Annekathryn Goodman

Phase III Trial of Doxorubicin Plus Cisplatin With or Without Paclitaxel Plus Filgrastim in Advanced Endometrial Carcinoma: A Gynecologic Oncology Group Study

PURPOSE To determine whether the addition of paclitaxel to doxorubicin plus cisplatin improves overall survival (OS) in women with advanced or recurrent endometrial carcinoma. Secondary comparisons included progression-free survival (PFS), response rate (RR), and toxicities. PATIENTS AND METHODS Eligible, consenting patients received doxorubicin 60 mg/m(2) and cisplatin 50 mg/m(2) (AP), or doxorubicin 45 mg/m(2) and cisplatin 50 mg/m(2) (day 1), followed by paclitaxel 160 mg/m(2) (day 2) with filgrastim support (TAP). The initial doxorubicin dose in the AP arm was reduced to 45 mg/m(2) in patients with prior pelvic radiotherapy and those older than 65 years. Both regimens were repeated every 3 weeks to a maximum of seven cycles. Patients completed a neurotoxicity questionnaire before each cycle. RESULTS Two hundred seventy-three women (10 ineligible) were registered. Objective response (57% v 34%; P <.01), PFS (median, 8.3 v 5.3 months; P <.01), and OS (median, 15.3 v 12.3 months; P =.037) were improved with TAP. Treatment was hematologically well tolerated, with only 2% of patients receiving AP, and 3% of patients receiving TAP experiencing neutropenic fever. Neurologic toxicity was worse for those receiving TAP, with 12% grade 3, and 27% grade 2 peripheral neuropathy, compared with 1% and 4%, respectively, in those receiving AP. Patient-reported neurotoxicity was significantly higher in the TAP arm following two cycles of therapy. CONCLUSION TAP significantly improves RR, PFS, and OS compared with AP. Evaluation of this regimen in the high-risk adjuvant setting is warranted, but close attention should be paid to the increased risk of peripheral neuropathy.

HPV Communication: Review of Existing Research and Recommendations for Patient Education†

The potential for human papillomavirus (HPV) DNA testing in cervical cancer prevention programs has been a topic at the forefront of cervical cancer policy discussions in recent years. To prevent some of the anxiety and psychological distress often experienced on HPV diagnosis and during the period of management, mass patient education must accompany the incorporation of HPV DNA testing into screening protocols. To contribute to a growing body of work that provides an empiric basis for development of effective counseling messages about HPV and HPV testing, this paper highlights womens most common information gaps and psychosocial concerns and describes the different perspectives offered by womens usual sources of information about HPV, including the crucial role of the clinical community in creating a shared decision making environment in which screening decisions and results can be discussed.

High-resolution imaging of gynecologic neoplasms using optical coherence tomography

BACKGROUND A modality capable of imaging the female reproductive tract, at or near the cellular level, could lead to the detection of diseases at earlier stages than currently possible. Optical coherence tomography achieves high resolutions in the cellular range (4-20 microm) and could accomplish that level of detection. METHOD Optical coherence tomography imaging of gynecologic tissue was studied in vitro on normal and neoplastic human cervical and uterine tissue. EXPERIENCE The structures of the normal ectocervix and endocervix, including epithelium, basal membrane, and glands, were identified clearly. These findings were compared with changes associated with carcinoma in situ and invasive carcinoma. The optical coherence tomography images of the uterus also showed changes between microstructural features of normal tissue and endometrial adenocarcinoma. CONCLUSION Optical coherence tomography of tissue microstructures showed potential for powerful, minimally invasive assessment of the female reproductive tract at a resolution greater than any current clinical imaging method.

Borderline tumors of the ovary: correlation of frozen and permanent histopathologic diagnosis

Objective To evaluate the correlation between the diagnosis of borderline tumor of the ovary by frozen and permanent pathology. Methods All pathology reports with diagnoses of borderline tumor of the ovary between 1980 and 1998 at Massachusetts General Hospital were reviewed. Univariate and multivariable logistic regression models were constructed for patient age, tumor size, histology, presence of bilateral or extraovarian disease, and concurrent diagnosis of endometriosis or endosalpingiosis. Results We reviewed 140 cases. The average age of patients was 52.3 years. Eighty tumors were serous, 47 mucinous, 11 mixed, and two endometrioid. The mean diameter overall was 13.7 cm (range 1–70 cm), 10.2 cm for serous, and 20.1 cm for mucinous. Diagnoses of borderline tumors by frozen and permanent pathology were consistent in 60% of cases. Frozen section interpreted a benign lesion as malignant (overdiagnosed) in 10.7% of cases, and interpreted a malignant lesion as benign (underdiagnosed) in 29.3%. No variable was a significant predicator of overdiagnosis. In univariate analysis, underdiagnosis was more likely for other types of tumors than serous (P < .001), tumors larger than 20 cm (P = .039), and tumors confined to the ovaries (P = .009). When all variables were included in a multiple regression model, only histology was a significant predictor of underdiagnosis (P = .039). Conclusion Frozen or permanent pathology reports of diagnoses of borderline tumor were consistent 60% of the time, whereas the positive predictive value of borderline by frozen section was 89.3%. Tumors other than serous are more likely to be misinterpreted.

Clinical evaluation of Atypical glandular cells of undetermined significance on cervical cytology

Abstract Objective: To determine the incidence of and identify risk factors for clinically significant diagnoses associated with the diagnosis on Papanicolaou test of atypical glandular cells of undetermined significance. Methods: A computer search was initiated of diagnoses of atypical glandular cells of undetermined significance at the Massachusetts General Hospital from January 1993 through December 1996. Seventy-three patients with 81 smears were identified that were seen in the Colposcopy Clinic. All cytology was reviewed. A clinically significant lesion was defined as high-grade squamous intraepithelial lesion (SIL) or worse, endocervical glandular atypia or worse, or carcinoma. Results: The rate of diagnoses of atypical glandular cells of undetermined significance was 0.167%. All patients underwent colposcopy, and 88% underwent endocervical curettage. A clinically significant diagnosis was made in 34.2% of patients, including cancer in 8.2%. A concurrent squamous diagnosis carried a risk of clinically significant lesion of 50%, compared with a risk of 25.5% for atypical glandular cells of undetermined significance alone (P = .043). Premenopausal and postmenopausal patients were both at risk for clinically important lesions, but premenopausal patients were more likely to have a high-grade SIL (30.4% versus 7.4%, P = .04). The subtype “suggestive of reactive” was a significant negative predictor of significant lesion (odds ratio = 0.09, 95% confidence interval 0.018, 0.482) in a logistic regression model controlling for age, menopausal status, and concurrent squamous diagnosis. Conclusion: Atypical glandular cells of undetermined significance is an important Papanicolaou test diagnosis that needs appropriate and careful evaluation. Further studies are required to clarify areas of risk and to make triage algorithms.

Comparison of the quality of life of early and advanced stage ovarian cancer survivors

OBJECTIVE The objective of this study was to compare the long-term adjustment and QOL of early and advanced stage ovarian cancer survivors (OCS). METHODS Early and advanced OCS >3 years from diagnosis with no evidence of recurrent cancer were interviewed. The following surveys were administered: EORTC QLQ-C30 (overall QOL) and QLQ-OV28 (ovarian specific issues), MHI-17 (anxiety, depression and global well-being), CALGB sexual functioning, FACT Fatigue, Becks Hopelessness Scale, Fear of Recurrence (FOR), PCL-C post-traumatic stress disorder (PTSD), Unmet Needs, FACT-Spirituality (FACT-Sp), complementary therapy (CAM use), and MOS Social Support Survey (MOS). The results of the surveys were compared between the early and advanced stage groups. RESULTS 42 advanced and 58 early stage patients were interviewed. The majority of survivors scored above the medical outpatient norm for emotional status (71% of early stage and 64% of advanced stage survivors). Overall QOL, fatigue, hopelessness, spirituality, social support, degree to which unmet needs were met and use of complementary therapy, did not differ between the two groups. No advanced stage OCS had diagnosable PTSD scores, while 6.9% of early stage survivors had scores indicative of PTSD. Decreased sexual interest attributed to cancer and anxiety when getting CA-125 testing were of concern for both groups. OCS used on average 5 CAM to improve their QOL. CONCLUSION Regardless of staging, OCS experience similarly overall positive QOL and adjustment, though PTSD, sexual problems and fear of recurrence are still important for some survivors.

Stage IA1 cervical adenocarcinoma: definition and treatment

OBJECTIVE To propose a definition for stage IA1 cervical adenocarcinoma, based on the International Federation of Gynecology and Obstetrics (FIGO) staging system, and to determine if patients meeting criteria might be candidates for conservative surgery. METHODS Two hundred women were diagnosed with early-stage cervical adenocarcinoma from 1982 to 1996. Histopathologic sections were reviewed by a gynecologic pathologist. Medical records were reviewed, and patients included in this study had microscopically identifiable lesions, up to 3 mm invasive depth, up to 7 mm tumor width, and negative margins if cone biopsy was performed. RESULTS Twenty-one patients with microinvasive adenocarcinoma met criteria for FIGO stage IA1 carcinoma of the cervix. The median (range) follow-up was 76 (30-172) months and median (range) patient age was 38 (24-75) years. Definitive treatment included type II or III radical hysterectomy in 16 cases, simple abdominal or vaginal hysterectomy in four cases, and loop electrosurgical excision procedure in one case; one patient received adjuvant pelvic radiation. The histologic subtypes were endocervical adenocarcinoma in 18 cases, adenosquamous carcinoma in two cases, and clear-cell adenocarcinoma in one case. There was no evidence of parametrial invasion or lymph node metastases in any patient who had radical surgery, and there were no disease recurrences. CONCLUSION Patients with microinvasive adenocarcinoma who met criteria for FIGO stage IA1 cervical carcinoma had disease limited to the cervix, and conservative surgery, such as cone biopsy or simple hysterectomy, might offer them definitive treatment.

Surveillance for endometrial cancer in women receiving tamoxifen.

Since the early 1980s, tamoxifen has become the standard adjuvant therapy for patients with breast cancer, reducing the risk for a second case of contralateral primary breast cancer by 30% to 50% (1, 2). The current recommended regimen for adjuvant tamoxifen therapy is 20 mg/d for 5 years. Results from the Breast Cancer Prevention Trial (3) have led to the recent approval of tamoxifen as a chemopreventive agent in women at high risk for developing breast cancer. Tamoxifen is structurally related to diethylstilbestrol and clomiphene citrate. While acting as an estrogen antagonist in the breast, it has estrogen agonist activity in other tissues, increasing thickness of the vaginal epithelium, reducing serum cholesterol levels, and preserving bone density in postmenopausal women (4-11). Laboratory studies have demonstrated estrogen-like effects on steroid hormone receptors in the endometrium (12) and growth-promoting effects on endometrial carcinoma cells (13). During the past decade, several reports (14-20) have cited an increased incidence of endometrial abnormality, ranging from polyps to cancer, in women receiving tamoxifen. Although tamoxifen has been implicated in the development of endometrial cancer, many epidemiologic and genetic risk factors that predispose women to breast cancer can also increase the overall risk for developing gynecologic cancer (21, 22). Many recommendations have been made regarding routine screening of these women for endometrial cancer, including the 1996 American College of Obstetricians and Gynecologists (ACOG) committee opinion, which left evaluation to the discretion of the individual practitioner (23). Because indications for tamoxifen use are broadening, a strategy for gynecologic surveillance is needed. Methods Studies that evaluated the relation between risk for endometrial cancer and tamoxifen use were identified by searching MEDLINE with the keywords tamoxifen and endometrial carcinoma for English-language articles published between 1966 and 1998. The resulting bibliographies were reviewed. Articles that compared the risk for endometrial cancer in tamoxifen-treated patients and untreated patients were selected. Studies that examined the use of various screening methods in this sample were also identified by searching MEDLINE (using the keywords endometrial cancer, pathology, tamoxifen, ultrasound, sonohysterography, endometrial biopsy, and hysteroscopy) and by reviewing abstracts to identify those in which screening methods were directly compared or were tested in patients who subsequently had a pathologic evaluation of the endometrium. Case reports and small case series were not included. Epidemiology of Endometrial Cancer Endometrial cancer is the most common gynecologic cancer in the United States; it is diagnosed in approximately 36 000 women each year (24). An estimated 1% to 3% of postmenopausal women will receive a diagnosis of endometrial cancer before 75 years of age, and the average age at diagnosis is estimated to be 61 years. Endometrial cancer occurs more frequently in white women, who have a lifetime risk of 2.4% (compared with 1.3% in black women). The risk factors for endometrial cancer that have been consistently found in epidemiologic studies are related to increased estrogen exposure and include nulliparity, late onset of menopause, unopposed estrogen hormone therapy, obesity, estrogen-producing ovarian neoplasms, and a history of anovulation, often caused by polycystic ovary disease (25-32) (Table 1). Women who have a family history of hereditary nonpolyposis colorectal cancer or have received pelvic radiation are also at higher risk for endometrial cancer (31, 32). Despite its prevalence, endometrial cancer results in approximately 50% fewer deaths in the United States than ovarian cancer does because most women present with abnormal bleeding when the disease is in the early stages. Table 1. Risk Factors Associated with Endometrial Cancer Screening for Ovarian and Endometrial Cancer Yearly screening with the Papanicolaou smear has dramatically reduced the incidence of cervical cancer in the United States. Endometrial and ovarian cancer can be detected by pelvic examination and Papanicolaou smear, but these screening tests are not reliable methods for detecting early disease. In most women, endometrial cancer is detected by endometrial biopsy performed because of abnormal bleeding; however, an abnormal finding on Papanicolaou smear can occasionally be the first indication of endometrial disease in asymptomatic women. A Papanicolaou smear-based diagnosis of atypical glandular cells of undetermined significance can indicate an endometrial lesion and should prompt evaluation with endometrial biopsy and colposcopy (33). The finding of benign endometrial cells on Papanicolaou smears of postmenopausal women who are not receiving hormone replacement therapy is associated with endometrial hyperplasia or cancer in 13% of cases (34) and also warrants follow-up with endometrial biopsy. Additional screening tests for ovarian epithelial adenocarcinoma and endometrial adenocarcinoma, the two types of gynecologic cancer most frequently associated with breast cancer, are not currently recommended for the general population (35). Serum CA-125 testing and pelvic ultrasonography have been offered to women at risk for ovarian cancer, but no effective screening test is available (36). Transvaginal ultrasonography allows evaluation of the endometrial cavity and measurement of the thickness of the endometrial lining. An endometrial thickness of 5 mm or less in a postmenopausal woman is a strong negative predictor for cancer [37]. Endometrial biopsy is recommended 1) for women with abnormal bleeding; 2) during evaluation of Papanicolaou smear findings of endometrial cells in postmenopausal women and atypical glandular cells of undetermined significance; and 3) for screening women with high-risk syndromes, such as hereditary nonpolyposis colon cancer (38, 39). However, other risk factors for endometrial cancer can indicate endometrial sampling in the absence of bleeding. Risk for Endometrial Cancer as a Result of Tamoxifen Use The reported relative risk for endometrial cancer associated with tamoxifen use ranges from 0.6 to 15.2. The Stockholm Trial (40) found a relative risk of 6.4 for endometrial cancer among 1846 women randomly assigned to receive tamoxifen, 30 to 40 mg/d, or placebo. Although two other large Scandinavian trials, the Danish Breast Cancer Trial and the South Sweden Breast Cancer Trial, did not show statistically significant increased risk (41-43), a meta-analysis (44) that combined these three studies and included data from 4914 women found a relative risk of 4.1 (95% CI, 1.9 to 8.9). These trials were not originally designed to evaluate risk for endometrial cancer and therefore did not control for other patient characteristics, such as use of hormone therapy, hysterectomy, or obesity. In addition, patients receiving tamoxifen have more frequent gynecologic symptoms, which leads to increased surveillance (45). Resulting concerns over selection and ascertainment bias have fueled debate over the degree of risk actually attributable to tamoxifen in these studies (46). The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14, which randomly assigned 2843 patients to receive tamoxifen, 20 mg/d, or placebo for 5 years, found that tamoxifen therapy was associated with a relative risk of 7.5 (CI, 1.7 to 32.7) for developing endometrial cancer (47). However, the placebo group in this trial had an unusually low incidence of endometrial cancer. When population data from the Surveillance, Epidemiology, and End Results (SEER) database of 87 323 patients with breast cancer was substituted as the comparison group, a relative risk of 2.2 was found. In the only available large cohort study (48), which also used the SEER database, patients receiving tamoxifen had an increased incidence of endometrial cancer; the ratio of observed incidence to expected incidence was 2.06 (CI, 1.59 to 2.55), compared with a slightly increased incidence in the no-treatment group (relative risk, 1.23 [CI, 1.11 to 1.36]). Several other randomized trials and casecontrol studies have not found a significant increased risk among patients receiving tamoxifen (49-61), but these studies have been criticized for lack of statistical power, inadequate follow-up time, and short duration of tamoxifen use in the women studied (Tables 2 and 3). Table 2. Randomized, Controlled Trials of Tamoxifen and Relative Risk for Endometrial Cancer Table 3. Case-Control and Cohort Studies of Tamoxifen Use and Endometrial Cancer Despite the problems of bias in the published studies, the overall data and the biological plausibility of an effect have led to a general consensus that tamoxifen confers an increased risk (perhaps two- to threefold) for endometrial cancer among postmenopausal women. Endometrial Surveillance in Women Who Use Tamoxifen Endometrial Sampling In a prospective cohort study of 2586 healthy, asymptomatic postmenopausal women (62), screening for endometrial cancer by biopsy was not found to be cost-effective because it detected only 1.7 cases of cancer per 1000 person-years. If a relative risk of 4.0 with tamoxifen use is assumed, approximately 6.8 cases of detected cancer per 1000 person-years would be expected. The yield from such a strategy would therefore be low. In addition, although outpatient biopsy is usually a simple and straightforward procedure, the presence of cervical stenosis can preclude outpatient sampling and require dilatation and curettage under anesthesia. In one study (63), 76 of 209 women with abnormal ultrasonography findings (31%) could not undergo outpatient endometrial sampling because of stenosis and would have required dilatation and curettage. Recent studies have found that endometrial abnormalities occurring in the setting of tamoxifen use seem to be more heteroge

Prognostic significance and predictors of the neutrophil-to-lymphocyte ratio in ovarian cancer

OBJECTIVE To investigate the neutrophil-to-lymphocyte ratio (NLR) from peripheral blood, a general measure of inflammation, in ovarian cancer. METHODS White cell counts and CA125 levels before treatment, tumor features, and questionnaire data on 519 women with ovarian cancer at two Boston hospitals were recorded. Counts were log-transformed and effects on these by tumor features and epidemiologic variables assessed by analysis of variance and generalized linear models. Cox proportional hazards models were used to assess effects on overall survival. RESULTS Greater NLR was associated with higher tumor stage and grade, presence of ascites, and bilateral disease and correlated with risk factors including Jewish ethnicity, taller height, more ovulatory cycles, and family history of cancer in premenopausal women and talc use in all women. CA125 was positively correlated with neutrophil count, monocyte count, and NLR and inversely correlated with lymphocyte count. In a multivariate adjusted analysis, high NLR predicted poorer survival and high lymphocyte count better survival. CONCLUSION An elevated NLR before treatment signals more aggressive disease and correlates with risk factors for ovarian cancer. CA125 directly correlates with neutrophils which may reflect secretion of both CA125 and neutrophilic growth factors by the tumor. CA125 inversely correlates with lymphocytes which may reflect the ability of some neutrophilic factors to induce lymphopenia and/or binding of CA125 to lymphocytes removing CA125 from the serum pool. Links between NLR, CA125, and epidemiologic factors may provide new clues about the pathogenesis and progression of ovarian cancer.

Acupuncture for Chemotherapy-Induced Neutropenia in Patients with Gynecologic Malignancies: A Pilot Randomized, Sham-Controlled Clinical Trial

OBJECTIVES The objective of this study was to investigate the effect of acupuncture administered during myelosuppressive chemotherapy on white blood cell (WBC) count and absolute neutrophil count (ANC) in patients with ovarian cancer. DESIGN This study is a pilot, randomized, sham-controlled clinical trial. Patients received active acupuncture versus sham acupuncture while undergoing chemotherapy. A standardized acupuncture protocol was employed with manual and electrostimulation. The frequency of treatment was 2-3 times per week for a total of 10 sessions, starting 1 week before the second cycle of chemotherapy. SETTING The setting was two outpatient academic centers for patients with cancer. SUBJECTS Twenty-one (21) newly diagnosed and recurrent ovarian cancer patients were the subjects. OUTCOME MEASURES WBC count, ANC, and plasma granulocyte colony-stimulating factor (G-CSF ) were assessed weekly. RESULTS The median leukocyte value in the acupuncture arm at the first day of the third cycle of chemotherapy was significantly higher than in the control arm after adjusting for baseline value (8600 cells/microL, range: 4800-12,000 versus 4400 cell/microL, range: 2300-10,000) (p = 0.046). The incidence of grade 2-4 leukopenia was less in the acupuncture arm than in the sham arm (30% versus 90%; p = 0.02). However, the median leukocyte nadir, neutrophil nadir, and recovering ANC were all higher but not statistically significantly different (p = 0.116-0.16), after adjusting for baseline differences. There were no statistically significant differences in plasma G-CSF between the two groups. CONCLUSIONS We observed clinically relevant trends of higher WBC values during one cycle of chemotherapy in patients with ovarian cancer, which suggests a potential myeloprotective effect of acupuncture. A larger trial is warranted to more definitively determine the efficacy of acupuncture on clinically important outcomes of chemotherapy-induced neutropenia.