Lilian T. Gien

Adenocarcinoma: A unique cervical cancer

Adenocarcinoma of the cervix constitutes only approximately 20% of all cervical carcinomas; therefore, specific Level 1 evidence to guide patient management is lacking. Most trials have included this histologic subtype but in insufficient numbers to do more than generate hypotheses from subset analyses. As a consequence, our understanding of the natural history and optimal management of adenocarcinoma of the cervix is limited. The optimal management of adenocarcinoma of the cervix continues to be a subject of debate among practitioners as to whether or not it should be different from squamous cell carcinoma and what would constitute this management. The purpose of this review was to give an overview of the current knowledge on adenocarcinoma of the cervix and its differences from squamous cell carcinoma with regard to risk factors, prognosis, survival rates, patterns of recurrence, and response to treatment. This article will focus on possible specific therapeutic directions to explore in the management of locally advanced adenocarcinomas.

Surgical outcome of robotic surgery in morbidly obese patient with endometrial cancer compared to laparotomy.

Introduction Before the introduction of robotic surgery at our institution, most obese women of class 2 or greater (body mass index [BMI] >35) underwent a laparotomy for the management of endometrial cancer. Since November 2008, we have performed most of these cases in a robotic fashion. This manuscript presents the outcome of these women in comparison with a historical cohort of women treated with laparotomy. Methods Women with clinical stage I or II endometrial cancer and a BMI greater than 35 kg/m2 treated with robotic surgery at our institution between November 2008 and November 2010 were compared with a historical cohort of similar patients who underwent laparotomy. Patients’ characteristics, operating room time, type of surgery, length of hospital stay, and incidence of perioperative complications were compared between the 2 groups. Results A total of 86 women were analyzed in this study (robotic surgery, 45; laparotomy, 41). The overall intraoperative complication rate is 5.8%. There is no statistical difference in age, number of comorbidities, BMI, prior abdominal surgery, and operative complications between the women who underwent robotic surgery versus laparotomy. Postoperative complication rates are higher in the laparotomy group (44% vs 17.7%; P = 0.007), and hospital length of stay is also higher in the laparotomy group (4 vs 2 days; P < 0.001). There is no difference in rates of (pelvic) lymph node dissection; however, para-aortic node dissection is more common in the robotic surgery group. Conclusion Robotic surgery for the surgical management of the morbidly obese patient is shown to be safe and have less perioperative complications compared with open surgery.

Sentinel node mapping with isosulfan blue dye in endometrial cancer.

OBJECTIVE To determine the feasibility of sentinel node mapping in endometrial cancer using hysteroscopic injection of isosulfan blue dye. METHODS Sixteen patients with endometrial cancer were enrolled in this pilot study. Hysteroscopy was performed at laparotomy to locate the tumour. Isosulfan blue dye was injected into the endomyometrium around the tumour by hysteroscopy, into the serosa overlying the tumour, or both. Blue lymph nodes were removed as sentinel nodes. Pelvic lymphadenectomy, total abdominal hysterectomy, and bilateral salpingo-oophorectomy were then performed. RESULTS Dye uptake into lymphatics occurred in 13 of the 16 cases (81%). Blue lymph nodes were identified in five cases with serosal injection alone (56%) and in two cases with combined serosal and hysteroscopic injection (50%). No blue lymph nodes were identified with hysteroscopic injection alone. The overall sentinel node identification rate was 44%, and the negative predictive value was 86%. CONCLUSION Although the concept of sentinel node mapping in endometrial cancer is appealing, the technique of hysteroscopic injection of isosulfan blue dye alone had minimal success in this study. Alternative methods should be explored.

Feasibility of same-day discharge after laparoscopic surgery in gynecologic oncology.

OBJECTIVE The purpose of this study is to evaluate whether same-day discharge after laparoscopic gynecologic oncology surgery is feasible and determines factors associated with admission. METHODS This retrospective cohort study included all patients consented for laparoscopy by two gynecologic oncologists at a tertiary care academic teaching hospital between January 2006 and June 2009. Procedures included those not typically discharged same-day, such as total laparoscopic simple or radical hysterectomies or radical trachelectomy +/- salpingo-oophorectomy +/- pelvic and para-aortic lymph node dissection +/- omentectomy. Those discharged same-day were compared to those admitted. Multivariate logistic regression analysis was done to determine factors associated with admission. RESULTS Three hundred three patients were included. 6.9% were converted to laparotomy. One hundred forty-seven (48.5%) had same-day discharge (median stay 295minutes). Among outpatients, 7 (4.8%) were readmitted within three weeks of surgery. Three patients (2%) could have avoided the ER or hospital admission had they been originally admitted postoperatively. No patients with same-day discharge had a major acute postoperative complication. Factors associated with admission include age (OR 1.76 for age 70years vs 50years, p=0.001), surgeon (OR 6.91, p<0.0001), conversion to laparotomy (p<0.0001), radical hysterectomy (OR 3.43, p=0.002), length of surgery (OR 2.94 for 4hours vs 2hours, p<0.0001), and surgery start time after 1PM (OR 3.77, p=0.0001). CONCLUSION Same-day discharge for laparoscopic gynecologic oncology surgery is feasible, with low morbidity and few readmissions within three weeks of surgery. Successful same-day discharge can increase by refining patient selection and operating room scheduling.

Lymph node assessment in cervical cancer: Prognostic and therapeutic implications

Lymph node status is not part of the staging system for cervical cancer, but provides important information for prognosis and treatment. This article reviews the incidence and patterns of lymph node metastasis, and the issues surrounding surgical assessment of lymph nodes. The preoperative assessment of lymph nodes by imaging, as well as the intraoperative assessment by sentinel nodes will be discussed. Finally, the prognostic and therapeutic implications of lymphadenectomy in cervical cancer will be reviewed. J. Surg. Oncol. 2009;99:242–247.

Is venous thromboprophylaxis necessary in patients undergoing minimally invasive surgery for a gynecologic malignancy

OBJECTIVES Current recommendations for the use of venous thromboprophylaxis in patients undergoing minimally invasive surgery (MIS) for a gynecologic malignancy are derived from patients undergoing open surgery. Our objective was to determine the 30-day prevalence of symptomatic venous thromboembolism (VTE) after laparoscopic gynecologic oncology procedures in patients who received no thromboprophylaxis. METHODS Between January 2006 and September 2013, women who underwent MIS for endometrial, cervical or ovarian cancer at a single institution were included. Data on patient demographics, diagnosis, comorbidities, perioperative characteristics, use of thromboprophylaxis, and diagnosis of VTE were collected retrospectively. RESULTS Of the 419 patients who underwent MIS for a gynecologic cancer, 352 (84%) received no VTE prophylaxis. At least a total laparoscopic hysterectomy (simple or radical) or pelvic lymph node dissection was performed in 95% of these patients. The median length of surgery was 137 min and 95% of patients were discharged home within 1 day of surgery. The rate of VTE in the 352 untreated patients was 0.57% (1 pulmonary embolism and 1 deep vein thrombosis). There were no VTE diagnosed within 30 days of surgery in the 67 patients who received anticoagulant thromboprophylaxis. CONCLUSION The rate of VTE is low in patients undergoing minimally invasive surgery for a gynecologic malignancy despite no VTE prophylaxis. The benefits of routine use of VTE prophylaxis in this population are questionable.

The Emerging Role of PARP Inhibitors in the Treatment of Epithelial Ovarian Cancer

Poly(ADP-ribose) polymerase-1 (PARP-1) is an important novel target in cancer therapy. This enzyme is essential in the repair of single-stranded breaks in DNA via the base excision repair pathway. Drugs which inhibit PARP are emerging as a promising new class of anticancer agents particularly effective against tumors which have lost homologous recombination (HR) through loss of functional BRCA1 and BRCA2. PARP inhibitors potentially represent a major breakthrough for patients with hereditary BRCA-associated cancers. Furthermore their role in sporadic epithelial ovarian cancer is emerging with identification of additional subpopulations of women who may benefit a priority. This paper will summarize the mechanism of action of PARP inhibition and its role in the treatment of BRCA1- and 2-associated cancers. We will then expand on the broader relevance and future directions for PARP inhibition in the clinical setting.

Fertility sparing treatment of complex atypical hyperplasia and low grade endometrial cancer using oral progestin

OBJECTIVE Oral progestin is an alternative to hysterectomy for women with complex atypical hyperplasia (CAH) or grade one endometrial cancer (G1EC) who wish fertility preservation. We evaluated treatment efficacy and fertility outcomes in this population. METHODS Women <45 y treated with oral progestin for CAH or G1EC were identified from two cancer centers. Data were obtained from medical records and telephone questionnaires. Time until complete response (CR), and from CR until recurrence was censored for patients without events and analyzed for associations with patient and treatment characteristics; cumulative incidence functions were used to estimate event probability over time. RESULTS 44 patients were identified, 19 (43%) with CAH and 25 (57%) with G1EC. Median age was 36.5 y (26-44). 24 (55%) achieved CR (median time: 5.7 months). Older age was associated with a lower likelihood of CR (HR 0.84, p=0.0003, 95% CI, 0.8-0.9). CR probability appeared to plateau after 12 months of therapy. Among those with CR, 13 (54%) recurred (median time 3.5 y). 24 patients (55%) underwent hysterectomy; 3 (13%) were upstaged. 11 (25%) underwent fertility treatment with the following outcomes: 6 (55%) no pregnancy, 2 (18%) at least one live infant, and 3 (27%) spontaneous abortion. One achieved a live birth without intervention. CONCLUSION Oral progestin is an effective temporizing fertility-sparing treatment for women with CAH/G1EC. Fertility specialist involvement is recommended due to the low live birth rate without intervention. Progestin therapy should be re-evaluated at 1 year in non-responders due to a low probability of success. Hysterectomy is recommended after childbearing due to a high recurrence rate.

Canadian high risk endometrial cancer (CHREC) consortium: Analyzing the clinical behavior of high risk endometrial cancers

OBJECTIVES The objective of this study is to analyze the clinical behavior of endometrial carcinomas by high risk(HR) histotype, including stage, overall survival, recurrence free survival and patterns of failure. METHODS This is a retrospective multi-institutional cohort study performed at 7 tertiary care centers across Canada between 2000 and 2012 and included: grade 3 endometrioid (EC3), endometrial serous cancer (ESC), clear cell carcinomas (CCC) and carcinosarcoma (CS). Clinicopathological and outcome data was collected. RESULTS 1260 women with endometrial carcinoma with 1013 having staging procedures were identified; 398 EC3, 449 ESC, 236 CS and 91 CCC. 51.8% had lymphovascular space invasion (LVSI) and 18.5% had omental involvement with a statistically significant difference between tumor types (p=0.0005 and 0.0047 respectively); ESC had a significantly greater rate of omental involvement compared to EC3 (22% to 9%, p=0.0005). Within the entire cohort 49.3% were stage 1, 10.6% were stage 2, 27.4% were stage 3 and 12.7% were stage 4. Overall survival and recurrence free survival were significantly different between histotypes (p<0.0001) with CS having the worst outcome. Overall 31.5% of patients recurred. CS and ESC had a higher distant recurrence rate compared to EC3 (29.6%, 31.0% compared to 16.4%, p=0.0002 and p<0.001). CONCLUSION This study is one of the largest clinical cohorts of HR endometrial cancers. We have further clarified the impact of histotype and stage on recurrence and survival, and the high likelihood of distant recurrence. However, the differences are modest and risk prediction models will require additional molecular markers.

Quality Control in Sentinel Lymph Node Biopsy in Cervical Cancer

In the current issue, Altgassen et al report on a prospective multicenter study comprising the largest number of cervical cancer patients in a single study undergoing sentinel lymph node (SLN) mapping. The authors analyzed 507 patients between December 1998 and October 2006 and included patients with cervical cancers of all stages. Although the majority of participating centers used both blue dye and technetium-99 for the SLN procedure, the protocol allowed either alone. The SLN and the nodes from the systematic lymphadenectomy were submitted for routine staining (hematoxylin and eosin); no ultrastaging was performed. It is important to note that the detection rate was calculated based on the number of patients with at least one detected SLN. The detection rate of pelvic SLN overall was 88.6% (95% CI, 85.8% to 91.1%) and was higher if a combination of technetium and patent blue was used (93.5%; 95% CI, 90.3% to 96%). Overall sensitivity of pelvic SLN detection was 77.4% (95% CI, 68.2% to 85.0%), which was lower than the predefined noninferiority margin of 90%. The subgroup analyses showed that the sensitivity of SLN detection was higher for patients with tumors 20 mm (90.9%) and with bilateral detection (87.2%). The authors have concluded that systematic lymphadenectomy in patients with cervical cancer should not be omitted at this time. Since the introduction of sentinel node mapping in early-stage melanomas by Morton et al, the SLN procedure has replaced systematic lymphadenectomies in both melanoma and breast cancer populations. More recently, among gynecologic malignancies, SLN mapping with blue dye and lymphoscintigraphy has been studied in both vulvar and cervical cancers. There have been many singleinstitution series in the literature reviewing their experiences with SLN mapping in cervical cancer, demonstrating high detection rates from 86% to 100%. In a recent systematic review, the sentinel node detection rate with the combined technique was 97%, with a sensitivity of 92%. However, the most recent multicenter study in this issue by Altgassen et al did not achieve similar detection and sensitivity rates as those previously published. The authors should be congratulated for accomplishing and advancing the SLN procedure in clinical practice by conducting a large multicenter study. However, this study raises further questions. Why did this promising procedure have less than the expected results? Will a systematic lymphadenectomy ever be omitted in cervical cancer? Will change in practice only be affected by a randomized trial? The results of this study highlight how the success of SLN detection depends on technique, individual surgeon experience, and the patient population chosen for this procedure. This multicenter study is a good example of how excellent results may be diluted if stringent criteria are not widely applied to a general population. The technical aspect of the SLN procedure plays a key role in maximizing results. Quality assurance, including physician training and experience, methods of detection, and central pathology review for both the primary tumor and lymph nodes are essential components to maximize success. For example, the multicenter study of SLN in vulvar cancer by van der Zee et al required each center to have successful experience with sentinel nodes in at least 10 vulvar cancer patients, use both blue dye and technetium, and submit the SLN for pathologic assessment by a protocol that included ultrastaging. Without stringent quality control measures, the overall sensitivity of the procedure can be significantly reduced. Although this study’s strength in patient numbers could only be achieved by including multiple centers, if not all centers had proven experience with the SLN procedure, the decreased detection rate could be a result of the obligatory learning phase, the definition of detection used, and lack of the other quality controls listed earlier. Altgassen et al accrued approximately 600 patients over 7 years from 18 centers. On average, that is less than five patients per year per center and potentially even less per surgeon. Although the ideal number of procedures required in cervix cancer has not been identified, Morton et al suggested a learning phase of at least 30 consecutive patients per center for cutaneous melanoma, whereas De Hullu et al suggested at least 20 consecutive patients for vulvar cancer. Time to perfect the technique, not only with the operative procedure itself, but also in conjunction with nuclear medicine and pathology, is important to consider before dismissing the sentinel node procedure. It would be interesting to know whether the accuracy was higher in the second half of the patients compared with the first half. The main theoretical benefit of the SLN procedure is to reduce the requirement for a complete lymphadenectomy with its associated morbidity in a patient population at low risk for lymph node metastases. In early-stage cervical cancer, the incidence of pelvic lymph node metastasis is approximately 10%; therefore, if the SLN is negative, 90% of patients can avoid a full pelvic lymphadenectomy and the associated morbidity of blood loss, neural injury, lymphocyst, and lymphedema. It is unclear whether more advanced cancers can obtain the same benefit and whether the SLN concept is valid in such patients. Altgassen et al included all stages of cervical cancer (20% of patients had stage IIA or greater). The incidence of pelvic lymph node involvement is approximately 25% to 30% for stage II cervical cancers and higher for subsequent stages. These tumors are also likely to present with adverse primary tumor features such as clinical tumor size more than 3 cm, depth of invasion more than 10 mm, and presence of capillary-lymphatic space involvement. Therefore, the likelihood of recommending adjuvant therapy postoperatively is high, and the usefulness of an SLN procedure in morbidity reduction in this JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 18 JUNE 2