Phase I study of cisplatin, hyperthermia, and lapatinib in patients with recurrent carcinoma of the uterine cervix in a previously irradiated area.

BACKGROUND: Patients with recurrent cervical cancer in a previously irradiated area might benefit from cisplatin combined with hyperthermia. Lapatinib inhibits the intracellular tyrosine kinase domain of the epidermal growth factor receptor (EGFR) and HER2. Overexpression of EGFR and HER2 is frequently seen in patients with cervical cancer and is potentially involved in chemotherapy resistance. In addition, preclinical data suggest a synergistic effect of combining cisplatin and lapatinib. Consequently, this phase I dose-escalation study was performed to determine the maximum tolerated dose (MTD) of lapatinib added to fixed doses of cisplatin and hyperthermia. METHODS: Eight patients with previously irradiated recurrent cervical carcinoma were enrolled and scheduled for 6 weekly administrations of 70 mg/m(2) cisplatin combined with locoregional hyperthermia. Hyperthermia consisted of the achievement of intraluminal temperatures of 40-43°C as homogeneously as possible over 60 minutes. Daily lapatinib was added on days 1-56, starting with a dose level of 1,000 mg. The MTD was defined as the highest dose at which ≤1 of 6 patients experienced dose-limiting toxicity (DLT). DLT was defined as grade 4 neutropenia lasting >7 days, febrile neutropenia grade ≥3, grade 4 thrombocytopenia, grade ≥2 renal toxicity, postponement of cisplatin and hyperthermia for ≥2 weeks, or grade ≥3 nonhematologic adverse events except for nausea or vomiting, diarrhea, or skin toxicity, for which the following DLT definitions were applied: grade ≥3 persistent nausea or vomiting or diarrhea despite optimal medical treatment or grade 4 skin toxicity. Safety, pharmacodynamics, and response were assessed. RESULTS: The first two patients of both the 1,000- and 750-mg dose level experienced DLTs. Of the four patients treated at dose level -2 (500 mg), only one patient was able to complete the treatment as planned, two patients experienced a DLT, and one patient was not evaluable because of early progressive disease. In the evaluable patients, one patient with progressive disease, four patients with stable disease, and two patients with partial response were observed. One patient with a partial response had a resection of the local recurrence. Pathological analysis showed a complete pathological response. Enumeration of circulating endothelial cells measured at baseline and during therapy did not show consistent results. The same applied for the pharmacodynamic effects on Ki-67, p27Kip1, and EGFR in pretreatment and on-therapy skin biopsies. CONCLUSION: It is not feasible to combine lapatinib with fixed doses of cisplatin and hyperthermia in patients with recurrent cervical carcinoma in a previously irradiated area mainly because of increased cisplatin-related toxicity. The observed complete pathological response is intriguing and warrants further investigation of combinations consisting of HER2 blockade and cisplatin plus hyperthermia.

Sexual rehabilitation after pelvic radiotherapy and vaginal dilator use: consensus using the Delphi method.

OBJECTIVE: This study aimed to reach consensus among professional experts on patient information provision and support regarding sexual rehabilitation and vaginal dilator use after radiotherapy (RT) for gynecological cancers. METHODS: A 3-round online Delphi study was conducted among 10 radiation oncologists, 10 gynecologic oncologists, and 10 oncology nurses from 12 gynecological cancer centers providing RT for gynecological tumors. We assessed the desired content and provider of instructions and patient support regarding sexuality and vaginal dilator use. Responses were measured on a 7-point scale varying from "totally disagree" to "totally agree." Consensus was reached when 70% of participants' answers fell within 2 scale categories with an interquartile range less than or equal to 1. RESULTS: The panel agreed that information about sexual rehabilitation using vaginal dilators should be provided by radiation oncologists before treatment. Information should always be provided to sexually active cervical and vaginal cancer patients younger than 70 years. Tailored information was recommended for vulvar and endometrial cancer patients, patients older than 70 years, and sexually inactive patients. Preferably, specifically trained oncology nurses should give psychological and practical support. Participants recommended vaginal dilation to prevent vaginal adhesions, tightening, and shortening. The panel advised to start dilation around 4 weeks after treatment to perform dilation 2 to 3 times a week for 1 to 3 minutes and to continue dilation for 9 to 12 months. Plastic dilator sets were considered the most suitable type of dilator. CONCLUSIONS: Consensus was reached on patient information provision and support during sexual rehabilitation after RT for gynecological cancers. Results were used to develop a sexual rehabilitation intervention.

The risk of primary and contralateral breast cancer after ovarian cancer in BRCA1/BRCA2 mutation carriers: Implications for counseling.

BACKGROUND: The objective of this study was to assess the incidence of primary breast cancer (PBC) and contralateral breast cancer (CBC) in patients who had BRCA1/BRCA2-associated epithelial ovarian cancer (OC). METHODS: From the database of the Rotterdam Family Cancer Clinic, patients who had BRCA-associated OC without a history of unilateral breast cancer (BC) (at risk of PBC; n = 79) or with a history of unilateral BC (at risk of CBC; n = 37) were selected. The control groups consisted of unaffected BRCA mutation carriers (n = 351) or mutation carriers who had a previous unilateral BC (n = 294), respectively. The risks of PBC and CBC were calculated using the Kaplan-Meier survival method with death considered as a competing risk event. RESULTS: Women with BRCA-associated OC had lower 2-year, 5-year, and 10-year risks of PBC (3%, 6%, and 11%, respectively) compared with unaffected mutation carriers (6%, 16%, and 28%, respectively; P = .03), although they had a considerably higher mortality rate at similar time points (13%, 33%, and 61%, respectively, vs 1%, 2%, and 2%, respectively; P < .001). In BRCA mutation carriers with a previous unilateral BC, the 2-year, 5-year, and 10-year risks of CBC were nonsignificantly lower in patients with OC than in those without OC (0%, 7%, and 7%, respectively, vs 6%, 16%, and 34%, respectively; P = .06), whereas the mortality rate was higher in patients with OC (19%, 34%, and 55%, respectively, vs 4%, 11%, and 21%, respectively; P < .001). CONCLUSIONS: Patients with BRCA-associated OC had a lower risk of developing a subsequent PBC or CBC than mutation carriers without OC, whereas the risk of dying from OC was greater than the risk of developing BC. These data may facilitate more tailored counseling for this patient subgroup, although confirmative studies are warranted.

Follow-up of women after a first episode of postmenopausal bleeding and endometrial thickness greater than 4 millimeters.

OBJECTIVE: To estimate the incidence of recurrent postmenopausal bleeding among women who were diagnosed with an endometrial thickness greater than 4 mm. METHODS: We designed a prospective cohort study and included consecutive women not using hormone replacement therapy, presenting with a first episode of postmenopausal bleeding. We evaluated patients who had an endometrial thickness greater than 4 mm at transvaginal ultrasonography and benign endometrial sampling; presence of carcinoma was ruled out by office endometrial sampling, hysteroscopy, and/or dilation and curettage. Time until recurrent bleeding was measured, and diagnosis at recurrent bleeding was recorded. RESULTS: Among 318 patients who had an endometrial thickness greater than 4 mm, 222 patients had benign histology results and were available for follow-up. During follow-up, 47 (21%, 95% confidence interval 16-27%) patients had recurrent bleeding, with a median time to recurrent bleeding of 49 weeks (interquartile range 18 to 86 weeks). There was no difference with respect to recurrence rate between patients with polyp removal, patients with a normal hysteroscopy, and patients with office endometrial sampling alone at the initial workup. Two patients were diagnosed with atypical endometrial hyperplasia upon recurrent bleeding. CONCLUSION: The recurrence rate of postmenopausal bleeding in women with endometrial thickness greater than 4 mm is 20%. This recurrence rate is not related to incorporation of hysteroscopy or polyp removal at the initial workup. LEVEL OF EVIDENCE: II.

Accuracy of transvaginal ultrasonography in diabetic or obese women with postmenopausal bleeding.

OBJECTIVE: We sought to assess the accuracy of endometrial thickness measurement in the diagnosis of endometrial cancer in patients with obesity, diabetes, and hypertension and to evaluate whether patient characteristics influence endometrial thickness irrespective of the final diagnosis. METHODS: This was a prospective study of women not using hormone replacement therapy who presented with postmenopausal bleeding at 8 hospitals in The Netherlands. All women underwent transvaginal ultrasonography and, in the event that the endometrial thickness (double layer) was more than 4 mm, subsequent endometrial sampling. The performance of endometrial thickness measurement in the diagnosis of atypical hyperplasia and endometrial cancer was evaluated in subgroups of patients with diabetes, hypertension, and obesity by using receiver operating characteristic analysis. RESULTS: Overall, we included 594 consecutive women, of whom 62 (10%) had endometrial carcinoma and 6 (1%) had atypical hyperplasia. In these women, transvaginal ultrasonography had an area under the receiver operating characteristic curve of 0.87 (standard error [SE] 0.03). In the absence of (pre)malignancy, women with diabetes or obesity were found to have thicker endometria than women without these risk factors, whereas in women with a (pre)malignancy, this difference was not present. The area under the receiver operating characteristic curve decreased to 0.74 (SE 0.05) and 0.75 (SE 0.07) in diabetic women and obese women, respectively. The presence or absence of hypertension had no impact on the accuracy of transvaginal ultrasonography. CONCLUSION: In view of the decreased diagnostic accuracy in diabetic women and obese women, the clinical value of transvaginal endometrial thickness measurement in these women is questionable.