Upper abdominal cytoreduction and thoracoscopy for advanced epithelial ovarian cancer: unanswered questions and the impact on treatment.

Gynaecological oncologists, by conducting Phase II and III chemotherapy trials, have sought to improve survival in women with epithelial ovarian cancer. The greatest impact on survival has been the use of intraperitoneal chemotherapy in women who have had all visible disease removed. No change in drug regimen has had an impact on survival equivalent to that associated with complete cytoreduction or the use of intraperitoneal chemotherapy. Interestingly, these two treatment modalities (complete cytoreduction and intraperitoneal chemotherapy) have not been universally adopted. Most often it is the inability to achieve optimal cytoreduction in the upper abdomen that defines the limit of the cytoreductive effort, and ultimately the integration of intraperitoneal chemotherapy. The importance of identifying disease outside the abdominal cavity, along with achieving complete cytoreduction, is paramount, if the use of intraperitoneal chemotherapy is to be logically integrated in treatment algorithms for women with advanced-stage epithelial ovarian cancer. This report summarises pertinent literature on upper abdominal cytoreduction, discusses surgical techniques and introduces new data on women with epithelial ovarian cancer undergoing thoracoscopy, suggesting consideration of its incorporation into the surgical management of advanced epithelial ovarian cancer.

Carbonic anhydrase IX (CA-IX) and high-risk human papillomavirus (H-HPV) as diagnostic biomarkers of cervical dysplasia/neoplasia in Japanese women with a cytologic diagnosis of atypical glandular cells (AGC): a Gynecologic Oncology Group (GOG) Study.

BACKGROUND: High-risk human papillomavirus (H-HPV) infection is linked to cervical neoplasia but its role in detecting cervical glandular lesions (GLs) is unclear. Carbonic anhydrase IX (CA-IX) is a hypoxic biomarker that is highly expressed in neoplastic cervical GLs. The diagnostic utility of these biomarkers was evaluated by the Gynecologic Oncology Group in Japanese women with a cytological diagnosis of atypical glandular cells. METHODS: Immunostaining was used to detect CA-IX in a conventional Pap smear. Immunoreactivity of CA-IX was interpreted by a panel of pathologists blinded to the histological diagnosis. Polymerase chain reaction was used to detect H-HPV in a liquid-based cytology specimen. RESULTS: Significant cervical lesions (SCLs), defined as cervical intraepithelial neoplasia (CIN2, CIN3), adenocarcinoma in situ or invasive carcinoma, were observed in 37/88 (42%) of women. CA-IX testing alone (n=88) had a sensitivity of 89, 100 or 73% for SCLs, GLs or significant squamous lesions (SLs), respectively, with a false negative rate (FNR) of 14%. Testing for H-HPV (n=84) had a sensitivity of 65, 53 or 80% for SCLs, GLs or SLs, respectively, with a FNR of 22%. The combination of CA-IX and H-HPV testing had a sensitivity of 97, 100 or 93% for SCLs, GLs or SLs, respectively, with a FNR of 5%. Among eight H-HPV-negative GLs, six (75%) had a diagnosis of lobular endocervical glandular hyperplasia (LEGH). CONCLUSION: The combination of CA-IX and HPV testing improved the diagnostic accuracy. The low rate of H-HPV positivity in the GLs was associated with coexisting LEGH independent of H-HPV.

Tumor heterogeneity in ovarian cancer as demonstrated by in vitro chemoresistance assays.

OBJECTIVE: Tumor heterogeneity has been demonstrated in solid tumors. In vitro assays were developed in an effort to predict in vivo tumor response to therapy. We compare the in vitro assay results from multiple synchronous tumor samples in primary and recurrent ovarian cancers. METHODS: 38 patients underwent surgery for primary (18) or recurrent (20) ovarian cancer. Two (22) or three (16) samples were obtained per patient and tested using the EDR assay (Oncotech, Inc.). The percentage of Extreme (E), Intermediate (I) and Low (L) drug resistance for each chemotherapy was compared between synchronous specimens. RESULTS: A total of 92 samples were collected and 787 drug assays were performed. Tumor heterogeneity was seen in 22.4% of all cases, including 18.6% primary and 26.1% recurrent diseases (p=0.01). Two category differences (L vs. E) were seen in 4.1% primary and 11.3% recurrent cases (7.8% of all cases). Overall, an increased frequency in EDR was seen in recurrent disease as compared to primary for all agents tested (22.9% primary vs. 31.6% recurrent, p=0.006). Marked heterogeneity of the drug resistance profiles was seen with paclitaxel as compared with cisplatin/gemcitabine (p=0.03), taxotere (p=0.04) or topotecan (p=0.04). No association was demonstrated between assay results and clinicopathologic parameters collected in this cohort. CONCLUSIONS: Treatment failure is often attributed to the development of chemoresistance. These results suggest that tumor heterogeneity may play an equally important role in treatment failure. Recurrent lesions exhibit greater heterogeneity and more frequent EDR. These data can influence therapeutic strategy i.e., multiple samples, sequential, or consolidation therapy.

Regional blood flow occlusion during extensive pelvic procedures for ovarian cancer: a randomized trial.

The objective of this study was to determine the effects of intraoperative aortic occlusion on blood loss and operative time when used during en bloc resection of internal reproductive organs, pelvic peritoneum, and rectosigmoid colon [modified posterior exenteration (MPE)] for primary cytoreduction of ovarian cancer. Patients undergoing MPE, without palpable distal aortic plaque or calcification, were randomized to: (a) complete distal aortic occlusion (

The relative importance of surgical training and laboratory research in a gynecologic oncology fellowship.

The objective was to determine trends of surgical skill acquisition during fellowships, and the consensus amongst gynecologic oncologists about the relative importance of surgical training and laboratory research in fellowships. A survey addressing surgical capability at the time of fellowship completion, and relative priorities that should be given to surgical training and laboratory research was mailed to gynecologic oncologists and fellows in the Society of Gynecologic Oncologists directory. Of 820 surveyed, 454 (55.4%) of provided utilizable data, of whom 56 (12.5%) were fellows, and 398 (87.5%) in practice (49.5% university-based and 50.5% community hospital-based). Relative to past graduates, recent ones report and current fellows anticipate a lower probability of being able to independently perform some procedures applicable to cervical and ovarian cancer, as well as others necessary to manage complications at the time of fellowship completion. 69.8% of all respondents think that greater emphasis should be placed on surgical training at the expense of doing less laboratory research. There is wide variation of opinion among respondents concerning the value of and most appropriate length of time that should be dedicated to laboratory research in a fellowship. There is an indication of a trend for more recent fellows to graduate having acquired less surgical skill and a prevalent opinion that surgical training should be more heavily emphasized in fellowships.

Radiation fields in gynecologic oncology: correlation of soft tissue (surgical) to radiologic landmarks.

OBJECTIVES: (1). To determine if radiation fields defined by bony structure landmarks correlate to anatomic boundaries of lymph node dissection marked intraoperatively; and (2). to determine if a patient's body mass index (BMI) correlates with these anatomic or radiographic boundaries. METHODS: One hundred patients undergoing exploratory laparotomy with pelvic and paraaortic lymph node dissection had three medium hemoclips placed at vascular junctions considered of clinical significance to lymph node dissection: insertion of the left ovarian vein into the renal vein, insertion of the right ovarian vein into the vena cava, inferior mesenteric artery (IMA), bifurcation of the aorta, bifurcation of the common iliacs (bilateral), and the insertion of the deep circumflex vein (DCV) in to the external iliac vein (bilateral). Postoperatively, an abdominal X-ray was obtained. Comparisons were made between these eight major vascular landmarks and radiographic bony landmarks that are used to define radiation field boundaries. The percentage of vascular landmarks that were encompassed or fell outside of traditional radiation fields was determined with a 1-cm margin considered an adequate boundary for radiation. These measurements were also compared to patient BMIs. RESULTS: Radiation fields defined by traditional bony landmarks would adequately encompass the paraaortic lymph nodes in the majority of patients (91%). For pelvic radiation fields, there was a significant "miss" (39%) of common iliac lymph nodes. Approximately one quarter (26%) of patients would receive inadequate coverage of one or both of the lateral boundaries of pelvic radiation. There was no apparent correlation of BMI to vascular or bony landmarks. CONCLUSIONS: Radiation fields determined by traditional bony landmarks do not adequately reflect the anatomic (surgical) landmarks associated with the lymphatic drainage of the female reproductive organs. Although the majority of tertiary care centers now use advanced imaging techniques (e.g. computed tomography) to plan their radiation treatments, the historical guidelines of radiographic landmarks are still used in smaller institutions and continue to be referenced in Gynecologic Oncology Group protocols. For centers still using radiographic landmarks, the application of hemoclips with X-ray identification is a low-cost modality that is easily reproducible and may be clinically useful in guiding treatment.

Surgical chores and approach in the management of endometrial cancer.

Carcinoma of the uterine corpus is the most common malignancy in the female pelvis. Surgical resection and staging are now the accepted approach to therapy, with excellent survival compared with other gynecologic malignancies. Several controversies exist, however, regarding optimal surgical management. Some of these controversies are addressed in this article, with a review of their recent and historic literature.

Procedures required to accomplish complete cytoreduction of ovarian cancer: is there a correlation with "biological aggressiveness" and survival?

OBJECTIVE: The aim of this study was to determine if the necessity of using specific procedures to attain complete cytoreduction in ovarian cancer correlates with innate biologic aggressiveness and independently influences survival. METHODS: Between 1990 and 2000, 213 patients with Stage IIIC epithelial ovarian cancer underwent complete cytoreduction before initiation of systemic platinum-based combination chemotherapy. Survival was stratified and analyzed (log rank and Cox regression) on the basis of whether extrapelvic bowel resection, diaphragm stripping, full-thickness diaphragm resection, modified posterior pelvic exenteration, peritoneal implant ablation and/or aspiration, and excision of grossly involved retroperitoneal lymph nodes were necessary to attain a visibly disease-free cytoreductive outcome. RESULTS: The median and estimated 5-year survival for the cohort were 75.8 months and 54%, respectively. Survival was influenced (log rank) by the requirement of diaphragm stripping (required, median 42 months vs not required, median 79 months; P = 0.03) and the extent of mesenteric and serosal implants that required removal (none, median not reached, vs 1-50 implants, median not reached, vs >50 implants, median 40 months; P = 0.002). Survival was independently influenced (Cox regression) only by the extent of peritoneal metastatic implants that required removal (P = 0.01). The other investigated procedures and type of chemotherapy used did not influence survival. CONCLUSIONS: The need to remove a large number of peritoneal implants correlates with biological aggressiveness and diminished survival, but not significantly enough to preclude long-term survival or justify abbreviation of the operative effort. The need to use the other investigated procedures had minimal or no observed influence on survival.

What are the current surgical objectives, strategies, and technical capabilities of gynecologic oncologists treating advanced epithelial ovarian cancer?

OBJECTIVE: The purpose of this survey was to determine the range of surgical objectives, strategies, and outcomes of primary cytoreductive operations performed by gynecologic oncologists. METHODS: A survey addressing the definition of "optimal" cytoreduction, the use of neoadjuvant chemotherapy, disease sites precluding optimal cytoreduction, reasons optimal cytoreduction or cytoreduction to a visibly disease-free outcome is or is not accomplished, the use of 15 specific operative procedures, and attitude toward postfellowship training in the surgical management of advanced stage epithelial ovarian cancer was mailed to candidate and full members of the Society of Gynecologic Oncologists. Analysis of discrete and binomial data utilized the chi(2) and independent samples t tests. Logistic regression confirmed relationships between responses and both the definition of optimal cytoreduction and the attitudes toward postfellowship training. RESULTS: Three hundred ninety-three (61.4%) of 640 physicians provided utilizable data. A median of 95% of patients were reported to be operated on primarily and 5% were treated with neoadjuvant chemotherapy (P < 0.0001). A median of 9 (range 0-15) of the surveyed procedures were utilized. Forty-seven (12.0%) respondents defined optimal cytoreduction as no residual disease, 54 (13.7%) used a 5-mm threshold, 239 (60.8%) used a 1-cm threshold, and 48 (12.6%) utilized a 1.5- to 2.0-cm threshold. Small dimensions of residual disease (0-5 mm versus 1-2 cm) defined optimal cytoreduction for physicians indicating that fewer disease sites precluded optimal cytoreduction (P = 0.02), using a larger number of the surveyed procedures (P = 0.04), and in practice longer (P = 0.001). Three hundred seventeen (83.9%) of 378 respondents favored development of postfellowship training in cytoreductive surgery. Physicians against postfellowship training used fewer of the surveyed procedures because of concerns about efficacy (P = 0.01). More recent fellowship graduates favored postfellowship training (P = 0.01). CONCLUSIONS: A range of surgical objectives, strategies, procedures used, and outcomes exists among gynecologic oncologists. Confirmation of the efficacy of cytoreductive surgery may cultivate a consensus about the most appropriate therapeutic objective and strategy for advanced ovarian cancer. Cooperative efforts should be undertaken to offer postfellowship training.

The clinical significance of occult macroscopically positive retroperitoneal nodes in patients with epithelial ovarian cancer.

OBJECTIVE: The goal of this study was to determine the time during primary cytoreduction when retroperitoneal lymph nodes that are involved with macroscopic disease are recognized to be involved with tumor, the dimensions of intranodal disease present, and the possible clinical significance of macroscopically positive nodes that are recognized at different phases of the operation. METHODS: One hundred consecutive patients with stage IIIC and IV epithelial ovarian cancer underwent a retroperitoneal lymph node dissection during primary cytoreductive surgery. The phase of the operation in which nodes were recognized to be macroscopically involved with tumor was noted. Nodes were classified to be positive by palpation if recognized to be macroscopically involved by transperitoneal palpation, positive by inspection if recognized to be macroscopically involved by palpation after opening the retroperitoneal area, and positive by dissection if recognized to be macroscopically involved anytime after starting the actual process of lymph node dissection. The largest dimension of the intranodal disease in macroscopically positive nodes was measured. Log rank analysis determined whether nodal status or the time at which the nodes were recognized to be macroscopically positive influenced the probability of survival. RESULTS: Of the 100 patients, 66 had positive lymph nodes. Five were microscopically positive and 61 were macroscopically positive, of which 19 (31.1%) were positive by palpation, 16 (26.2%) were positive by inspection, 26 (42.6%) were positive by dissection. Of the 39 patients with negative and microscopically positive nodes 15 (38.5%) were clinically suspicious. Compared with patients with negative and microscopically positive lymph nodes, survival was not significantly different for patients who required excision of macroscopically positive nodal tissue. Survival was not influenced by the specific phase of surgery in which macroscopically positive nodes were recognized. CONCLUSIONS: A significant percentage of patients had retroperitoneal nodes recognized to be involved with macroscopic disease only after a lymph node dissection was in progress. The decision not to perform a lymph node dissection for optimally and completely cytoreduced patients may result in unrecognized macroscopic residual disease that is larger than what would otherwise be documented.

Second-look laparotomy after modified posterior exenteration: patterns of persistence and recurrence in patients with stage III and stage IV ovarian cancer.

OBJECTIVE: The purpose of this study was to determine patterns of persistence and recurrence in patients with advanced ovarian cancer (stage IIIC and stage IV) after modified posterior exenteration. STUDY DESIGN: Retrospective chart review was used to determine patterns of persistence and recurrence of disease in patients undergoing modified posterior exenteration. From January 1, 1987, to September 15, 1998, 151 of 212 (71.2%) patients undergoing modified posterior exenteration in addition to other cytoreductive surgical procedures for stage IIIC and stage IV ovarian cancer underwent second-look laparotomy. The average age of the patients was 60.3 years (range, 20.3-86.3). A total of 207 of the 212 (97.6%) had grade 2 or 3 disease. Papillary serous carcinoma (113/212; 53.3%) and adenocarcinoma (75/212; 35.4%) were the most frequent cell types encountered. After initial cytoreductive surgery, minimal disease (<5 mm) was present in 206 of the 212 (96.2%) patients with 153 of 212 (72.2%) having no visible residual disease. There were 4 (1.9%) postoperative deaths. In 13 patients (6.1%) progressive disease was noted. Second-look laparotomy was not undertaken in 61 of the 212 (28%) patients. Fluid for cytologic testing was obtained from all four intra-abdominal quadrants, and biopsies of previously noted sites of disease were performed, in addition to random biopsies of diaphragmatic peritoneum, colonic gutters, and pelvic peritoneum. If present, the retroperitoneal lymph nodes were resected; biopsy specimens of these sites were obtained if there was no evidence of intraperitoneal disease. RESULTS: Findings at second-look laparotomy were negative for cancer in 85 of 151 (56.3%) and positive for cancer in 66 of 151 (43.7%). Only 8 of 151 (5.3%) patients had persistent disease in the pelvis. In the remainder (58/151; 38.4%) disease was found either in the upper abdomen or in the bowel mesentery. Recurrence was documented in the upper abdomen only (71/212; 33.5%), upper abdomen and pelvis (18/212; 8.5%), multiple sites excluding the pelvis (22/212; 10.4%), pelvis only (2/212; 0. 9%), chest alone (5/212; 2.4%), head alone (4/212; 1.9%), or groin alone (2/212; 0.9%). Median survival in the overall group was 51.1 months, with estimated 5- and 10-year survival rates of 44.2% and 32. 9%, respectively. CONCLUSIONS: Modified posterior exenteration is an effective surgical means of eliminating pelvic disease in patients with advanced ovarian cancer. Results of second-look laparotomy confirmed that only 8 of 151 (5.3%) had persistent disease in the pelvis.

The role of secondary cytoreductive surgery in the treatment of patients with recurrent epithelial ovarian carcinoma.

BACKGROUND: This study examined the impact of secondary cytoreductive surgery on survival of patients with recurrent epithelial ovarian carcinoma. METHODS: One hundred six patients with a disease free interval (DFI) > 6 months after primary treatment underwent secondary cytoreductive surgery. Multivariate analysis determined which variables influenced the cytoreductive outcome and survival. RESULTS: Eighty-seven patients (82.1%) underwent removal of all visible tumor. The median and estimated 5-year survival for the entire cohort after recurrence was 35.9 months and 28%, respectively. The probability of complete cytoreduction was influenced by the largest size of recurrent tumor (< 10 cm ¿90.0% vs. > 10 cm ¿66.7%; P = 0.003), use of salvage chemotherapy before secondary surgery (chemotherapy given ¿64.3% vs. chemotherapy not given ¿93.8%; P = 0.001), and preoperative Gynecologic Oncology Group performance status (0 ¿100%, 1 ¿91.4%, 2 ¿82.4%, and 3 ¿47.4%; P = 0.001). Survival was influenced by the DFI after primary treatment (6-12 months ¿median, 25.0 months vs. 13-36 months ¿median, 44.4 months vs. > 36 months ¿median, 56.8 months; P = 0.005), the completeness of cytoreduction (visibly disease free ¿median, 44.4 months vs. any residual disease ¿median, 19.3 months; P = 0.007), the use of salvage chemotherapy before secondary surgery (chemotherapy given ¿median, 24.9 months vs. chemotherapy not given ¿median, 48.4 months; P = 0.005), and the largest size of recurrent tumor (< 10 cm ¿median, 37.3 months vs. > 10 cm ¿median, 35.6 months; P = 0.04). CONCLUSIONS: Complete cytoreduction is possible for the majority of patients with recurrent epithelial ovarian carcinoma and maximizes survival if undertaken before salvage chemotherapy. The authors believe a randomized trial should be initiated to confirm these findings.

Phase II trial of intraperitoneal paclitaxel in carcinoma of the ovary, tube, and peritoneum: a Gynecologic Oncology Group Study.

PURPOSE: To determine the response rate of intraperitoneal (i.p.) paclitaxel in patients with small-volume residual carcinomas of the ovary, fallopian tube, or peritoneum. PATIENTS AND METHODS: Eligibility criteria included patients with one of the cancers noted above, with the largest residual disease 0.5 cm or less in maximum diameter at the end of second-look surgery, and prior treatment with systemic paclitaxel was permitted. The treatment plan was paclitaxel 60 mg/m2 i.p. weekly for 16 weeks, followed by surgical evaluation in patients without evidence of disease progression. RESULTS: Of 80 patients entered onto the study, 76 were eligible, of whom 86% were considered to be potentially cisplatin-sensitive. Although five patients (7%) did not complete the first course of therapy because of catheter leakage or blockade, 53 patients (70%) received all 16 planned courses. Only 14 patients (18%) received fewer than 11 courses. Treatment was well tolerated, which included only moderate abdominal pain (grade 2, 12 patients; grade 3, one patient) and minimal neutropenia (grade 2, three patients; grade 3, one patient). Of 28 assessable patients with microscopic disease at the start of i.p. therapy, 17 patients (61%) achieved a surgically defined complete response (CR). Only one of 31 patients (3%) with any macroscopic disease achieved a CR. Of the eligible patients, 18 of 76 (24%) achieved a CR. CONCLUSION: Salvage i.p. paclitaxel is tolerable and active in patients with microscopic residual disease. The impact of this treatment strategy on survival remains to be assessed in a phase III trial.

Flow cytometric analysis of lymph node metastases in advanced ovarian cancer: clinical and biologic significance.

OBJECTIVE: This study was undertaken to evaluate the deoxyribonucleic acid content and S-phase fraction in advanced epithelial ovarian carcinomas to determine whether lymph node metastases are biologically distinct from peritoneal sites of metastases. STUDY DESIGN: Thirty-five patients with stage III or IV epithelial ovarian cancer who had undergone complete pelvic and paraaortic lymphadenectomy had representative samples from the primary ovarian tumor, peritoneal metastases, and lymph node metastases analyzed by flow cytometry for deoxyribonucleic acid nuclear content and S-phase fraction. RESULTS: Diploid cell lines are found in metastatic lymph nodes (52%) significantly more frequently than in peritoneal metastases (25%, p < 0.02) or in primary ovarian tumors (26%, p < 0.001). The ploidy category frequency distribution of peritoneal metastases mirrors that found in the primary tumor, and both are significantly different from the ploidy category frequency distribution found in metastatic lymph nodes. Heterogeneity among sites is common, being identified in 54% of patients. Peritoneal metastases are more likely to be concordant with the primary tumor (69%) than are lymph node metastases (39%, p < 0.001). Mean S-phase fraction did not differ overall by site but was significantly different between diploid and aneuploid samples by site. Diploid lymph node metastases were found to have the lowest mean S-phase fraction (7.2% +/- 3.3%), and aneuploid lymph node metastases had the highest mean S-phase fraction (22.3% +/- 10.2%). Diploidy of the primary tumor is a positive predictor of long-term survival. Tumoral heterogeneity and lymph node metastases are not related to survival in this group of patients who underwent therapeutic pelvic and aortic lymphadenectomy. CONCLUSIONS: A high proportion of tumor deposits found in metastatic lymph nodes are diploid with a low S-phase fraction. Therapeutic pelvic and aortic lymph node dissection removes disease that, on the basis of flow cytometric characteristics, may be predicted to be resistant to chemotherapy and radiation therapy.

Laparoscopic radical hysterectomy (type III) with aortic and pelvic lymphadenectomy.

OBJECTIVE: The purpose of this study was to incorporate a wide range of operative laparoscopic techniques to complete a type III radical hysterectomy with aortic and pelvic lymphadenectomy. STUDY DESIGN: A type III radical hysterectomy with bilateral aortic and pelvic lymph node dissection was separated into eight component parts: (1) right and left aortic lymphadenectomy, (2) right and left pelvic lymphadenectomy, (3) development of the paravesical and pararectal spaces, (4) ureteral dissection, (5) ligation and dissection of the uterine artery, (6) development of the vesicouterine and rectovaginal spaces, (7) resection of the parametria, and (8) resection of the upper vagina. The adequacy of the component parts was determined and documented on video. RESULTS: Complete aortic and pelvic lymphadenectomy and a type III radical hysterectomy were performed by operative laparoscopy. Argon beam coagulation and countertraction facilitated pelvic and aortic lymph node dissection, including removal of nodal tissue lateral to the iliac vessels. Ureteral dissection with resection of the cervicovesical fascia ("the tunnel") was completed with right-angle dissectors, vascular clips, and argon-beam coagulation. Resection of the cardinal and ureterosacral ligaments was successful by use of Endo-GIA stapling instruments (United States Surgical Corporation, Norwalk, Ct.). CONCLUSION: A complete pelvic and aortic lymphadenectomy and type III radical hysterectomy were performed laparoscopically. This approach could potentially decrease morbidity historically associated with radical hysterectomy and lymphadenectomy performed either abdominally or vaginally. Only prospective randomized trails will allow for the evaluation of potential benefits associated with this surgical technique.