated with acceptable toxicities and may be considered for use in future single-agent phase II trials.

Olaparib With or Without Cediranib Versus Platinum-Based Chemotherapy in Recurrent Platinum-Sensitive Ovarian Cancer (NRG-GY004): A Randomized, Open-Label, Phase III Trial.

PURPOSE: Platinum-based chemotherapy is the standard of care for platinum-sensitive ovarian cancer, but complications from repeated platinum therapy occur. We assessed the activity of two all-oral nonplatinum alternatives, olaparib or olaparib/cediranib, versus platinum-based chemotherapy. PATIENTS AND METHODS: NRG-GY004 is an open-label, randomized, phase III trial conducted in the United States and Canada. Eligible patients had high-grade serous or endometrioid platinum-sensitive ovarian cancer. Patients were randomly assigned 1:1:1 to platinum-based chemotherapy, olaparib, or olaparib/cediranib. The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included activity within germline BRCA-mutated or wild-type subgroups and patient-reported outcomes (PROs). RESULTS: Between February 04, 2016, and November 13, 2017, 565 eligible patients were randomly assigned. Median PFS was 10.3 (95% CI, 8.7 to 11.2), 8.2 (95% CI, 6.6 to 8.7), and 10.4 (95% CI, 8.5 to 12.5) months with chemotherapy, olaparib, and olaparib/cediranib, respectively. Olaparib/cediranib did not improve PFS versus chemotherapy (hazard ratio [HR] 0.86; 95% CI, 0.66 to 1.10; P = .077). In women with germline BRCA mutation, the PFS HR versus chemotherapy was 0.55 (95% CI, 0.32 to 0.94) for olaparib/cediranib and 0.63 (95% CI, 0.37 to 1.07) for olaparib. In women without a germline BRCA mutation, the PFS HR versus chemotherapy was 0.97 (95% CI, 0.73 to 1.30) for olaparib/cediranib and 1.41 (95% CI, 1.07 to 1.86) for olaparib. Hematologic adverse events occurred more commonly with chemotherapy; however, nonhematologic adverse events were higher with olaparib/cediranib. In 489 patients evaluable for PROs, patients receiving olaparib/cediranib scored on average 1.1 points worse on the NFOSI-DRS-P subscale (97.5% CI, -2.0 to -0.2, P = .0063) versus chemotherapy; no difference between olaparib and chemotherapy was observed. CONCLUSION: Combination olaparib/cediranib did not improve PFS compared with chemotherapy and resulted in reduced PROs. Notably, in patients with a germline BRCA mutation, both olaparib and olaparib/cediranib had significant clinical activity.

Feasibility of a lifestyle intervention for ovarian cancer patients receiving adjuvant chemotherapy.

OBJECTIVES: This study aimed to assess the feasibility of a lifestyle intervention for promoting physical activity (PA) and diet quality during adjuvant chemotherapy for ovarian cancer. METHODS: Patients were enrolled post-operatively and received PA and nutrition counseling, at every chemotherapy visit for six cycles. Quality of life (QoL) was measured with the Functional Assessment of Cancer Therapy (FACT-G), PA with the Leisure Score Index (LSI), dietary intake with 3-day food records, and symptom severity/distress by the Memorial Symptom Assessment Scale (MSAS). Pedometer step count was collected during chemotherapy cycles. RESULTS: Recruitment was 73% with 27 patients enrolled. Mean [95% confidence interval] change in minutes of PA from cycle #3 to following cycle #6 was 61 min [-3, 120] p=0.063, and from baseline to after cycle #6 was 73 min [-10, 15]; p=0.082. Mean change in total fruit and vegetable consumption between baseline and during chemotherapy was 0.56 [-0.09, 0.64]; p=0.090. FACT-G increased from 75.4 at baseline to 77.6 during chemotherapy and 83.9 following chemotherapy (p=0.001 for change from baseline to post-chemotherapy). Mean total MSAS score was 20.6 at baseline, 26.6 at cycle #3 and decreased to 17.0 following chemotherapy (p=0.01 comparison of cycle #3 and following chemotherapy). Increased moderate to strenuous PA was correlated with higher physical well-being during chemotherapy (r=0.48, p=0.037). CONCLUSIONS: Lifestyle counseling during adjuvant chemotherapy for ovarian cancer is feasible and may improve PA and diet quality. Randomized controlled trials examining the effects of lifestyle counseling on quality of life and treatment outcomes in ovarian cancer patients are warranted.

The effect of sleep disturbance on quality of life in women with ovarian cancer.

OBJECTIVE: To estimate the prevalence of sleep disturbances, and to determine if there is an association between sleep disturbances with quality of life (QOL), depression or clinical demographic variables. METHODS: Patients diagnosed with ovarian, fallopian tube or primary peritoneal cancer during the last 5years completed questionnaires regarding sleep patterns and disturbances [Pittsburgh Sleep Quality Index (PSQI)], depression [Beck Depression inventory (BDI)], and QOL [The Functional Assessment of Cancer Therapy-Ovarian (FACT-O), fatigue module (-F)]. Data were analyzed by Student's t-test or Pearson correlation coefficient to determine if there were differences between PSQI score with QOL, depression or clinical demographic variables. RESULTS: 86/275 (31% response) of patients returned the surveys. Mean age was 58.1 (SD=14.6) years and 70% had advanced disease at diagnosis. Thirty-six percent had current disease of which 81% were receiving chemotherapy. Sixty-seven percent of patients had a PSQI score≥5 corresponding to overall poor sleep quality and 46% of patients reported using sleep medication at least once during the prior month. PSQI score was significantly inversely correlated with all QOL domains (physical: r=-.599, p<.001, functional: r=-.692, p<.001, social: r=-.212, p<.001, emotional: r=-.379, p<.001, fatigue; r=-.655 p<.001) and with depression (r=.539, p<.001). PSQI was not correlated with age, time since diagnosis, number of previous chemotherapy regimens. PSQI score did not differ by current disease or chemotherapy status. CONCLUSIONS: Sleep disturbances reduce QOL, a prognostic indicator for survival, in ovarian cancer patients. These patients should undergo routine screening and would benefit from interventions that aim to promote restful sleep.

Low-dose abdominal radiation as a docetaxel chemosensitizer for recurrent epithelial ovarian cancer: a phase I study of the Gynecologic Oncology Group.

OBJECTIVES: The aim of this study was to determine the maximum tolerated dose and dose-limiting toxicity (DLT) of whole abdomen radiation as a chemosensitizer of weekly docetaxel for women with recurrent epithelial ovarian fallopian tube, or peritoneal cancers. PATIENTS AND METHODS: Women were enrolled on one of three dose levels of docetaxel (20, 25, or 30 mg/m(2)) administered weekly with concurrent low-dose whole abdominal radiation given as 60 cGy bid 2 days weekly for a total of 6 weeks. RESULTS: Thirteen women were enrolled and received 70 weekly treatments of docetaxel in combination with radiation therapy. At the first dose level, docetaxel 25mg/m(2), grade 3 fatigue and thrombocytopenia were observed. At the next dose level, docetaxel 30 mg/m(2), grade 3 febrile neutropenia, grade 4 thrombocytopenia with epistaxis, and grade 3 diarrhea were observed. Given these dose-limiting toxicities, a lower dose of docetaxel 20mg/m(2) was administered and found to be tolerable. No objective responses were observed among the 10 patients with measurable disease; however, the median progression-free survival (PFS) in all patients was 3.3 months, and 3 of the patients with measurable disease were free of tumor progression after 6 months (30%; 90% confidence interval 8.7-61%). CONCLUSIONS: Twice weekly low-dose whole abdomen radiation during weekly docetaxel 20 mg/m(2) was well-tolerated. Given the PFS demonstrated in these women with resistant ovarian cancer, further study of whole abdominal radiation and concurrent chemotherapy may be warranted.

Smoking behavior in women with locally advanced cervical carcinoma: a Gynecologic Oncology Group study.

OBJECTIVE: The purpose of this study was to assess cigarette use and environmental smoke exposure in women with cervical cancer. STUDY DESIGN: Smoking behavior was recorded prospectively in a clinical trial of women with locally advanced cervical carcinoma. RESULTS: Of 315 participants, 133 women (42%) were current smokers; 72 women (23%) were former smokers, and 110 women (35%) were never smokers. Current smokers began smoking earlier (16 vs 18 years; P = .009), for more years (29 vs 24 years; P = .005), and in greater amounts (20 vs 11 cigarettes/d; P < .001) than former smokers. Active smokers lived more often with another smoker (63.3%), compared with former smokers (35.0%; P < .001) or never-smokers (28.7%; P < .001). Agreement between self-report and urine cotinine level was high (kappa = 0.872; P < .001). A significant decrease in cotinine level during treatment occurred in 5.2% of current smokers. CONCLUSION: Prevalence of smoking and tobacco consumption was twice that of the North American female population. Few smokers quit or decreased consumption during treatment.

Feasibility and effectiveness of a lifestyle intervention program in obese endometrial cancer patients: a randomized trial.

OBJECTIVE: The majority of endometrial cancer survivors (ECS) are obese and at risk for premature death. The purpose of this study was to assess feasibility of a lifestyle intervention program for promoting weight loss, change in eating behaviors, and increased physical activity in obese ECS. STUDY DESIGN: Early stage ECS (n=45) were randomized to a 6-month lifestyle intervention (LI; n=23) or usual care (UC; n=22). The LI group received group and individual counseling for 6 months. The primary endpoint was weight change. Secondary endpoints were physical activity, [Leisure score index (LSI)] and nutrient intake (3-day food records). Quantitative vitamin C and folate intake were used to assess fruit/vegetable intake. RESULTS: Recruitment was 29%, adherence (LI group) was 73% and 84% of participants completed follow-up assessments. At 12 months, the intervention group lost 3.5 kg compared to a 1.4 kg gain in the control group [mean difference=-4.9 kg; 95% CI: -9.0 to -0.9 kg; p=.018] and had an increased LSI score of 16.4 versus -1.3 in the control group from baseline [mean group difference=17.8; 95% CI=7.1 to 28.4; p=.002]. There were no differences in vitamin C and folate intake. The LI group had lower intake of kilocalories, although differences were not significant. CONCLUSION(S): A lifestyle intervention program in obese ECS is feasible and can result in sustained behavior change and weight loss over a 1-year period.

Limited access trial using amifostine for protection against cisplatin- and three-hour paclitaxel-induced neurotoxicity: a phase II study of the Gynecologic Oncology Group.

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

Cervical cancer.

Cervical cancer is a serious health problem, with nearly 500000 women developing the disease each year worldwide. Most cases occur in less developed countries where no effective screening systems are available. Risk factors include exposure to human papillomavirus, smoking, and immune-system dysfunction. Most women with early-stage tumours can be cured, although long-term morbidity from treatment is common. Results of randomised clinical trials have shown that for women with locally advanced cancers, chemoradiotherapy should be regarded as the standard of care; however, the applicability of this treatment to women in less developed countries remains largely untested. Many women with localised (stage IB) tumours even now receive various combinations of surgery and radiotherapy, despite unresolved concern about the morbidity of this approach compared with definitive radiotherapy or radical surgery. Treatment of recurrent cervical cancer remains largely ineffective. Quality of life should be taken into account in treatment of women with primary and recurrent cervical cancer.

Clitoral therapy device for treatment of sexual dysfunction in irradiated cervical cancer patients.

PURPOSE: The purpose of this pilot study was to evaluate the efficacy of the clitoral therapy device (Eros Therapy) in alleviating sexual dysfunction in irradiated cervical cancer patients. METHODS AND MATERIALS: Eligible patients had a history of cervical cancer treated with radiotherapy and self-reported sexual dysfunction of sexual arousal and/or orgasmic disorders. Patients used the noninvasive, nonpharmacologic clitoral therapy device using a hand-held, battery-powered vacuum to cause clitoral engorgement four times weekly for 3 months during foreplay and self-stimulation. Study instruments included the Female Sexual Function Index, Derogatis Interview for Sexual Functioning, and Dyadic Adjustment Scale. The outcome evaluation was performed at 3 months. RESULTS: Between 2001 and 2002, 15 women were enrolled and 13 completed the study. The median patient age and radiotherapy-enrollment interval was 43.5 years and 2 years, respectively. At baseline, all patients reported symptoms of sexual arousal and/or orgasmic disorders, and some also had sexual desire and pain disorders. At 3 months, statistically significant improvements were seen in all domains tested, including sexual desire, arousal, lubrication, orgasm, sexual satisfaction, and reduced pain. The median Female Sexual Function Index total score increased from 17 to 29.4 (maximal score, 36; p <0.001). The median Derogatis Interview for Sexual Functioning total raw score increased from 46 to 95 (maximal score, 118; p <0.001). At baseline, the Derogatis Interview for Sexual Functioning total T-score corresponded to the bottom 10th percentile of normal sexual functioning. At 3 months, the total T-score placed the patients at the normalcy cutoff. Gynecologic examinations revealed improved mucosal color and moisture and vaginal elasticity and decreased bleeding and ulceration. CONCLUSION: Our results from this pilot study suggest that the clitoral therapy device may alleviate sexual dysfunction in irradiated cervical cancer patients. A randomized, controlled trial is warranted to assess the full benefits of this approach.

Phase I Trial of Carboplatin and Gemcitabine Chemotherapy and Stereotactic Ablative Radiosurgery for the Palliative Treatment of Persistent or Recurrent Gynecologic Cancer.

BACKGROUND: We conducted a phase I trial to determine the safety of systemic chemotherapy prior to abdominopelvic robotic stereotactic ablative radiotherapy (SABR) in women with persistent or recurrent gynecologic cancers. METHODS: Patients were assigned to dose-finding cohorts of day 1 carboplatin (AUC 2 or 4) and gemcitabine (600 or 800 mg/m(2)) followed by day 2 to day 4 Cyberknife SABR (8 Gy × three consecutive daily doses). Toxicities were graded prospectively by common terminology criteria for adverse events, version 4.0. SABR target and best overall treatment responses were recorded according to response evaluation criteria in solid tumors, version 1.1. FINDINGS: The maximum tolerated dose of chemotherapy preceding SABR was carboplatin AUC 4 and gemcitabine 600 mg/m(2). One patient experienced manageable, dose-limiting grade 4 neutropenia, grade 4 hypokalemia, and grade 3 nausea attributed to study treatment. One patient had a late grade 3 rectovaginal fistula 16 months after trial therapy. Among 28 SABR targets, 22 (79%) showed a partial response and 6 (21%) remained stable. INTERPRETATION: Systemic chemotherapy may be given safely prior to abdominopelvic robotic SABR with further investigation warranted.

Intensity-modulated whole pelvic radiotherapy in women with gynecologic malignancies.

PURPOSE: To describe our initial clinical experience with intensity-modulated whole pelvic radiotherapy (IM-WPRT) in women with gynecologic malignancies. METHODS AND MATERIALS: Between February 2000 and August 2001, 40 gynecology patients underwent IM-WPRT. After fabrication of customized immobilization, all patients underwent contrast-enhanced CT, and a clinical target volume was contoured consisting of the upper vagina, parametria, uterus (if present), and presacral and pelvic lymph node regions. The clinical target volume was expanded by 1 cm to create a planning target volume (PTV). Using commercially available software, 7- or 9-field, 6-MV, coplanar IM-WPRT plans were generated for all patients. The worst acute gastrointestinal and genitourinary toxicity during treatment was scored on a 4-point scale: 0, none; 1, mild, no medications required; 2, moderate, medications required; and 3, severe, treatment breaks or cessation, hospitalization. As a comparison, acute toxicities in 35 previously treated conventional WPRT patients were analyzed. No significant differences were noted in the clinicopathologic and treatment factors between the two groups. RESULTS: IM-WPRT plans provided excellent PTV coverage, with considerable sparing of the surrounding normal tissues. On average, 98.1% of the PTV received the prescription dose. The average percentage of the PTV receiving 110% and 115% of the prescription dose was 9.8% and 0.2%, respectively. IM-WPRT was well tolerated, with no patient developing Grade 3 toxicity. Grade 2 acute gastrointestinal toxicity was less common in the IM-WPRT group (60 vs. 91%, p = 0.002) than in the conventional WPRT group. Moreover, the percentage of IM-WPRT and WPRT patients requiring no or only infrequent antidiarrheal medications was 75% and 34%, respectively (p = 0.001). Although less Grade 2 genitourinary toxicity was seen in the IM-WPRT group (10% vs. 20%), this difference was not statistically significant (p = 0.22). CONCLUSION: IM-WPRT is a promising approach in gynecology patients. IMRT planning resulted in excellent PTV coverage, with considerable sparing of normal tissues. Treatment was well tolerated and associated with less acute gastrointestinal sequelae than conventional WPRT. Longer follow-up and more patients are needed, however, to evaluate the full merits of this novel approach.

Lifestyle challenges in endometrial cancer survivorship.

OBJECTIVE: To examine lifestyle behaviors that may contribute to endometrial cancer survivor morbidity and to identify associations with quality of life. METHODS: Patients with early-stage (I or II) endometrial cancer with a body mass index of at least 25 kg/m2 completed questionnaires on smoking, physical activity, fruit and vegetable intake, and the Functional Assessment of Cancer Therapy (FACT) and Short-Form medical outcomes (SF-36) quality-of-life surveys. Behaviors were compared with American Cancer Society 2006 guidelines for cancer survivors (150 min/wk of moderate-to-vigorous physical activity; five servings fruit and vegetables per day; no smoking). Effect size (d) was calculated for the difference in means between meeting and not meeting guidelines (d=0.5 moderate effect). RESULTS: A total of 120 participants were enrolled. Of those, 43% had hypertension, 35% osteoarthritis, 33% metabolic syndrome, 21% type 2 diabetes mellitus, and 93% abdominal obesity. Only 12% of participants were meeting physical activity guidelines. Fifteen percent reported five or more servings of fruit and vegetables per day; mean intake was 2.6 servings per day. Seventy-four percent of participants were nonsmokers. Only 1% of participants met all three American Cancer Society guidelines; 22% met none of the recommendations. The emotional well-being (mean 17.4 [±4.1] compared with 20.1 [±4.1]; d=0.66) and fatigue scores (mean 34.6 [±9.5] compared with 40.5 [±9.6]; d=0.62) indicate that those who do not meet the guidelines had lower emotional well-being and increased fatigue. CONCLUSION: Endometrial cancer survivors have unhealthy lifestyles that put them at risk for morbidity. This survivor group should be offered multi-behavioral lifestyle interventions after diagnosis. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT 00420979 and NCT00732173. LEVEL OF EVIDENCE: II.