Diane C. Bodurka

American Society of Clinical Oncology Guideline Recommendations for Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer

PURPOSE To develop a guideline for the use of sentinel node biopsy (SNB) in early stage breast cancer. METHODS An American Society of Clinical Oncology (ASCO) Expert Panel conducted a systematic review of the literature available through February 2004 on the use of SNB in early-stage breast cancer. The panel developed a guideline for clinicians and patients regarding the appropriate use of a sentinel lymph node identification and sampling procedure from hereon referred to as SNB. The guideline was reviewed by selected experts in the field and the ASCO Health Services Committee and was approved by the ASCO Board of Directors. RESULTS The literature review identified one published prospective randomized controlled trial in which SNB was compared with axillary lymph node dissection (ALND), four limited meta-analyses, and 69 published single-institution and multicenter trials in which the test performance of SNB was evaluated with respect to the results of ALND (completion axillary dissection). There are currently no data on the effect of SLN biopsy on long-term survival of patients with breast cancer. However, a review of the available evidence demonstrates that, when performed by experienced clinicians, SNB appears to be a safe and acceptably accurate method for identifying early-stage breast cancer without involvement of the axillary lymph nodes. CONCLUSION SNB is an appropriate initial alternative to routine staging ALND for patients with early-stage breast cancer with clinically negative axillary nodes. Completion ALND remains standard treatment for patients with axillary metastases identified on SNB. Appropriately identified patients with negative results of SNB, when done under the direction of an experienced surgeon, need not have completion ALND. Isolated cancer cells detected by pathologic examination of the SLN with use of specialized techniques are currently of unknown clinical significance. Although such specialized techniques are often used, they are not a required part of SLN evaluation for breast cancer at this time. Data suggest that SNB is associated with less morbidity than ALND, but the comparative effects of these two approaches on tumor recurrence or patient survival are unknown.

Grading ovarian serous carcinoma using a two-tier system.

In this study, we evaluate a two-tier system for grading ovarian serous carcinoma. This system is based primarily on the assessment of nuclear atypia with the mitotic rate used as a secondary feature. The study included 50 cases of low-grade ovarian serous carcinoma and 50 cases of high-grade ovarian serous carcinoma retrieved from the files of the Department of Pathology at the University of Texas M. D. Anderson Cancer Center from a 28-year period. Cases assigned to the low-grade category were characterized by the presence of mild to moderate nuclear atypia. As a secondary feature, they tended to show up to 12 mitoses per 10 high power fields (HPFs), whereas those in the high-grade category had marked nuclear atypia and as a secondary feature more than 12 mitoses per 10 HPFs. For comparison, the tumors were also graded using the Shimizu/Silverberg and the FIGO grading systems. Patients in the low-grade ovarian serous carcinoma group ranged in age from 19 to 75 years (mean 41.7 years) while patients in the high-grade ovarian serous carcinoma group ranged in age from 27 to 76 years (mean 55 years). All of the cases except one were advanced FIGO stage. Using the Shimizu/Silverberg system, the low-grade ovarian serous carcinoma cases were distributed as follows: grade 1, 47 cases; grade 2, 3 cases. Using the FIGO grading system, 35 cases were grade 1 and 15 cases were grade 2. Regarding the high-grade ovarian serous carcinoma group using the Shimizu/Silverberg system, 14 of the cases were grade 2 and 36 cases were grade 3. Using the FIGO grading system, 1 case was grade 1, 38 cases were grade 2, and 11 cases were grade 3. Most of the patients in both groups were treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy and also received cisplatinum-based chemotherapy. On follow-up, 37 patients in the low-grade ovarian serous carcinoma group had died of disease at a median 4.2 years after diagnosis compared with 46 patients in the high-grade ovarian serous carcinoma group who died of disease at a median of 1.7 years. Eight patients in the low-grade ovarian serous carcinoma group and 4 patients in the high-grade ovarian serous carcinoma group were alive with disease at median follow-ups of 4.3 and 3.85 years, respectively. Four patients with low-grade serous carcinoma were alive without evidence of disease after a follow-up that ranged from 4.4 to 22.6 years (median 6.85 years), and one died of other causes 14 years after the diagnosis of her ovarian tumor. On multivariate analysis, residual tumor and tumor grade based on the M. D. Anderson two-tier system for grading ovarian serous carcinoma were found to be significant independent prognostic factors (P = 0.003 and 0.04, respectively). Of interest, 60% of the low-grade ovarian serous carcinomas in this study were associated with a serous neoplasm of low malignant potential, whereas this association was present in only 2% of the high-grade ovarian serous carcinomas. This finding could reflect a difference in the pathogenesis of ovarian serous carcinomas of different grades. In summary, there is usually a good correlation between the two-tier grading system herein presented and the Shimizu/Silverberg and the FIGO grading systems. Because this system is based on defined criteria that are easy to follow and because it involves only two diagnostic categories, it should provide better reproducibility in the grading of ovarian serous carcinoma. However, additional studies are required to validate these statements.

Quality of Life and Sexual Functioning in Cervical Cancer Survivors

PURPOSE To compare quality of life and sexual functioning in cervical cancer survivors treated with either radical hysterectomy and lymph node dissection or radiotherapy. METHODS Women were interviewed at least 5 years after initial treatment for cervical cancer. Eligible women had squamous cell tumors smaller than 6 cm at diagnosis, were currently disease-free, and had either undergone surgery or radiotherapy, but not both. The two treatment groups were then compared using univariate analysis and multivariate linear regression with a control group of age- and race-matched women with no history of cancer. RESULTS One hundred fourteen patients (37 surgery, 37 radiotherapy, 40 controls) were included for analysis. When compared with surgery patients and controls using univariate analysis, radiation patients had significantly poorer scores on standardized questionnaires measuring health-related quality of life (physical and mental health), psychosocial distress and sexual functioning. The disparity in sexual function remained significant in a multivariate analysis. Univariate and multivariate analyses did not show significant differences between radical hysterectomy patients and controls on any of the outcome measures. CONCLUSION Cervical cancer survivors treated with radiotherapy had worse sexual functioning than did those treated with radical hysterectomy and lymph node dissection. In contrast, these data suggest that cervical cancer survivors treated with surgery alone can expect overall quality of life and sexual function not unlike that of peers without a history of cancer.

Rankings and symptom assessments of side effects from chemotherapy: Insights from experienced patients with ovarian cancer

Goals of workAlthough many patients with ovarian cancer achieve favorable responses to primary chemotherapy, the majority of women will experience recurrence of their cancer. Selection of second- or third-line chemotherapy ultimately depends on patient preferences for different side effects. To better understand this process, we evaluated preferences and symptom distress in patients with ovarian cancer.Patients and methodsA total of 70 women with ovarian cancer who had previously received at least three cycles of platinum-based chemotherapy and currently undergoing chemotherapy for newly diagnosed or recurrent disease were interviewed in an outpatient chemotherapy clinic. The patients were asked to rank order 27 health states using a modified visual analog scale and to complete the Memorial Symptom Assessment Scale (MSAS).Main resultsMost favorable health states included perfect health, clinical remission and complete control of chemotherapy-induced nausea and vomiting (CINV). Least favorable health states included more severe CINV health states and death. Patients on first-line chemotherapy had less symptom distress, and rated sexual dysfunction, fatigue and memory loss more favorably than patients on second- or third-line chemotherapy (P<0.05). Married patients generally had less symptom distress compared to patients who were not married, but married patients indicated more distress with sexual dysfunction (P=0.04). Married patients rated alopecia less favorably than unmarried patients (P=0.03), but married patients viewed certain CINV health states more favorably (P=0.02–0.04).ConclusionsCINV remains one of the most dreaded side effects of chemotherapy. Separate preference profiles exist for patients with newly diagnosed and recurrent disease, as well as for married versus unmarried patients. While MSAS scores and VAS rankings showed consistency across some health states, this was not true for CINV, suggesting that current symptom status may only influence patient preferences for selected side effects.

Clinical behavior of stage II-IV low-grade serous carcinoma of the ovary

OBJECTIVE: To analyze the clinical behavior of patients with stage II-IV low-grade serous carcinoma of the ovary seen at our institution who underwent primary surgery followed by platinum-based chemotherapy. METHODS: Patients with stage II-IV low-grade serous carcinoma of the ovary from 1978 to 2003 were identified using existing databases. Clinicopathologic information was obtained from medical records. Progression-free survival and overall survival were estimated by the method of Kaplan and Meier. The log-rank test was used to compare differences between survival curves. Univariable and multivariable analyses were performed using Cox proportional hazards regression. RESULTS: We identified 112 eligible patients. Median age was 43 years.; 90% had stage III disease. Preoperative serum CA 125 was elevated in 86% of patients. The most common sites of extraovarian disease were omentum, fallopian tubes, pelvic peritoneum, and uterus. Response rate to platinum-based chemotherapy in 10 evaluable patients (15% of patients with gross residual disease) was 80%, and 42 patients underwent second-look surgery: microscopically negative findings, 2 (5%); microscopically positive disease, 13 (33%); macroscopically positive disease, 24 (62%); and insufficient information, 3 (7%). Median progression-free survival and overall survival times were 19.5 and 81.8 months. Persistent disease after primary chemotherapy was the only factor associated with shorter overall survival time (hazard ratio 3.46, 95% confidence interval 2.00–5.97, P<.001). CONCLUSION: Metastatic low-grade serous carcinoma of the ovary is characterized by young age at diagnosis and prolonged overall survival. Segregating women with this diagnosis in future clinical trials is warranted. LEVEL OF EVIDENCE: II-3

Predictors of Sexual Functioning in Ovarian Cancer Patients

PURPOSE To characterize sexual functioning of ovarian cancer patients and identify factors predicting sexual activity, functioning or satisfaction, discomfort, and habit or frequency. PATIENTS AND METHODS Data were collected on 232 women with epithelial ovarian cancer, 47% of whom were receiving treatment. RESULTS Fifty percent of the patients had engaged in sexual activity in the past month. Of those who were sexually active, 47% reported no or little desire, 80% reported problems with vaginal dryness, and 62% reported pain or discomfort during penetration. Of those who were sexually inactive, reasons included no partner (44.1%), lack of interest (38.7%), physical problems making sex difficult (23.4%), and fatigue (10.8%). Partner factors also were identified, including physical problems (16.2%), lack of interest (15.3%), and fatigue (5.4%). A multivariate model was used to predict sexual activity and included demographic, medical, and psychosocial factors as predictors. Women who were married (P <.001), were younger than 56 years (P <.001), were not receiving active treatment (P <.01), had a longer time since original diagnosis (P =.104), and liked the appearance of their bodies (P =.004) were more likely to be sexually active. Univariate analyses indicated that demographic, medical, and psychosocial factors are significantly associated with sexual functioning or satisfaction, sexual discomfort, and sexual frequency or habit. CONCLUSION Sexual rehabilitation for ovarian cancer patients should address management of physical and psychologic symptoms and include the patients partner when appropriate.

Correlation of Smoking History and Other Patient Characteristics With Major Complications of Pelvic Radiation Therapy for Cervical Cancer

PURPOSE The purpose of this study was to identify patient-related factors that influence the risk of serious late complications of pelvic radiation therapy. PATIENTS AND METHODS The records of 3,489 patients treated with radiation therapy for International Federation of Gynecology and Obstetrics stage I or II carcinoma of the cervix were reviewed for information about patient characteristics, treatment details, and outcomes. Any complication occurring or persisting more than 3 months after treatment that required hospitalization, transfusion, or an operation or caused severe symptoms or the patients death was considered a major late complication. Complication rates were calculated actuarially. The median duration of follow-up was 85 months, and 99% of patients were followed for at least 3 years or until they died. RESULTS Heavy smoking was the strongest independent predictor of overall complications (multivariate hazard ratio, 2.30; 95% confidence interval [CI], 1.84 to 2.87). The most striking influence of smoking was on the incidence of small bowel complications (hazard ratio for smokers of one or more packs per day, 3.25; 95% CI, 2.21 to 4.78). Hispanics had a significantly lower rate of small bowel complications than whites, and blacks had higher rates of bladder and rectal complications than whites. Thin women had an increased risk of gastrointestinal complications, and obese women were more likely to have serious bladder complications. CONCLUSION Complications of pelvic radiation therapy are strongly correlated with smoking, race, and other patient characteristics. These factors should be considered before the results of clinical studies are generalized to different cultural and racial groups.

Carcinoma of the Lower Uterine Segment: A Newly Described Association With Lynch Syndrome

PURPOSE Endometrial carcinoma in the lower uterine segment (LUS) is a poorly described cancer that can be clinically confused with endocervical carcinoma. We performed a case-comparison study to document the clinicopathologic characteristics of LUS tumors and their association with risk factors for endometrial cancer. PATIENTS AND METHODS The clinical records and pathology reports from women who underwent hysterectomy at our institution for endometrial or endocervical adenocarcinoma over an 11-year interval were reviewed. The LUS group consisted of women with endometrial tumors that clearly originated between the lower uterine corpus and the upper endocervix. Immunohistochemistry and microsatellite instability and MLH1 methylation assays were performed. RESULTS Thirty-five (3.5%) of 1,009 women had endometrial carcinoma of the LUS. Compared with patients with corpus tumors, LUS patients were younger, had higher stage tumors, and had more invasive tumors. Preoperative diagnosis of the LUS tumors more frequently included the possibility of endocervical adenocarcinoma. Seventy-three percent of the LUS tumors had an immunohistochemical expression pattern typical of conventional endometrioid adenocarcinoma. Ten (29%) of 35 women with LUS tumors were confirmed to have Lynch syndrome or were strongly suspected to have Lynch syndrome on the basis of tissue-based molecular assays. CONCLUSION The prevalence of Lynch syndrome in patients with LUS endometrial carcinoma (29%) is much greater than that of the general endometrial cancer patient population (1.8%) or in endometrial cancer patients younger than age 50 years (8% to 9%). On the basis of our results, the possibility of Lynch syndrome should be considered in women with LUS tumors.

Response and survival in patients with progressive or recurrent serous ovarian tumors of low malignant potential

OBJECTIVE To evaluate the response to therapy and survival of patients with progressive or recurrent serous ovarian tumors of low malignant potential. METHODS Fifty‐three patients with progressive or recurrent serous ovarian tumors of low malignant potential were identified. Response was assessed and progression‐free and overall survival were analyzed. The influence of clinicopathologic factors on survival was determined. RESULTS In 49 patients with known histology of progression or recurrence, 36 (73%) had low‐grade serous carcinoma, and 13 (27%) had serous ovarian tumors of low malignant potential. Forty‐five patients received nonsurgical therapy and had an evaluable response. There were six (13%) patients with a complete response and six (13%) patients with a partial response. The median time to first progression or recurrence was 5.6 years. Median survival from diagnosis of first recurrence was 7.7 years. Median survival from initial diagnosis was 21 years. Nineteen (36%) patients are dead of tumor. Patients who recurred with low‐grade serous carcinoma were more likely to die of tumor than those with serous ovarian tumors of low malignant potential (47% versus 0%, P = .045). Optimal cytoreduction was associated with improved survival (P = .007). CONCLUSION Patients with progressive or recurrent serous ovarian tumors of low malignant potential have a long interval from diagnosis to progression and from progression to death, resulting in extended overall survival. Recurrence as low‐grade serous carcinoma and failure to achieve optimal secondary cytoreduction were adverse prognostic factors. There were few responses to nonsurgical therapy.

Overexpression of the Centrosomal Protein Aurora-A Kinase is Associated with Poor Prognosis in Epithelial Ovarian Cancer Patients

Purpose: To assess the clinical significance of Aurora-A kinase, a centrosome-regulating serine-threonine kinase, in ovarian carcinoma. Experimental Design: Aurora-A kinase expression was assessed by Western blot (cell lines) or immunohistochemistry (high-grade epithelial ovarian cancers), and clinical variables were collected by retrospective chart review. Centrosome amplification was assessed by immunofluorescence in cell lines, and by immunohistochemistry in patient samples. Results: All ovarian cancer cell lines exhibited significant Aurora-A kinase protein overexpression, and all except A2780-par had centrosome amplification, a characteristic of mitotic dysregulation leading to genomic instability. Fifty-eight of 70 patient samples (82.8%) exhibited Aurora-A kinase overexpression compared with normal ovarian surface epithelium. High Aurora-A kinase expression was strongly associated with supernumerary centrosome count in tumor cells (P < 0.001). Tumors with the greatest Aurora-A overexpression (n = 24) had decreased patient survival (median survival, 1.44 versus 2.81 years; P = 0.01). High Aurora-A expression and suboptimal surgical cytoreduction remained predictors of poor survival (P < 0.05) by multivariate analysis. Conclusions: Aurora-A kinase is overexpressed by a substantial proportion of ovarian cancers and is associated with centrosome amplification and poor survival. It may be a useful prognostic marker and target in ovarian cancer.