A pilot study of nimotuzumab plus single agent chemotherapy as second- or third-line treatment or more in patients with recurrent,persistent or metastatic cervical cancer

Nimotuzumab is a humanized IgG1 monoclonal antibody against the EGFR extracellular domain that has been evaluated in solid tumors as a single agent or in combination with chemotherapy and radiation. Cervical cancer patients who are refractory or progressive to first-line chemotherapy have a dismal prognosis, and no second- or third-line chemotherapy is considered standard. This pilot trial aimed to evaluate the efficacy and safety of nimotuzumab in 17 patients with pre-treated advanced refractory or progressive cervical cancer. Nimotuzumab was administered weekly at 200 mg/m² as single agent for 4 weeks (induction phase), then concurrent with 6 21-day cycles of gemcitabine (800 mg/m²) or cisplatin (50 mg/m²) for 18 weeks (concurrent phase) and then once every 2 weeks (maintenance phase). Nimotuzumab could be continued beyond disease progression. Seventeen patients were accrued and evaluated for safety and efficacy. The median number of nimotuzumab applications was 20 (5–96). The median number of chemotherapy cycles administered was 6 (1-6). No toxicity occurred during induction and maintenance phases (single agent nimotuzumab). In the concurrent phase, grade 3 toxicity events observed were leucopenia, anemia and diarrhea in 11.7%, 5.8% and 11.7% respectively. No complete or partial responses were observed. The stable disease (SD) rate was 35%. The median PFS and OS rates were163 days (95% CI, 104 to 222), and 299 days (95% IC, 177 to 421) respectively. Nimotuzumab is well tolerated and may have a role in the treatment of advanced cervical cancer.     

Menstrual pattern and lipid profiles during use of medroxyprogesterone acetate and estradiol cypionate and NET-EN (200 mg) as contraceptive injections

The objectives of this study were to compare effects of medroxyprogesterone acetate 25 mg + estradiol cypionate 5 mg (Cyclofem) and norethisterone enanthate (NET-EN) upon the menstrual pattern and determine changes in lipoprotein parameters after 12 months of use. One-hundred females were included and 87 (45 with Cyclofem and 42 with NET-EN) women completing 12 months were evaluated. Menstrual changes were the leading complaint among users. At the end of 12 months, 20/45 (44.4%) and 18/41 (43.9%) Cyclofem and NET-EN users, respectively, had normal menstrual pattern. Irregular and infrequent bleeding were the two most important changes that occurred. The discontinuation rate at 12 months due to menstrual disturbances did not show any significant differences between the two preparations, but showed lower incidence compared to other studies. Total cholesterol, high-density, low-density and very low-density lipoprotein cholesterol and triglyceride levels decreased at 12 months in both groups and these changes were statistically significant.     

Modern management of locally advanced cervical carcinoma

Radiation was until recently the key and only modality for the routine treatment of locally advanced cervical carcinoma. However after years of studying multi-modality treatments as an alternative to radiation alone in randomized phase III trials, the standard treatment has changed to chemo-radiation based on cisplatin. Three recent meta-analyses have confirmed that cisplatin-based chemo-radiation adds an absolute 12% benefit in five-year survival over radiation therapy alone. Neoadjuvant chemotherapy followed by radiation has not been of proven benefit, but when neoadjuvant chemotherapy is followed by surgery, an absolute increase of 15% in five-year survival over radiation alone is seen. This benefit in survival is comparable to that obtained with the current chemo-radiation schedules based on cisplatin. Despite these encouraging results there remains room for improvement as the five-year survival of patients treated with chemo-radiation ranges from nearly 80% in bulky IB tumours to only 25% in stage IVA disease. Other therapeutic approaches need to be fully evaluated including the use of chemo-radiation after neoadjuvant chemotherapy; the use of new drug combinations and the multi-modality combination of neoadjuvant chemotherapy followed by radical surgery plus adjuvant chemo-radiation. Likewise, the addition of radiosensitizers to cisplatin, preoperative chemo-radiation and/or adjuvant chemotherapy may eventually improve the currents results of cisplatin-based chemo-radiation. Nevertheless, it is hard to foresee a dramatic increase in cure rate, even with the most optimal combination of cytotoxic drugs, surgery and radiation, and thus the testing of molecular targeted therapies against cervical cancer is a logical step to follow.     

Effect of counseling to improve compliance in Mexican women receiving depot-medroxyprogesterone acetate

This study purported to determine the effect of pretreatment counseling upon discontinuation of 150 mg depot-medroxyprogesterone acetate (Depo-Provera) given for contraception. A total of 350 Mexican women participated: 175 received detailed structured pretreatment counseling about the hormonal effects of the injectable vs. routine counseling upon duration of use and efficacy of the method. Study termination rates were significantly lower in the structured counseling group than in the control group. Cumulative life table discontinuation rates were 17% (30/175) and 43.4% (76/175), respectively (p <0.05). The most common reasons for terminating DMPA were menstrual changes (8.6 and 32% for counseling and control group, respectively). The findings suggest that pretreatment counseling on expected side effects increases the continuation rates of DMPA users.     

A double-blind, placebo-controlled, randomized phase III trial of chemotherapy plus epigenetic therapy with hydralazine valproate for advanced cervical cancer. Preliminary results

The reversing of epigenetic aberrations using the inhibitors of DNA methylation and histone deacetylases may have therapeutic value in cervical cancer. This is a randomized phase III, placebo-controlled study of hydralazine and valproate (HV) added to cisplatin topotecan in advanced cervical cancer. Patients received hydralazine at 182 mg for rapid, or 83 mg for slow acetylators, and valproate at 30 mg/kg, beginning a week before chemotherapy and continued until disease progression. Response, toxicity, and PFS were evaluated, and 36 patients (17 CT + HV and 19 CT + PLA) were included. The median number of cycles was 6. There were four PRs to CT + HV and one in CT + PLA. Stable disease in five (29%) and six (32%) patients, respectively, whereas eight (47%) and 12 (63%) showed progression (P = 0.27). At a median follow-up time of 7 months (1-22), the median PFS is 6 months for CT + PLA and 10 months for CT + HV (P = 0.0384, two tailed). Although preliminary, this study represents the first randomized clinical trial to demonstrate a significant advantage in progression-free survival for epigenetic therapy over one of the current standard combination chemotherapy in cervical cancer. Molecular correlates with response and survival from this trial are pending to analyze.     

A comparative clinical trial of Norinyl 1+35 versus Norinyl 1+50 in Merida,Yucatan, Mexico

A comparative clinical trial of two combined oral contraceptives differing only in estrogen type and dosage was conducted at the Centro de Investigaciones Hideyo Noguchi in Merida, Yucatan, Mexico. The trial was designed to determine the differences between Norinyl 1+50 (Syntex) and Norinyl 1+35 (Syntex) in rates of discontinuation and frequency of selected side-effects which might contribute to method discontinuation.Three hundred women were randomly assigned to either the Norinyl 1+35 group or to the Norinyl 1+50 group and follow-up visits were scheduled at 1, 4, 8 and 12 months after admission. In the Norinyl 1+35 group, more women experienced an increase in intermenstrual bleeding (primarily staining and spotting) (p<0.05), breast discomfort (p<0.05) and nausea than in the Norinyl 1+50 group. There was a significantly higher discontinuation rate for personal reasons, such as desired change of method and method not needed, among the women taking Norinyl 1+35 (p<0.05). The largest number of discontinuations comprised women discontinuing for menstrual problems in both groups.The life-table total discontinuation rate at 12 months was 52.0 for the Norinyl 1+35 group and 50.7 for the Norinyl 1+50 group. The lost-to-follow-up rates at 12 months were 17.8 for the Norinyl 1+35 group and 22.8 for the Norinyl 1+50 group.

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Resumen En un ensayo clínico realizado en el Centro de Investigaciones Hideyo Noguchi, de Mérida, provincia de Yucatán, México, se compararon dos anticonceptivos orales combinados que sólo diferían en cuanto al tipo de estrógeno y a sus dosis. El objetivo de este ensayo era determinar las diferencias existentes entre Norinyl (1+50 (Syntex) y Norinyl 1+35 (Syntex)) en cuanto a porcentajes de abandono y a la frecuencia de efectos secundarios precisos que pudieran contribuir al abandono del método.Trescientas mujeres fueron elegidas al azar para formar parte de dos gupos. A uno de los grupos se le prescribió Norinyl 1+35 y al otro Norinyl 1+50. Las visitas de control se fijaron en 1, 4, 8 y 12 meses después de la admisión. Las mujeres que experimentaron pérdidas intermenstruales (esencialmente manchas y microrragias) (p<0,05), molestias en las mamas (p<0,05) y náuseas fueron más numerosas en el grupo de Norinyl 1+35 que en el de Norinyl 1+50. El porcentaje de abandono por motivos personales, tales como el deseo de cambiar de método o de no recurrir a la anticoncepción, fue asimismo significativamente más elevado en las mujeres que empleaban Norinyl 1+35 (p<0,05). En los dos grupos, el abandono fue más frecuente entre las mujeres con problemas menstruales.La tabla de supervivencia de la proporción de abandono establecida a los 12 meses indica 52,0 para el grupo de Norinyl 1+35 y 50,7 para el grupo de Norinyl 1+50. Las proporciones de interrupción de supervivencia a los 12 meses ascendieron a 17,8 para el grupo de Norinyl 1+35 y a 22,8 para el de Norinyl 1+50.

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Résumé Dans un essai clinique conduit au Centro de Investigaciones Hideyo Noguchi à Merida dans la province du Yucatan aub Mexique, on a comparé deux contraceptifs oraux combinés qui ne différaient que par le type d'oestrogène et ses doses. Cet essai avait pour but de déterminer les différences existant entre le Norinyl 1+50 (Syntex) et le Norinyl 1+35 (Syntex) en termes de pourcentages d'abandon et de la fréquence d'effets secondaires précis pouvant contribuer à l'abandon de la méthode. Trois cents femmes ont été choisies au hasard pour faire partie de deux groupes. A l'un des groupes, on a prescrit le Norinyl 1+35 et à l'autre le Norinyl 1+50. Les visites de contrôle ont été fixées à 1, 4, 8 et 12 mois après l'admission. Les femmes ayant eu des saignements intermenstruels (essentiellement des traces et microragies) (p<0,05), une gène mammaire (p<0,05) et des nausées on été plus nombreuses dans le groupe du Norinyl 1+35 que dans le groupe du Norinyl 1+50. Le pourcentage d'abandon pour des raisons personnelles, telles que le désir de changer de méthode ou de ne plus avoir recours à la contraception, était aussi significativement plus élevé chez les femmes utilisant le Norinyl 1+35 (p<0,05). Dans les deux groupes, l'abandon a été le plus fréquent chez des femmes ayant eu des problèmes menstruels.La table de survie du taux d'abandon total établie à 12 mois indique 52,0 pour le groupe du Norinyl 1+35 et 50,7 pour le groupe du Norinyl 1+50. Les taux d'interruption du suivi établis à 12 mois se montent à 17,8 pour le groupe du Norinyl 1+35 et à 22,8 pour le groupe du Norinyl 1+50.