Advanced Gynecologic Malignancies Research Articles

Surgery for colorectal peritoneal carcinomatosis

Peritoneal carcinomatosis occurs in patients with advanced gastrointestinal and gynecological malignancies and also in patients who experience recurrence after treatment failure of the primary tumor. Malignant disease in the peritoneal cavity is a morbid and significant predictor of a diminished survival in a cancer patient. Systemic chemotherapy alone will not be adequate to palliate or treat patients with peritoneal carcinomatosis. Cytoreductive surgery is a new surgical technique that is performed using peritonectomy procedures to allow total eradication of peritoneal tumors. Intraperitoneal chemotherapy regimens such as intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) and early postoperative intraperitoneal chemotherapy (EPIC) are effective adjuvant treatment to treat the minimal residual disease after cytoreductive surgery to reduce the risk of locoregional recurrence. A substantial body of evidence available in the current literature has documented the survival benefits of combining cytoreductive surgery and intraperitoneal chemotherapy to treat a previously fatal phase of malignancy. This review provides a summary of the developments in the understanding and treatment of peritoneal surface malignancy from colorectal cancer.

Ezrin is an Essential Marker for Metastasis of Gynecologic Cancer

Worldwide, gynecologic cancers account for approximately 22.9% of all female cancers, second only to breast cancer. In 2004, approximately 73,000 women in the United States were diagnosed with a cancer affecting the reproductive organs, and approximately 27,000 women died from gynecologic cancer. Among the different types of gynecologic cancer, endometrial cancer is the most common while ovarian cancer is the most deadly. It is ranked the fifth most common cause of cancer deaths in women. This condition is strongly related to late detection and increased prevalence in older women. Furthermore, in spite of having advanced diagnostic tools for gynecologic cancer detection and improved treatment modalities, there is no outstanding achievement of survival rate in patients with gynecologic cancer, and a lot of cases of advanced gynecologic malignancies are resistant to chemotherapy. So, many researchers have focused on the basic mechanism of cancer progression and distant metastasis to find clues that will improve the efficacy of cancer treatment. Many researchers are trying to find key proteins that are relevant in transforming normal cells to dysplastic or cancer cells. These proteins can better explain the complicated ISSN 1226-8704 http://dx.doi.org/10.6118/jksm.2012.18.2.81 J Korean Soc Menopause 2012;18:81-93

A Phase I Trial of Liposomal Doxorubicin, Bevacizumab, and Temsirolimus in Patients with Advanced Gynecologic and Breast Malignancies

Liposomal doxorubicin (D) and bevacizumab (A) are active single agents in gynecologic and breast malignancies which share a resistance mechanism: upregulation of hypoxia inducible factor (HIF-1α). We, therefore, added temsirolimus (T), which inhibits HIF-1α, to D and A (DAT). Trial objectives were assessment of safety, preliminary efficacy, and identification of biological response correlates. Cycle length was 21 days, with IV D, A, and T on day 1; T on days 8 and 15 (3+3 dose-escalation design with expansion cohorts). Mutational assays for PIK3CA, BRAF, KRAS, and immunhistochemistry for PTEN loss were conducted. This article details 74 patients with gynecologic and breast malignancies who received at least one dose of drug on study. Median patient age: 52 (27-79); prior regimens: 4 (1-11). Responses: 1 (1.4%) complete response (CR), 14 (18.9%) partial responses (PR), and 13 (17.6%) with stable disease (SD) ≥ 6 months (total = 37.9%). The most common grade 1 toxicities were fatigue (27%) and anemia (20.2%). Notable grade 3/4 toxicities: thrombocytopenia (9.5%), mucositis (6.7%), and bowel perforation (2.7%). PIK3CA mutations or PTEN loss were identified in 25 of 59 (42.3%) of tested patients. Among these, nine (36%) achieved CR/PR and four (16%) had SD ≥ 6 months (CR+PR+SD ≥ 6 months = 52%). DAT is well tolerated with manageable side effects. Responses observed warrant further evaluation. Mutational analyses were notable for a high percentage of responders with phosphoinositide-3-kinase pathway aberrations.

The use of Interactive, Real-time, Three-dimensional (3D) Volumetric Visualization for Image Guided Assistance in the Brachytherapy Needle Placement for Advanced Gynecological Malignancies

It is often difficult to predetermine needle length to target, proximity to bowel, vascularity (in relation to the needle path), and bony interference when performing a needle implant for advance gynecological malignancies. Needle placement can often require laparoscopic guidance. Three-dimensional, interactive, measurable volumetric software utilized by other subspecialties, i.e.: cardiovascular interventions is evaluated to see if it can accomplish this task. A patient with a vaginal recurrence of endometrial carcinoma status post exenteration with bowel adherent to tumor preventing the use of laparoscopic guidance was evaluated for brachytherapy needle placement utilizing interactive, 3D volumetric, image guided visualization. CTA study (computer tomographic angiography) was fused with a PET imaging study was used to define and refine target. Acquisition of the CTA data set occurred at .625 mm slices as compared to standard of care routine 2 - 5 mm acquisition, in an effort to improve 3D targeted path. Acquisition at .625 mm adds no additional dose of radiation to the patient and measurably improves 3D targeting and volume visualization. Skin to target distance, template to target distance, and ideal measured placement and trajectory of needles were predetermined prior to going to the operating room. The image-guided volume metrics were recorded on an iPad for additional insight during the intra-operative procedure. The only diagnostic imaging available in the operating room was fluoroscopy. Postoperative CT imaging verified needle placement with standard of care 3D treatment plan analysis. Needle placement was within 1 - 2mm of ideal placement. There was no boney obstruction of the needle, perforation of the bowel, or any vascular penetration of the of the needles. This was verified clinically and radiographically by postoperative imaging. Three-dimensional volumetric reconstructive software can assist the radiation oncologist in preplanning brachytherapy needle placement in advanced gynecological malignancies. In order to optimize the 3D volumetric reconstruction process the radiation oncologist needs to understand that CT data sets are routinely acquired at .625 mm slice thickness but are routinely stored at 5mm thickness on PACS or other storage devices. The technology of interactive image guided 3D volume reconstruction and visualization needs to be evaluated in a larger number of patients.

Guidelines on Chemotherapy in Advanced Stage Gynecological Malignancies: An Evaluation of 224 Professional Societies and Organizations

BackgroundClinical practice guidelines are important for guiding practice, but it is unclear if they are commensurate with the available evidence.MethodsWe examined guidelines produced by cancer and gynecological societies and organizations and evaluated their coverage of and stance towards chemotherapy for advanced stage disease among 4 gynecological malignancies (breast, ovarian, cervical, endometrial cancer) where the evidence for the use of chemotherapy is very different (substantial and conclusive for breast and ovarian cancer, limited and suggesting no major benefit for cervical and endometrial cancer). Eligible societies and organizations were identified through systematic internet searches (last update June 2009). Pertinent websites were scrutinized for presence of clinical practice guidelines, and relative guidelines were analyzed.ResultsAmong 224 identified eligible societies and organizations, 69 (31%) provided any sort of guidelines, while recommendations for chemotherapy on advanced stage gynecological malignancies were available in 20 of them. Only 14 had developed their own guideline, and only 5 had developed guidelines for all 4 malignancies. Use of levels of evidence and grades of recommendations, and aspects of the production, implementation, and timeliness of the guidelines did not differ significantly across malignancies. Guidelines on breast and ovarian cancer utilized significantly more randomized trials and meta-analyses. Guidelines differed across malignancies on their coverage of disease-free survival (p = 0.033), response rates (p = 0.024), symptoms relief (p = 0.005), quality of life (p = 0.001) and toxicity (p = 0.039), with breast and ovarian cancer guidelines typically covering more frequently these outcomes. All guidelines explicitly or implicitly endorsed the use of chemotherapy.ConclusionsClinical practice guidelines are provided by the minority of professional societies and organizations. Available guidelines tend to recommend chemotherapy even for diseases where the effect of chemotherapy is controversial and recommendations are based on scant evidence.

Lack of communication and control: experiences of distance caregivers of parents with advanced cancer.

To explore the new and complex phenomenon of distance caregiving in the advanced cancer population. Qualitative. A large comprehensive cancer center in the midwestern region of the United States. 14 distance caregivers of parents with advanced cancer. Patients with advanced lung, gastrointestinal, and gynecologic malignancies consented to have their distance caregiving adult children contacted to participate in the study. Responses to three open-ended questions guided the tape-recorded telephone interviews with the distance caregivers. Following transcription, content analysis with inductive coding was performed. Two major themes, communication and control, and five subthemes, benefits and burdens of distance caregiving, dealing with uncertainty, direct action through information seeking, protecting, and staying connected, emerged from the data. Distance caregivers experience some of the same stressors that local caregivers of patients with cancer experience. In addition, they have unique psychosocial needs related to the burden of geographic distance. Distance caregivers could benefit from nursing interventions targeted at their unique needs. Innovative interventions using Web-based computer technology for improved communication, as well as supportive care interventions, may be helpful.

Pelvi-perineal flap reconstruction: normal imaging appearances and post-operative complications on cross-sectional imaging

Radical pelvic surgery is often required in patients with advanced, persistent or recurrent gynaecological and anorectal malignancies. In the last decade, pedicled flap reconstructions have been increasingly used for pelvic floor and neovaginal reconstruction, introducing well-vascularised non-irradiated tissue into the wound cavity and hence reducing wound complications. The aim of this pictorial review is to describe the normal post-operative cross-sectional imaging appearances of the most commonly used pelvi-perineal flap reconstructions and to illustrate the complications that may arise at the flap donor and recipient sites.

Dosimetric comparison of high dose rate brachytherapy and intensity-modulated radiation therapy for cervical carcinoma

Intracavitary brachytherapy is an integral part of radiotherapy for locally advanced gynecologic malignancies. A dosimetric intercomparison of high dose rate intracavitary brachytherapy (HDR_BT) and intensity-modulated radiotherapy in cervical carcinoma has been made in the present study. CT scan images of 10 patients treated with HDR_BT were used for this study. A sliding-window IMRT (IMRT_SW) and step-and-shoot IMRT plans were generated using 6-MV X-rays. The cumulative dose volume histograms of target, bladder, rectum and normal tissue were analyzed for both techniques and dose distributions were compared. It was seen that the pear-shaped dose distribution characteristic of intracavitary brachytherapy with sharp dose fall-off outside the target could be achieved with IMRT. The integral dose to planning target volume was significantly higher with HDR_BT in comparison with IMRT. Significant differences between the two techniques were seen for doses to 1 cc and 2 cc of rectum, while the differences in 1 cc and 2 cc doses to bladder were not significant. The integral doses to the nontarget critical and normal structures were smaller with HDR_BT and with IMRT. It is concluded that IMRT can be the choice of treatment in case of non-availability of HDR brachytherapy facilities or when noninvasive treatments are preferred

Ileal Conduit and Continent Ileocecal Pouch for Patients Undergoing Pelvic Exenteration: Comparison of Complications and Quality of Life

Objectives:Creating a continent urinary pouch has become an alternative to the ileal conduit for patients undergoing exenteration for advanced gynecologic malignancies. The objective of this study was to compare clinical outcomes for the 2 methods.Methods:In this retrospective study, we compared intraoperative and postoperative complications and quality-of-life scores for the modified ileocecal pouch and the ileal conduit in anterior or total pelvic exenteration.Results:In 33 of 100 patients, an ileal pouch (IP) was created; the other 67 were treated by an ileal conduit (IC). Creating an IP prolonged the exenterative procedure by 97 minutes compared to an IC (IC, 453 minutes vs IP, 550 minutes;P= 0.009). Overall complication rates were similar, but patients with an IP had significantly more complications of urinary diversion (48%) than patients with an IC (31%;P= 0.03). Follow-up showed urinary loss and frequency of micturition to be comparable, but in patients with an IP, surgery for stomal complications (n = 2) and treatment of bladderstones were necessary more frequently (n = 3). Quality of life according to the 12-item Short Form Health Survey questionnaire was similar in both groups.Conclusion:A continent IP is an alternative to the IC in cases of pelvic exenteration. Early complications are more frequent with an IP than with an IC. The mode of urinary diversion has little influence on the quality of life in patients with advanced genital cancer.

Review Article: Palliative Care in Gynecologic Oncology

Patients with advanced gynecologic malignancies have a multitude of symptoms; pain, nausea, and vomiting, constipation, anorexia, diarrhea, dyspnea, as well as symptoms resulting from intestinal obstruction, hypercalcemia, ascites, and/or ureteral obstruction. Pain is best addressed through a multimodal approach. The optimum palliative management of end-stage malignant intestinal obstruction remains controversial, with no clear guidelines governing the choice of surgical versus medical management. Patient selection for palliative surgery, therefore, should be highly individualized because only carefully selected candidates may derive real benefit from such surgeries. There remains a real need for more emphasis on palliative care education in training programs.

Long‐term clinical outcome of pelvic exenteration in patients with advanced gynecological malignancies

We evaluated the outcome of pelvic exenteration in women with locally advanced primary or recurrent gynecological malignancies. All pelvic exenteration procedures performed between 01/2003 and 06/2009 were evaluated. Extent of surgical radicality, operative techniques, and outcome were evaluated. Kaplan-Meier curves were calculated for Overall (OS) and progression-free survival (PFS). Forty-seven patients (median age: 52.5 years) were evaluated. Ten of 47 patients (21.3%) had a primary and 37(78.7%) a relapsed cancer. Most common (80.8%) site of origin was the cervix. Patients (80.8%) had undergone previous pelvic irradiation. A total exenteration was performed in 32/47 patients (68%). A complete tumor resection was obtained in 23 patients (49%). Thirty-three patients (70.2%) had at least one major complication, including ileus (8.5%), intestinal-fistula (29.8%), ureteral anastomotic insufficiency (6.4%), abscess (6.4%), and cardiothrombotic events (23.4%). At a median follow-up of 7 months (range: 1-42), 22/47 patients (46.8%) died and 22/47 (46.8%) experienced a relapse. Median OS was 4 months (range: 0.1-16) and 22 months (range: 6-42) for patients with versus without postoperative tumor residuals, respectively (P = 0.0006), while median PFS was 4 months (range:0.1-16) versus 12 months (range: 6-42) (P < 0.0001). Radical pelvic exenteration due to advanced pelvic malignancies may be associated with a high morbidity. Complete tumor resection is associated with a significantly higher overall and PFS.

CT-Guided Interstitial Brachytherapy for Locally Advanced Gynecologic Malignancies

CT-Guided Interstitial Brachytherapy for Locally Advanced Gynecologic Malignancies

A phase I study of weekly temsirolimus and topotecan in the treatment of advanced and/or recurrent gynecologic malignancies

Objective The mTOR inhibitor, temsirolimus, has clinical activity in the treatment of gynecologic malignancies, particularly endometrial cancer. We sought to determine the tolerability of the combination of weekly topotecan with weekly temsirolimus. Methods Women with a history of advanced or recurrent gynecologic malignancy refractory to curative therapy were enrolled. A starting dose of 1 mg/m 2 of intravenous topotecan days 1, 8 and 15 was combined with 25 mg temsirolimus days 1, 8, 15 and 22 of a 28 day cycle. Patients with and without prior pelvic radiotherapy (RT) were dose-escalated in separate cohorts. Results Fifteen patients were treated on study. Forty-three cycles were administered, with between 1 and 7 cycles received per patient. Patient characteristics included ovarian cancer ( n = 7), endometrial cancer ( n = 3), uterine carcinosarcoma ( n = 3), and cervical cancer ( n = 2); performance status 0 ( n = 10) and 1 ( n = 5); prior chemotherapy regimens one ( n = 8), two ( n = 4), and three ( n = 3). Dose-limiting toxicity included asymptomatic neutropenia and thrombocytopenia. Four patients without prior pelvic RT were successfully treated with 1 mg/m 2 topotecan with 25 mg temsirolimus, days 1, 8, and 15 of a 28 day cycle. The combination was not tolerated in patients with a history of pelvic RT. Conclusions Dose-limiting toxicity for the combination of temsirolimus with topotecan was myelosuppression. The regimen may be safe in women who have not previously received radiation, but full doses of each agent could not be administered in combination.

The treatment of vesicovaginal fıstula by endoscopic injection of fıbrin glue

Creation of a vesicovaginal fistula (VVF) is a complication seen in a variety of patients from prolonged labour and elective hysterectomies to advanced gynaecological malignancies. Causing distressing symptoms such as a loss of continence and vulval excoriation, conventional teaching has always advocated an open surgical approach as described by Sims in 1852. This however may not be feasible in cases of advanced malignancy or attractive to the post-operative patient. In this article the case of a 46-year-old lady with a VVF following elective hysterectomy is discussed. She was successfully managed with endoscopic closure of her fistula with fibrin glue.

A phase I open-label dose-escalation study of oral BIBF 1120 combined with standard paclitaxel and carboplatin in patients with advanced gynecological malignancies

BackgroundThe purpose of the phase I dose-escalation study was to evaluate the maximum tolerated dose (MTD) of BIBF 1120, an oral triple angiokinase inhibitor of vascular endothelial growth factor, platelet derived growth factor and fibroblast growth factor receptors, combined with paclitaxel and carboplatin. Patients and methodsPatients with advanced gynecological malignancies received BIBF 1120 twice-daily (b.i.d.) continuously at 100, 150, 200 or 250 mg, combined with paclitaxel (175 mg/m2) and carboplatin (area under the curve 5 min·mg/ml) every 3 weeks. The MTD, safety, pharmacokinetics (PK) and clinical activity were evaluated. ResultsTwenty-two patients were treated. Three experienced dose-limiting toxic effects in the first treatment cycle: 1 of 13 at 200 mg b.i.d. BIBF 1120 [diarrhea, common terminology criteria for adverse events (CTCAE) grade 3]; two of two at 250 mg b.i.d. BIBF 1120 (elevated alanine aminotransferase and aspartate aminotransferase, CTCAE grade 3/4). The MTD was defined as 200 mg b.i.d. Principal adverse events were gastrointestinal disorders. No clinically relevant drug–drug interaction was observed after 20 days treatment with 200 mg b.i.d. BIBF 1120 on the PK of paclitaxel or carboplatin and vice versa. ConclusionsThe MTD of BIBF 1120 in a 20-day continuous dosing regimen with standard-dose paclitaxel and carboplatin was 200 mg b.i.d. This combination had an acceptable safety profile and no clinically relevant drug–drug interactions. Further evaluation of this combination is warranted in this indication.

1252 Outcome and characteristics of patients with advanced gynaecological malignancies enrolled in phase I trials

1252 Outcome and characteristics of patients with advanced gynaecological malignancies enrolled in phase I trials

Total pelvic exenteration with a split-thickness skin graft neovagina, continent orthotopic neobladder and rectal reanastomosis, resulting in no external ostomies and adequate sexual function

Recurrent and advanced gynecologic malignancies have limited treatment options. In 1948, Alexander Brunschwig described the total pelvic exenteration (TPE) as the en bloc removal of pelvic tumors and incorporated pelvic organs as surgical management for advanced/recurrent pelvic malignancies [1]. In this manuscript, we report the successful addition of a split-thickness skin graft to an ileal orthotopic neobladder with rectal reanastomosis.

GYN 4: phase I study of BIBF 1120 in combination with paclitaxel/carboplatin in patients with advanced gynecological malignancies

Aims: BIBF 1120 is an angiokinase inhibitor targeting VEGFR, PDGFR, FGFR kinases. Maximal tolerated dose (MTD), safety, and pharmacokinetics (PK) of twice daily BIBF 1120 in combination with carboplatin AUC 5 and paclitaxel 175mg/m² q21 (CP) was evaluated in advanced gynecological malignancies.

Surgical resection and reconstruction for advanced and recurrent gynecologic malignancies

The treatment of gynecologic malignancies entails surgery, systemic therapy and radiation therapy. Depending on the primary disease site and extent of the disease, the treatment strategies are applied alone or in combination. Over the past few decades, specialist knowledge and understanding of the pathophysiology and behavior of gynecologic neoplasms has led to a significant improvement in the relevant treatment modalities. The surgical management of gynecologic malignancies has evolved from the simple hysterectomy to more comprehensive staging procedures that are of pivotal importance for improving and estimating the prognosis and guiding the treatment of affected patients. These sometimes complex procedures encompass radical pelvic and upper abdominal surgery, including the associated urologic and intestinal procedures that are required to adequately resect the neoplasm. In this article, we will review and summarize the literature on the surgical resection and reconstruction of advanced and recurrent gy...

Laterally extended endopelvic resection (LEER)—Principles and practice

Exenteration has been used for the last 6 decades, mainly to treat cancers of the lower and middle female genital tract in the irradiated pelvis. New ablative techniques based on developmentally derived surgical anatomy termed laterally extended endopelvic resection ( LEER) aim to increase the curative resection rate, even of tumors extending to and fixed to the pelvic side wall. LEER is performed as a combination of at least two of the following procedures: total mesorectal excision, total mesometrial resection, and total mesovesical resection. In cases of lateral tumor fixation, the inclusion of pelvic side wall and floor muscles, such as the obturator internus muscle and pubococcygeus, iliococcygeus and coccygeus muscles, and eventually of the internal iliac vessel system assures the completeness of the multicompartmental resection. One hundred patients with locally advanced ( n = 25) and recurrent ( n = 75) gynecologic tumors have been treated with these new procedures. In 76 patients, the tumors were fixed to the pelvic side wall. Two patients with advanced age and extensive comorbidity died during the early postoperative period. Moderate and severe treatment-related morbidity was 70%, mainly due to compromised healing of irradiated tissue and the performance of complex reconstructions. At a median follow-up period of 30 months (range, 1–136 months), 5-year recurrence-free and disease-specific overall survival probabilities are 62% (95% CI, 52–72%) and 55% (95% CI, 43–67%), respectively. LEER has significant potential to salvage selected patients with locally advanced and recurrent gynecologic malignancies, including those with pelvic side wall disease, traditionally not considered for surgical therapy.