A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours.

BACKGROUND: Two strategies to interrogate the insulin growth factor 1 receptor (IGF-1R) pathway were investigated: vertical inhibition with dalotuzumab and MK-2206 or ridaforolimus to potentiate PI3K pathway targeting and horizontal cross-talk inhibition with dalotuzumab and MK-0752 to exert effects against cellular proliferation, angiogenesis, and stem cell propagation. METHODS: A phase I, multi-cohort dose escalation study was conducted in patients with advanced solid tumours. Patients received dalotuzumab (10 mg kg(-1)) and escalating doses of MK-2206 (90-200 mg) or escalating doses of dalotuzumab (7.5-10 mg kg(-1)) and MK-0752 (1800 mg) weekly. Upon maximum tolerated dose determination, patients with low-RAS signature, high-IGF1 expression ovarian cancer were randomised to dalotuzumab/MK-2206 versus dalotuzumab/ridaforolimus, whereas patients with high IGF1/low IGF2 expression colorectal cancer received dalotuzumab/MK-0752. RESULTS: A total of 47 patients were enrolled: 29 in part A (18 in the dalotuzumab/MK-2206 arm and 11 in the dalotuzumab/MK-0752 arm) and 18 in part B (6 in each arm). Dose-limiting toxicities (DLTs) for dalotuzumab/MK-2206 included grade 4 neutropenia and grade 3 serum sickness-like reaction, maculopapular rash, and gastrointestinal inflammation. For dalotuzumab/MK-0752, DLTs included grade 3 dehydration, rash, and diarrhoea. Seven patients remained on study for >4 cycles. CONCLUSIONS: Dalotuzumab/MK-2206 and dalotuzumab/MK-0752 combinations were tolerable. Further developments of prospectively validated predictive biomarkers to aid in patient selection for anti-IGF-1R therapies are needed.

Overview of a chemoresponse assay in ovarian cancer.

The objective of this review is to summarize recent scientific and medical literature regarding chemoresponse assays or chemotherapy sensitivity and resistance assays (CSRAs), specifically as applied to epithelial ovarian cancer. A total of sixty-seven articles, identified through PubMed using the key words "in vitro chemoresponse assay," "chemo sensitivity resistance assay," "ATP," "HDRA," "EDR," "MiCK," and "ChemoFx," were reviewed. Recent publications on marker validation, including relevant clinical trial designs, were also included. Recent CSRA research and clinical studies are outlined in this review. Published findings demonstrate benefits regarding patient outcome with respect to recent CSRAs. Specifically, analytical and clinical validations, as well as clinical utility and economic benefit, of the most common clinically used CSRA in the United States support its use to aid in making effective, individualized clinical treatment selections for patients with ovarian cancer.

Evaluation of tamoxifen in persistent or recurrent nonsquamous cell carcinoma of the cervix: a Gynecologic Oncology Group study.

This study was undertaken to estimate the antitumor activity of tamoxifen in patients with persistent or recurrent nonsquamous cell carcinoma of the cervix. Furthermore, the nature and degree of adverse effects from tamoxifen in this cohort of individuals was examined. Tamoxifen citrate was to be administered at a dose of 10 mg per orally twice a day until disease progression or unacceptable side effects prevented further therapy. A total of 34 patients (median age: 49 years) were registered to this trial; two were declared ineligible. Thirty-two patients were evaluable for adverse effects and 27 were evaluable for response. There were only six grades 3 and 4 adverse effects reported: leukopenia (in one patient), anemia (in two), emesis (in one), gastrointestinal distress (in one), and neuropathy (in one). The objective response rate was 11.1%, with one complete and two partial responses. In conclusion, tamoxifen appears to have minimal activity in nonsquamous cell carcinoma of the cervix.

Value of multilevel sectioning for improved detection of micrometastases in sentinel lymph nodes in invasive squamous cell carcinoma of the vulva.

UNLABELLED: Clinical usefulness of sentinel lymph node (SLN) biopsy has been demonstrated in the management of early vulvar cancer. However, what constitutes a negative SLN has not been well defined. Furthermore, to what extent the SLNs should be sectioned for the greatest likelihood of detection of micrometastases and whether multilevel sectioning will further increase this detection rate in this setting have not been well studied. We analyzed 280 groin lymph nodes (SLNs=45, non-sentinel [NSLNs]=235) in 14 patients with invasive squamous cell carcinoma (ISCC) of the vulva treated with vulvectomy and inguinal SLN and NSLN dissection at the H. Lee Moffitt Cancer Center (HLMCC) between 1996 and 2001. Each SNL was evaluated for micrometastases by H&E and pancytokeratin AE1/3 (CKAE1/3) immunohistochemical staining. All negative SNLs (N=40) were sectioned times 3 (x3) at 50-micron intervals and independently reviewed by two pathologists in order to assess the utility of this inexpensive and logical approach to identifying additional micrometastases. Also, the Wilcoxon Rank Sum Test was used to determine if there was an association between tumor size, depth of invasion and SNL status. The patient age ranged from 35 to 81 years (mean 59 yrs); size of invasive tumor from 1.0 to 7.0 cm (mean 3.4 cm); depth of invasion from 3 to 25 mm (mean 10.8 mm). Of 45 SLNs examined from 14 patients, 11% (5/45) SNLs were positive for micrometastases on initial H&E and/or CKAE1/3 stains. Eighty-nine per cent (40/45) SNLs were negative in the remaining 9 patients. None of the latter 40 SNLs showed micrometastases on additional multilevel sectioning. Instead 3 of 135 NSLNs examined in these 9 patients revealed micrometastases on H&E (skip-micrometastases). Mean tumor size (cm) and depth of invasion (cm) were 4.06 (s.d. 1.89) and 1.20 (s.d. 0.35) for SLN (+) and 3.02 (s.d. 2.12) and 1.01 (s.d. 0.86) for SLN (-) tumor subsets (p values 0.385 and 0.348, respectively). CONCLUSION: Following routine H&E and CK AE1/3 stains, multilevel sectioning does not appear to detect additional micrometastases in sentinel lymph nodes in squamous cell carcinoma of the vulva. Even though mean tumor size and depth of invasion were greater in SNL (+) as compared to SLN (-) tumor subsets in our series, this difference did not reach statistical significance.

Phase II trial of topotecan and cisplatin in persistent or recurrent squamous and nonsquamous carcinomas of the cervix.

OBJECTIVE: Cisplatin is a standard treatment in advanced, recurrent cervical cancer. Because topotecan is an established treatment in gynecologic malignancies such as ovarian cancer and exhibits nonoverlapping toxicity with cisplatin, a phase II trial was conducted to evaluate the tolerability and antitumor activity of a cisplatin/topotecan doublet in persistent or recurrent cervical cancer patients. METHODS: Patients with bidimensionally measurable persistent or recurrent squamous cell and non squamous cell cervical cancer and adequate bone marrow were enrolled. Patients received 50 mg/m(2) of cisplatin intravenously over 1 h on Day 1 and 0.75 mg/m(2) of topotecan intravenously over 30 min on Days 1, 2, and 3 of 21-day cycles for six cycles or until disease progression. Tumor response and regimen toxicity were assessed using established Gynecologic Oncology Group criteria. RESULTS: Thirty-two of 35 enrolled patients were evaluable for toxicity and tumor response. All but 2 evaluable patients had received previous radiotherapy. No patient received prior chemotherapy. The cisplatin/topotecan doublet was well tolerated, with 77 and 78% of courses given without interruption or delay and at full doses, respectively. As anticipated, the most common toxicity was hematologic, with grade 3/4 neutropenia and thrombocytopenia reported in 30 and 10% of cycles, respectively. The overall response rate was 28% (9/32), with 3 complete and 6 partial responses. The antitumor response in nonirradiated fields (30%) was similar to the response observed in previously irradiated fields (33%), suggesting good drug penetration. Median duration of response was 5 months (range, 2 to 15+ months). An additional 9 (28%) patients achieved stable disease. Median survival was 10 months, with 3 patients in lasting remission. CONCLUSIONS: These results demonstrate that the cisplatin/topotecan combination is safe, well tolerated, and active in persistent or recurrent cervical cancer patients. A phase III, multicenter trial is under way (cisplatin/topotecan versus cisplatin) based on these favorable results to confirm the safety and efficacy profile in this patient population.

What is the role of interval blood testing in the management of chemotherapy for gynecologic malignancies.

PURPOSE: To determine the safety of omitting routine interval laboratory assessments, dietary restrictions, and isolation precautions between cycles of chemotherapy for gynecologic malignancies. METHODS: Data were retrospectively obtained from the records of women receiving chemotherapy for gynecologic cancer from July 1999-June 2000. Routine nadir determinations were not performed between treatment cycles; social interaction was encouraged, and pathogen-free diet recommendations were not provided. RESULTS: Eighty women received 449 cycles of chemotherapy. Four (5%) patients developed neutropenic fevers, and one of these women succumbed to sepsis. Eighteen (22.5%) women had 29 cycles delayed due to persistent myelosuppression when the ensuing chemotherapy infusion was to be administered. Hematopoietic growth factors overcame these delays during subsequent cycles in all but two patients. CONCLUSION: Omitting scheduled interval laboratory monitoring, dietary restrictions, and isolation precautions between chemotherapy cycles is convenient for patients, likely cost-effective, and does not increase morbidity in the gynecologic oncology population.

Bartholin's gland carcinoma: a 15-year experience.

OBJECTIVE: Our objective was to review our experience with carcinoma of Bartholin's gland relative to treatment and oncologic outcome. METHODS: Patient names were collected from our vulvar cancer database for the period September 1985 to September 2000. The medical records were retrospectively reviewed, and data were abstracted relative to demographics, presenting symptoms, treatment, and oncologic outcome. RESULTS: We treated 12 women with Bartholin's gland carcinoma, and 11 patients are reported. Seven women presented with a painless vulvar mass, and 8 of 11 had initially been treated for an infectious process before referral to our institution. Squamous histology was most common, and the right gland was more frequently involved. Ten patients were treated with primary surgery, followed by adjuvant radiation in 7 for inadequate resection margins or lymphatic metastases. One patient was treated with primary chemoradiation. Stage I, II, III, IVA, and IVB disease was present in 3, 1, 4, 2, and 1 patient, respectively. Recurrence was suffered by 54.5% during a mean follow-up time of 73.5 months (median, 60; range, 8-180 months). Overall survival is 58.3% to date. CONCLUSIONS: Conventional therapy for Bartholin's gland carcinoma yielded a 67% 5-year survival. Seventy-one percent of women receiving adjuvant radiotherapy recurred despite this precaution. Work is needed to identify an effective systemic therapy and to better determine which patients may benefit from pelvic radiotherapy.

Mammography.

Breast cancer is the most common female malignancy in the USA and second only to lung malignancy in cancer mortality. The only screening modality that effectively detects early breast cancer and decreases mortality is mammography. Because many females turn to obstetrician gynecologists for breast cancer screening, an understanding of the benefits and limitations of mammography and the breast imaging reporting and data system is imperative. Mammography remains the most cost effective and sensitive tool for early detection.

Prevention and treatment of breast cancer.

In the new millennium, practitioners who provide primary care for women of all ages must be well educated in the diagnosis and treatment modalities for breast carcinoma. This disease strikes one of eight women. That statistic alone should encourage diligent and persistent efforts to detect this disease early enough to prevent the large number of deaths annually Early detection will reduce the morbidity associated with breast cancer. Strong efforts are ongoing in the fields of genetics and breast cancer research to achieve earlier detection of breast cancer and a reduction in morbidity regardless of the stage of the breast carcinoma. As results of ongoing studies materialize and new studies are funded, it is hoped that more answers will emerge to combat the devastating effects of breast cancer.

Accuracy of lymph node palpation to determine need for lymphadenectomy in gynecologic malignancies.

OBJECTIVE: To assess the accuracy of intraoperative lymph node palpation for identifying lymph node metastasis in gynecologic malignancies. METHODS: We prospectively evaluated 126 women who had lymphadenectomies for staging of various gynecologic malignancies from August 1995 to June 1997. Surgeries were done by obstetrician-gynecologists with subspecialty certification in gynecologic oncology from the American Board of Obstetrics and Gynecology, who had practiced gynecologic oncology for at least 5 years. Data were collected on gynecologic oncologists' opinions of lymph node status by palpation. Nodes believed to be positive were sent separately. We recorded operating time for lymphadenectomies, and intraoperative and postoperative complications. RESULTS: Mean (range) patient age was 55 (18-83) years. Mean (range) operating time was 188 (85-435) minutes. The mean (range) lymphadenectomy time was 46 (5-150) minutes. The total number of lymph nodes dissected was 2138. One hundred seven of 2138 (5%) nodes were positive for malignancy. Thirty-eight of 107 (36%) positive lymph nodes were missed by palpation. Fifty-six of 2031 (3%) negative lymph nodes were selected as positive. Sixty-nine of 107 (64%) positive lymph nodes were identified correctly. Sensitivity and specificity of palpation were 72% and 81%, respectively. The positive and negative predictive values of lymph node palpation were 56% and 89%, respectively. CONCLUSION: Intraoperative lymph node palpation has low sensitivity and positive predictive value even when done by experienced board-certified gynecologic oncologists.

Innovations in the management of vulvar carcinoma.

Radical surgery has resulted in impressive cure rates in women with locally advanced vulvar carcinoma. Unfortunately, morbidity mostly related to inguinofemoral lymphadenectomy, is common. The present review discusses innovations in the management of vulvar disease with attempts to reduce attendant morbidity.

Surveillance of the endometrium in tamoxifen treated women.

There is much debate about the risks and benefits of tamoxifen, most specifically about the incidence of associated endometrial cancer. Nearly all of the published trials on the subject have been criticized for methodological flaws and various forms of bias, making resolution of this controversy difficult. There is a consensus, however, that tamoxifen results in an increased incidence of both premalignant and malignant lesions of the endometrium. As the indications for tamoxifen continue to broaden, a larger number of women will be subjected to the potential adverse effects of tamoxifen. Many techniques for screening patients on tamoxifen for the development of endometrial abnormalities have been suggested. None of these methods appears to be consistently clinically or cost effective. We have reviewed the literature on endometrial surveillance in tamoxifen treated women with a focus on the larger publications reported within the past year. From this, we have provided what we hope to be safe and cost-effective recommendations for the management of these patients.

Lymphatic mapping in gynecologic malignancies.

Gynecologic malignancies account for 15% of all cancer diagnosis in women. Primary lymphatic spread is well recognized in vulvar, cervical, uterine, and ovarian carcinomas. Vulvar carcinoma spreads locally to the inguinofemoral lymph nodes in a relatively predictable fashion similar to the local spread of breast carcinoma. Lymphatic mapping using radioactive colloid should provide adequate means to sample these nodal basins while attempting to reduce postoperative morbidity. Methods of vulvar lymphoscintigraphy are described.

Lateral microscopic extension of squamous cell carcinoma of the vulva.

PURPOSE: The aim of this study was to measure the radial occult microscopic spread of tumor in patients with invasive squamous cell carcinoma of the vulva. MATERIALS AND METHODS: In the operating room the gross tumor border was marked. The pathologist took a radial section in each quadrant and measured the distance of occult lateral spread of the tumor. RESULTS: From 7/01/93 to 6/30/96, 24 tumors from 21 patients were studied. The mean maximum tumor diameter was 3. 2 cm (0.5-7.0) and the mean depth of invasion was 9.1 mm (1.1-28.0). The gross and microscopic extent correlated in 20 tumors. Maximum lateral microscopic extent of the other 4 tumors was 3.5, 5 (to the margin), 10, and 16 mm. These 4 tumors were ulcerative and infiltrative and arose from or involved mucosa. CONCLUSION: The gross and microscopic periphery of most invasive squamous vulvar cancers are approximately the same. Ulcerative tumors with an infiltrative pattern of invasion which involve mucosal epithelium may be more likely to extend beyond what is grossly apparent. Measurement of the tumor-free margin should be included in future studies.

Detection of sentinel lymph nodes with lymphazurin in cervical, uterine, and vulvar malignancies.

BACKGROUND: Identification of sentinel lymph nodes may allow prediction of metastatic disease in cancer patients. We did a prospective study to determine whether lymphazurin dye could identify sentinel lymph nodes in patients with cervical, uterine, and vulvar cancer. METHODS: In 33 patients having surgery for either uterine, cervical, or vulvar carcinoma, lymphazurin dye was injected into the respective organs before the tumor and node dissection began. Sentinel lymph nodes were identified and dissected in situ. RESULTS: The identification rate of sentinel lymph nodes was 0/8 (0%) for uterine cancer patients, 2/13 (15.4%) for cervical cancer patients, and 9/12 for vulvar cancer patients (75%). CONCLUSIONS: In a limited number of patients, lymphazurin day may be useful in identifying or assessing the sentinel nodes draining vulvar and cervical cancers. The role of this procedure in treatment planning for patients with gynecologic malignancies is yet to be determined.

Does ligation of the hypogastric artery at the time of radical hysterectomy and lymphadenectomy decrease blood loss? Results of a prospective randomized trial.

A prospective, randomized study of patients undergoing radical hysterectomy for gynecologic malignancies was undertaken from 10/95 to 11/96 to determine if ligation of the hypogastric arteries at the time of radical hysterectomy decreases blood loss. Patients were randomized to either ligation of the hypogastric artery (Group 1) or no ligation (Group 2) prior to a standard Piver type III radical hysterectomy. Surgeries were performed by Board certified gynecologic oncologists with gynecologic oncology fellows and/or OB/GYN residents. Patients were analyzed for demographic characteristics and intraoperative and postoperative parameters. Statistical analysis was performed with independent samples t-test, Mann-Whitney rank sum test, Chi square and Fisher exact test. Twenty-one patients were randomized to group 1 and 22 to group 2. Groups were similar with respect to demographics and preoperative parameters except for age. There were no differences among the groups with respect to intraoperative and postoperative parameters. The mean estimated blood loss for group 1 was 600 ml and 550 ml for group 2 (P = NS). Hypogastric artery ligation (HAL) at the time of radical hysterectomy for gynecologic malignancy does not reduce blood loss.

Body mass predicts the survival of patients with new International Federation of Gynecology and Obstetrics Stage IB1 and IB2 cervical carcinoma treated with radical hysterectomy.

BACKGROUND: The authors evaluated the impact of body mass on survival and morbidity of patients with new International Federation of Gynecology and Obstetrics (FIGO) Stage IB1 and IB2 cervical carcinoma managed with radical hysterectomy. METHODS: Two hundred twenty-nine patients with Stage IB1 or IB2 cervical carcinoma treated with radical hysterectomy were studied in a multivariate logistic regression analysis. The body mass index (BMI) and the ponderal index (PI) were used as measures of body mass and were analyzed as predictors of recurrence, survival, and complications in light of the new staging system. RESULTS: Twenty-seven of 229 patients died of recurrent disease. A low BMI or a high PI were predictive of poor survival. Tumor greatest dimension, lymph node involvement, BMI, and PI were all independent predictors of survival (P=0.0006). The only independent predictor of complications was para-aortic lymph node dissection (P=0.0026). CONCLUSIONS: Cervical carcinoma patients with a low body mass, as indicated by a low BMI or a high PI, were found to have poor survival after undergoing radical hysterectomy. Additional predictors of poor survival included lymph node metastases and increased tumor size. BMI and PI are more important predictors of survival than the new FIGO Stages IB1 and IB2. Body mass is not predictive of complications.

Inherited susceptibility to breast and ovarian cancer.

Approximately 5-10% of breast and ovarian cancer cases are due to an inherited susceptibility. The majority of inherited breast and ovarian cancer susceptibility is due to mutations in the BRCA1 and BRCA2 genes; however, other genes responsible for inherited susceptibility to these diseases are yet to be identified. A small proportion of inherited breast and ovarian cancers are due to other genetic cancer susceptibility syndromes including Li-Fraumeni syndrome, Cowden disease and hereditary non-polyposis colorectal cancer. It is recommended that individuals at risk for inherited susceptibility to breast and/or ovarian cancer who are requesting DNA testing be provided with pre-test genetic counseling and education and post-test counseling and follow-up to ensure that all aspects of genetic testing have been disclosed and that the patient has truly given informed consent.