Krishnansu S. Tewari

Improved Survival with Bevacizumab in Advanced Cervical Cancer

BACKGROUND Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer. METHODS Using a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area, plus paclitaxel at a dose of 135 or 175 mg per square meter or topotecan at a dose of 0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square meter on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary end point was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important. RESULTS Groups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. Topotecan-paclitaxel was not superior to cisplatin-paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P=0.004 in a one-sided test) and higher response rates (48% vs. 36%, P=0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%). CONCLUSIONS The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival. (Funded by the National Cancer Institute; GOG 240 ClinicalTrials.gov number, NCT00803062.).

Malignant germ cell tumors of the ovary

Objective To evaluate the efficacy of adjuvant therapy for ovarian germ cell tumors. Methods We reviewed records of women who had malignant germ cell tumors of the ovary from 1977–1997. Results Seventy-two women had surgical resections of malignant ovarian germ cell tumors and most received adjuvant therapy. Fifty-six women (78%) presented with stage I disease, and 16 (22%) had more advanced disease. Tumor subtypes included dysgerminoma (n = 20), yolk sac tumor (n = 8), immature teratoma (n = 29) and mixed germ cell tumor (n = 15). Surgical management of the 56 with stage I disease consisted of total abdominal hysterectomy, bilateral salpingo-oophorectomy, and extensive surgical staging in ten women, whereas a conservative surgical approach, consisting of unilateral adnexectomy with or without comprehensive surgical staging, was adopted in later years (n = 46). Fifty-six women were treated with postoperative chemotherapy, predominantly platinum-based regimens. The 5-year actuarial survival rate was 93%. None of the 36 women who presented after 1984 have died of disease. Conclusion These data confirmed that platinum-based adjuvant treatments allow most women with ovarian germ cell malignancies to have conservative surgery without compromising survival.

Multimodality Therapy for Locally Advanced Cervical Carcinoma: State of the Art and Future Directions

Globally, cervical cancer is the second most common cause of cancer-related mortality among women causing approximately 234,000 deaths annually among developing countries and killing 40,000 in developed nations. Most of these deaths occur in women with bulky or locally advanced cervical cancer, International Federation of Gynecology and Obstetrics (FIGO) stages IIB through IVA, when lesions are not amenable to high cure rates with surgery or radiation (RT). The standard prescription for RT used to treat locally advanced cervical cancer has been dictated by common practice and patterns of care studies. In contrast, the addition of concomitant chemotherapy to RT has been studied in a number of randomized prospective trials, which are discussed in detail. When added to RT, cisplatin reduces the relative risk of death from cervical carcinoma by approximately 50% by decreasing local/pelvic failure and distant metastases. In 1999, weekly intravenous cisplatin at 40 mg/m2 for 6 weeks in combination with RT was established as a new standard for the treatment of locally advanced cervical carcinoma. More recently, this recommendation has been expanded to include women with FIGO stage IB2 lesions as well as those with bulky stage IIA cancers. This monograph reviews the state of the art in treating locally advanced cervical cancer with combined chemotherapy and RT and discusses clinical and pathologic prognostic factors that impact cure. Quality of life during and after multimodality therapy is considered as well as ongoing clinical trials and future directions.

Ambiguous genitalia in infant exposed to tamoxifen in utero

Irregularly ossified ribs have been described in the offspring of pregnant rats who were given tamoxifen. Toxicological experiments with tamoxifen resulted in metaplastic changes of the uterine epithelium of fetal rats and vaginal adenosis in newborn mice. Cunha showed that the use of tamoxifen on human fetal genital tracts resulted in delayed proliferation and maturation of the vaginal epithelium. There are no adequate and well-controlled trials of tamoxifen in pregnant women. Baum stated that in 85 women who became pregnant while receiving prophylactic tamoxifen as part of a trial in healthy women at high risk for breast cancer, there were no fetal abnormalities. He did not state whether any women received tamoxifen during the first 20 weeks of pregnancy. In recent times, more women are delaying pregnancy until later years, and so the number of women of child-bearing age with breast cancer will increase. It is reasonable to expect an increase in the number of reports of infants exposed to tamoxifen during pregnancy. Our report suggests the potential for teratogenicity of tamoxifen on the developing human genital tract. In addition to structural abnormalities, it appears that the fetus may be at risk for dysplastic changes of the reproductive tract, analogous to in-utero exposure to diethylstilbestrol and the development of adenosis and adenocarcinoma of the vagina and cervix. Close follow-up is necessary for this infant and all other females exposed to tamoxifen in utero. We recognise that the circumstances in this case were unusual and that a causal link is unproven. Nonetheless, the incident does suggest the need for a registry of pregnancies and their outcomes in women taking tamoxifen, analogous to the registry established for diethylstilbestrol.

Long-term results of low-dose-rate interstitial-intracavitary brachytherapy in the treatment of carcinoma of the cervix

PURPOSE Brachytherapy plays a major role in the treatment of patients with carcinoma of the cervix. However, routine intracavitary brachytherapy may not be feasible or adequate to treat locally advanced disease. The purpose of this retrospective study (spanning a 20-year period) was to determine the outcome of interstitial low-dose-rate brachytherapy in the treatment of bulky or locally advanced cervical cancer. The long-term survival and safety of this technique were evaluated, along with its impact on local and locoregional control, disease-free survival, and complications. METHODS AND MATERIALS A total of 185 previously untreated patients with cervical cancer were treated between 1977 and 1997. According to the International Federation of Gynecology and Obstetrics classification, 21 patients had Stage IB (barrel), 77 Stage II, 77 Stage III, and 10 Stage IV disease. All patients were treated by a combination of external megavoltage irradiation to the pelvis to a dose of 5040 cGy followed by interstitial-intracavitary implants to a dose of 40-50 Gy to the implanted volume in two applications. RESULTS Clinical local control was achieved in 152 (82%) of the 185 patients. A 5-year disease-free survival rate of 65%, 67%, 49%, and 17% was achieved for patients with Stage IB, II, III, and IV disease, respectively. Eighteen (10%) of the 185 patients developed Radiation Therapy Oncology Group Grade 3 or 4 late complications. CONCLUSION Patients with locally advanced cervical cancer, or with distorted anatomy, may be treated adequately with interstitial brachytherapy to achieve excellent locoregional control and a reasonable chance of cure with acceptable morbidity.

Cervical neoplasia in pregnancy. Part 1: screening and management of preinvasive disease.

Cervical cancer screening is an essential component of prenatal care. The diagnosis and management of cervical intraepithelial neoplasia (CIN) during pregnancy are challenging, and sufficient information does not exist to allow for a definitive evidence-based approach. The American Society for Colposcopy and Cervical Pathology has recently published guidelines regarding the evaluation of abnormal Papanicolaou tests and the treatment of CIN in this setting. Many techniques traditionally recommended in the evaluation of abnormal cervical cytology and the treatment of CIN in the nonpregnant woman, such as colposcopy, cervical biopsy, and electrosurgical excision, can be applied to the pregnant patient with important exceptions. The vascular cervix associated with the gravid condition and the risk of premature pregnancy loss mandates deviation from existing consensus guidelines in screening for cervical cancer in pregnancy and treating associated CIN. In the present review, current guidelines regarding cervical cancer screening are reviewed, and data from studies of pregnant populations are summarized.

Lapatinib and potential prognostic value of EGFR mutations in a Gynecologic Oncology Group phase II trial of persistent or recurrent endometrial cancer

OBJECTIVE A phase II trial was performed to evaluate the efficacy and safety of the tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and HER2, lapatinib, and to explore EGFR, HER2 (EGFR2), phosphorylated ERK MAP kinase (pERK), and Ki67 expression, as well as EGFR mutations in persistent/recurrent endometrial cancer (EC). METHODS Women with histologically-confirmed, measurable, persistent/recurrent EC following one or two prior regimens were eligible and treated with 1500 mg oral lapatinib daily until progression or severe toxicity. A 2-stage group sequential design was used to evaluate the regimen with 6 month PFS as the primary endpoint. The trial had a 10% type I error rate with 90% power. EGFR, HER2, pERK, and Ki67 were evaluated by immunohistochemistry (IHC) from hysterectomy specimens, pre-treatment biopsies, and post-treatment biopsies (when available). Exons 18-21 of EGFR were sequenced. RESULTS Three patients of 30 evaluable had PFS ≥6 months, one had a partial response, seven had stable disease, 21 had progressive disease and one was indeterminate. Three mutations in EGFR were identified. Two of these, L688F and K754E, were not associated with response or PFS. However, a newly identified mutation in exon 18, E690K, occurred in the patient with a partial response and progression-free survival extending past six months. CONCLUSION While lapatinib has limited activity in unselected cases, the identification of a previously unreported mutation in EGFR (E690K) with a response suggests that lapatinib may be beneficial in some cases of EC.

Vaginal hysterectomy as primary treatment of endometrial cancer in medically compromised women

Objective To study the survival, rates and patterns of recurrence, and perioperative morbidity in medically compromised women with endometrial cancer treated by primary vaginal hysterectomy. Methods Fifty-one patients with endometrial cancer treated initially by vaginal hysterectomy between 1977 and 1999 were identified at the University of California, Irvine Medical Center and affiliated hospitals. Data were retrieved from hospital and office records. Statistical analysis, including Kaplan-Meier methods, was performed and the disease-specific survival rates were estimated. This study has 80% power to demonstrate a greater than 20% improvement in 5-year survival over historical controls. Results Fifty-one women with uterine carcinoma clinically confined to the uterus underwent primary vaginal hysterectomy with (n = 26) or without (n = 25) salpingo-oophorectomy. Eighty-four percent were obese with a body mass index greater than 27. Additional risk factors for surgical complications included hypertension (57%), diabetes mellitus (27%), and cardiovascular disease (18%). One-third of patients had three or more risk factors. Surgical morbidity included one episode of acute hemorrhage necessitating transfusion and abdominal exploration. Blood transfusions were given to four additional patients. There were no perioperative deaths. Five women recurred and expired at a median of 13 months (range 3–53 months) after surgery. The 3- and 5-year disease-specific survival rates were 91.4% and 88.0%, respectively. Conclusion Vaginal hysterectomy for the initial treatment of early-stage endometrial cancer is associated with a high rate of cure and minimal morbidity. Thus, it may be considered a reasonable alternative to the abdominal approach in medically compromised women.

Randomized phase III trial of tamoxifen versus thalidomide in women with biochemical-recurrent-only epithelial ovarian, fallopian tube or primary peritoneal carcinoma after a complete response to first-line platinum/taxane chemotherapy with an evaluation of serum vascular endothelial growth factor (VEGF): A Gynecologic Oncology Group Study

PURPOSE To compare progression-free survival (PFS), overall survival (OS) and toxicities of thalidomide versus tamoxifen and to evaluate serum vascular endothelial growth factor (VEGF) in biochemical-recurrent epithelial ovarian cancer, primary peritoneal cancer or fallopian tube carcinoma (EOC/PPC/FTC). METHODS Biochemical recurrence was defined as a rising CA-125 exceeding twice the upper limit of normal without evidence of disease as defined by RECIST 1.0 criteria. Women with FIGO stages III and IV, histologically confirmed EOC/PPC/FTC who were free of disease following first-line chemotherapy were randomized to oral thalidomide 200mg daily with escalation to a maximum of 400 mg or tamoxifen 20mg orally twice daily for up to 1 year, progression or adverse effect prohibited further treatment. VEGF was quantified by ELISA in pre and post-treatment serum. RESULTS Of the 139 women randomized, 138 were eligible. Interim analysis showed that thalidomide did not reduce the recurrence rate relative to tamoxifen, and the trial was closed. Thalidomide versus tamoxifen was associated with a similar risk of progression (HR = 1.31, 95% confidence interval [CI] = 0.93-1.85), an increased risk of death (HR = 1.76, 95% CI = 1.16-2.68) and more grades 3 and 4 toxicities (55% versus 3%). The most common grades 3 and 4 toxicities were constitutional (12%), somnolence (12%), pulmonary (9%), venous thromboembolism (VTE) (6%) and peripheral neurologic (6%) for thalidomide, with VTE (1.4%) and gastrointestinal (1.4%) for tamoxifen. Serum VEGF was not associated with clinical characteristics, treatment, PFS or OS. CONCLUSION Thalidomide was not more effective than tamoxifen in delaying recurrence or death but was more toxic. VEGF was not prognostic in this cohort.

Cervical neoplasia in pregnancy. Part 2: current treatment of invasive disease

Although the incidence of cervical cancer in the United States has declined sharply, many young women are diagnosed with the disease every year. Naturally, coincident pregnancies will occur in this subset of reproductively active patients. Although the treatment of cervical cancer has evolved under the drive of multicenter, randomized trials, the same level of evidence does not exist for the treatment of this malignancy in pregnancy. Treatment algorithms are therefore proposed as a series of modifications to the guidelines intended for the nonpregnant patient, taking into account the tremendous social, ethical, and emotional dilemmas specific to each trimester at presentation.