A feasibility study of 1-h paclitaxel infusion in patients with solid tumors.

The optimal schedule for paclitaxel administration has not yet been determined. This phase I/II study was carried out to evaluate the safety of paclitaxel administration by 1-h infusion in the outpatient setting. A total of 43 patients with advanced pretreated malignancies (18 breast, 18 ovarian, and 7 non-small-cell lung cancers) received at least 2 cycles of paclitaxel given at 175 mg/ m2 in a single dose by 1-h i.v. infusion. This protocol was repeated every 21 days. All patients were premedicated as follows: promethazine given i.m. at 50 mg, dexamethasone given at 16 mg in 250 ml normal saline by i.v. infusion for 20 min and ranitidine given i.v. at 50 mg in 250 ml normal saline over 15 min, all premedication being carried out 1 h before the paclitaxel infusion. In a total of 156 cycles, only 1 patient presented with a hypersensitivity reaction (grade 2 urticaria in 1 cycle) and another patient developed transient facial flushing (in 1 cycle: this was resolved by slowing of the infusion rate) on this schedule of paclitaxel administration. Other adverse side effects were usually mild and well tolerated. Alopecia was universal; myelosuppression was uncommon because our patients were supported with granulocyte colony-stimulating factor (G-CSF, lenograstim) given at 34 IU/day in the presence of a neutrophil count of < 500 microliters; neutropenia was seen in 50/156 (32%) cycles and was mild. Neurotoxicity was the most serious adverse effect, and all patients experienced mild to severe neuro-muscular toxicity, mainly in the form of peripheral sensorimotor neuropathy and myalgias. In conclusion, 1-h paclitaxel administration is safe and reduces the duration of treatment, making its use more convenient and easy in the outpatient setting. A prospective comparison of 1-h versus 3-h paclitaxel infusion in terms of efficacy and toxicity is the subject of our current randomized study.

Transvaginal sonography of the endometrium in women with postmenopausal bleeding.

OBJECTIVE: The purpose of this study was to determine the value of screening transvaginal ultrasonography for the evaluation of endometrial abnormalities in women with postmenopausal bleeding. MATERIALS AND METHODS: 250 women with postmenopausal bleeding underwent transvaginal ultrasonographic examinations before undergoing dilatation and curettage. Women who had any pelvic symptoms or were on hormone replacement therapy were excluded. RESULTS: In 151 women, the histologic diagnosis was atrophic endometrium. In these patients, the mean endometrial thickness was 3.4 +/- 1.2 mm. In 24 patients with endometrial carcinoma, the mean endometrial thickness was 16.5 +/- 6.2 mm. The measurement included both endometrial layers (i.e. double layer). Thirty six cases of other pelvic pathologic conditions were discovered on ultra sonography. CONCLUSIONS: We believe that is reasonable to have a cutoff limit for normal postmenopausal endometrium at 5 mm. Endovaginal ultrasound is a valuable diagnostic instrument, as sensitive as dilatation and curettage, for detecting pathological conditions in the uterine mucosa.

Transdermal estrogen with a levonorgestrel-releasing intrauterine device for climacteric complaints versus estradiol-releasing vaginal ring with a vaginal progesterone suppository: clinical and endometrial responses.

OBJECTIVE: Our purpose was to compare the effects of a new estradiol-releasing vaginal ring with progesterone given as a vaginal suppository, versus the efficacy, safety and acceptability of an intrauterine device releasing levonorgestrel combined with estradiol, delivered transdermally from a patch. Climacteric symptoms, bleeding pattern and endometrial histologic features were studied. METHODS: Fifty six parous, postmenopausal women with urogenital symptoms were allocated in two groups for one year: 28 women receiving estradiol by a vaginal ring and a 100 mg vaginal progesterone suppository 7 days every month and 28 women receiving a continuous transdermal daily dose of 50 micrograms of estradiol with a levonorgestrel-releasing intrauterine device inserted. All the patients were subjected to vaginosonographic examination followed by thorough pathological examination of the uterine curetting samples. RESULTS: A mean endometrial thickness (double layer) of 2.9 and 3.0 mm, respectively, was found to be predictive of normal endometrium. Both treatment regiments effectively relieved climacteric symptoms. Endometrial proliferation was not observed. Spotting was more common in the intrauterine device group than in the vaginal ring group. CONCLUSIONS: Treatment of urogenital symptoms in postmenopausal women with these two forms of hormone replacement therapy is shown to be an effective and safe method, exhibiting advantages over other methods of treatment.

Second-line chemotherapy with cisplatin-ifosfamide in patients with ovarian cancer previously treated with carboplatin-cyclophosphamide.

In an effort to use antineoplastic drug combinations which are active in platinum resistant ovarian cancer or which can induce a second response after a platinum first-line treatment, we conducted a study on 30 ovarian cancer patients previously treated with carboplatin plus cyclophosphamide who were given ifosfamide 5 g/m2 i.v. divided over days 1 to 3 plus mesma combined with cisplatin 100 mg/m2 i.v. divided over days 1 to 3 every 4 weeks as second-line treatment. Eight patients had never entered remission with first-line chemotherapy while 22 patients had tumor recurrence within 6 to 18 months after the end of chemotherapy and their tumors were considered potentially platinum sensitive. Responding patients received 6 courses while palliative treatment for nonresponders was provided. Of the 22 patients with tumor recurrence, 8 patients responded with one partial response (PR) and 7 complete clinical responses (CCR). Two out of the 8 patients with platinum resistant disease demonstrated short lasting PR. Seven patients with CCR underwent second-look operation and in two a pathological CR was documented. Median time to progression was 6 mo (4-12). The median overall survival was 12 mo (4-20). Myelotoxicity despite G-CSF administration was significant with grade 4 leukopenia in 40% and grade 3 thrombocytopenia in 20% of patients. Central nervous system (CNS) toxicity was significant with 30% somnolence, 20% disorientation and an episode of grand-mal epilepsy ascribed to ifosfamide. With a 33% response rate the combination is as effective as new agents employed in relapsed ovarian cancer. Platinum-refractory disease may respond to a lesser degree. The most important determinant of response was the progression-free interval from first-line chemotherapy. Whether patients recurring after carboplatin plus cyclophosphamide have a greater chance to respond to cisplatin plus ifosfamide or vice-versa cannot be supported by the current data and therefore randomized studies should be performed to this end.

Vaginal intraepithelial neoplasia (VAIN) following hysterectomy in patients treated for carcinoma in situ of the cervix.

OBJECTIVE: To determine the number of patients with carcinoma in situ of the cervix treated by hysterectomy who proceeded to develop vaginal intraepithelial neoplasia (VAIN) and define whether the subsequent development of VAIN justifies intensive cytology and colposcopy follow-up. MATERIALS AND METHODS: Nine hundred and ninety-three women who were subjected to hysterectomy with CIN, (793 patients had completed 10 years of cytology and colposcopy follow-up) were identified. RESULTS: Forty-one patients with VAIN presented with CIN 3 after hysterectomy. The upper one half of the vagina was the area more affected. The middle age group developed VAIN in the shortest time. Atypical Cells (ASCUS) were found in 42% of these patients. Colposcopy revealed VAIN involving the vault angles of the suture line in 54% of the cases. In 51% of the cases the grade of vaginal abnormality was the same as that of the original lesion in the cervix. CONCLUSION: With such data we would propose screening over a 5-year period. Follow-up should also include colposcopic review during every examination.

Predictive factors used to justify hysterectomy after loop conization: increasing age and severity of disease.

OBJECTIVE: To determine the interpretability and significance of the traditional factors used to predict residual dysplasia in hysterectomy specimens after loop conization. MATERIALS AND METHODS: Loop electrosurgical cervical conization was performed on 372 patients. Ninety three women had a hysterectomy within 6 months of the loop conization. Residual disease was defined as cervical intraepithelial neoplasia or cancer in the hysterectomy specimen. RESULTS: Of the 93 patients having a subsequent hysterectomy, 36 (38.7%) has residual disease in their hysterectomy specimen. The mean age of the patients with residual disease in the post loop conization hysterectomy specimen was 42.22. The mean age of those free of residual disease was 29.42. By multivariate analysis, dysplasia involving the ectocervical margin (p = 0.34) and the endocervical margin (p = 0.35) was not predictive of disease in the hysterectomy specimens. Endocervical curettage (p = 0.005), glandular involvement (p = 0.01), loop conization pathology findings (p < 0.05) and cytological examination (p < 0.001) were predictive of residual dysplasia. CONCLUSIONS: Cytological reports, increasing age, severity of disease, gland involvement and endocervical curettage were the only factors that accurately predicted residual dysplasia. The presence or absence of dysplasia in the loop conization, ectocervical margin and endocervical margin was not predictive of residual dysplasia in post loop conization hysterectomy specimens.

Hematometra and extended vaginal haematoma after laser conization. A case report.

A very rare case of haematometra and extended vaginal haematoma in a 53-year-old woman after laser conization is reported. The patient presented with amenorrhea and complete urinary retention. The possible pathogenesis of this complication is discussed. Ultrasonography, combined with physical examination were very helpful in determining the diagnosis. Cervical dilation and protection of surrounding tissues from thermal damage is recommended during laser conization to avoid similar complications.

Transvaginal Doppler ultrasound with color flow imaging in the diagnosis of luteal phase defect (LPD).

OBJECTIVE: Our purpose was to determine whether color flow pulsed Doppler could predict a luteal phase defect (LDP). METHOD: Twenty-one women with regular menstrual cycles and at risk for luteal phase defect were examined by transvaginal color Doppler during the follicular and luteal phase of the menstrual cycle. Progesterone was measured on the day of the Doppler exam. Ovulation was determined from the lutenizing hormone (LH) surge. Endometrial biopsy during the late luteal phase was performed on each patient. RESULT: Six patients (28.5%) were diagnosed with luteal phase defect. Mean resistance index in patients with luteal phase defect was significantly higher only throughout the luteal phases (p = 0.02). Mean progesterone levels were significantly lower for patients with LPD than for normal women (p < 0.001). Mean pulsatility index in luteal phase deficient cycles was significantly higher throughout the follicular and luteal phases (p = 0.03). CONCLUSION: Color Doppler may aid in assessing luteal phase adequacy. Doppler indices of corpus luteum blood flow in combination to plasma progesterone may be a useful index of luteal function.

Tibolone in the treatment of psychosomatic symptoms in menopause.

The purpose of this study was to investigate the value of tibolone in the treatment of psychosomatic symptoms in menopause. Forty-two menopausal women (aged 46-63, mean 53.9) with nightly perspiration, vasomotor flushes, disturbance of libido, dyspnea and other psychosomatic symptoms were assigned to one of two treatment groups for three months: 1st group) 21 users of tibolone; 2nd group) 21 users of placebo. At the end of the trial disturbance of libido was observed in 4 (19.0%) cases tin the 1st group and 11 (52.4%) cases in the 2nd (p < 0.05) and nightly perspiration was observed in 3 cases (14.3%) in the 1st group and 9 cases (42.9%) in the 2nd (p < 0.05). Although vasomotor flushes were observed in only 3 (14.3%) cases in the 1st group and 7 cases (33.3%) in the 2nd group, this difference was not significant (p > 0.05). There was no significant effect of tibolone or placebo in dyspnea, vertigo and headache. From the results it can be concluded that tibolone can have a beneficial effect on some psychosomatic symptoms in postmenopausal women.

A comparative study of the effects of an estradiol-releasing vaginal ring combined with an oral gestagen versus transdermal estrogen combined with a levonorgestrel-releasing IUD: clinical findings and endometrial response.

OBJECTIVE: Our purpose was to compare the effects of a new estradiol-releasing vaginal ring with an oral progestin versus the efficacy, safety and acceptability of an intrauterine device releasing levonorgestrel combined with estradiol, delivered transdermally from a patch. Climacteric symptoms, bleeding pattern, and endometrial histologic features were studied. MATERIALS AND METHODS: Fifty-six parous, postmenopausal women with urogenital symptoms were allocated to two groups for 1 year" 28 women receiving estradiol by a vaginal ring (2 mg/3 months) and an oral progestin for 7 days every month and 28 women receiving a continuous transdermal daily dose of 50 micrograms of estradiol with a levonorgestrel-releasing (20 micrograms/day) intrauterine device inserted. All the patients were subjected to vaginosonographic examination followed by thorough pathological examination of uterine curetting samples. RESULTS: A mean endometrial thickness (double layer) of 2.9 and 3.0 mm, respectively, was found to be predictive of normal endometrium. Both treatment regimens effectively relieved urogenital symptoms. Endometrial proliferation was not observed. CONCLUSIONS: Treatment of urogenital symptoms in postmenopausal women with these two forms of hormone replacement therapy was shown to be an effective and safe method, exhibiting possible advantages over other methods of treatment.

PIP: At the outpatient obstetric-gynecologic clinic of Areteion Hospital in Athens, Greece, 56 postmenopausal women, 48-76 years old and with signs and symptoms of estrogen deficiency-induced atrophic vaginitis, were randomly assigned to either the group using a silicon vaginal ring containing 2 mg micronized 17-beta- estradiol and oral medroxyprogesterone acetate for 7 days at the beginning of each month (group A) or the group using a combination of 50 mcg estradiol via a transdermal patch and a levonorgestrel-releasing IUD (group B). The women were using these regimens for 12 months. The purpose of the study was to compare the clinical and endometrial effects of the new vaginal ring with an oral progestin with those of the established hormone replacement regimen of transdermal estrogen and a levonorgestrel-releasing IUD. Vaginal ultrasound and pathologic examination of uterine curettage samples were used to determine endometrial effects. The urogenital complaints of all 56 women disappeared. The mean endometrial thickness before treatment was similar for both groups (2.9 mm for group A and 3 mm for group B) and was not significantly different than endometrial thickness after treatment (2.6 and 2.8 mm, respectively). Endometrial proliferation was not observed. The mean endometrial thickness at baseline predicted normal endometrium. After 3 months of treatment, vaginal bleeding patterns were similar in both groups. These findings confirm that both regimens effectively treat estrogen deficiency-induced urogenital disorders and do not increase the risk of endometrial proliferation.

Comparison of flutamide and cyproterone acetate in the treatment of hirsutism: a randomized controlled trial.

The objective of this study was to compare the efficacy of flutamide and cyproterone acetate in the treatment of hirsutism. Twenty-two women with idiopathic hirsutism were randomized to receive either flutamide or cyproterone acetate. Each patient underwent a complete gynecological examination as well as an endocrinological profile and hematological, hepatic and renal function analyses. Hirsutism scores were determined using a modified Ferriman-Gallwey scoring system. These tests were then repeated at 3 and 9 months of therapy. Eleven patients received 250 mg of flutamide twice daily and 11 patients received 100 mg of cyproterone acetate on days 5-14 of the menstrual cycle. Ferriman-Gallwey scores were decreased significantly in both groups at the end of 9 months. There was a trend towards a better response with flutamide, that did not achieve significance. Another significant difference was the increased sex hormone-binding globulin in both groups. A statistically significant decrease was also observed for the levels of testosterone on both drugs. No subject withdrew from the study due to a side-effect. The data suggest that both flutamide and cyproterone acetate were similarly effective in treatment of hirsutism, and that the pure antiandrogen flutamide is a safe, well-tolerated and effective alternative in treatment.

Low beta-hCG is associated with poor prognosis in association with an embryo with positive cardiac activity.

Seven pregnancies with positive fetal heart activity and low or very low serum beta-human chorionic gonadotropin (beta-hCG) levels were investigated. The gestational age by dates was between 6 weeks 3 days and 8 weeks 4 days at the time of the first ultrasound scan and beta-hCG ranged between 282 and 10,000 mIU/ml of the Second International Standard. The crown-rump lengths ranged between 6 and 13 mm and heart activity was always detected. Four cases were scanned because beta-hCG was lower than that expected for the gestational age; in these cases the yolk sac was present but the gestational sacs were small, with a trophoblastic ring that looked thin and subjectively seemed abnormal. The beta-hCG level was measured in the other three cases, because the gestational sacs were small and had a thin trophoblastic ring. In these cases, fetal heart activity was clearly imaged. All cases were scheduled for a repeat ultrasound scan 2 weeks later. Three cases aborted spontaneously the following week, whereas in the other four no heart activity was detected in a repeat sonogram 2 weeks later. Low serum beta-hCG levels indicate a poor prognosis even when associated with an embryo with positive cardiac activity detected ultrasonographically.

Alterations of p16-pRb pathway and chromosome locus 9p21-22 in sporadic invasive breast carcinomas.

The p16-pRb pathway represents a vital cell-cycle checkpoint. In the present study we investigated the alterations of this G1-phase protein pathway using immunohistochemical and molecular methods in a series of 55 breast carcinomas and correlated the findings with clinicopathological features of the patients. Furthermore, we examined its relationship with the status of the chromosomal region 9p21-22 performing a deletion map analysis because there are indications that, in addition to CDKN2 and MTS2/p15(INK4B) tumor suppressor genes (TSGs), this area harbors other TSG(s). Aberrant expression (Ab) of p16 and pRb was observed in 26 (47%) and 16 (29%) of the carcinomas, respectively. A statistical trend pointing out an inverse relationship between p16 and pRb expression was found (p = 0.079). Analysis of the region that encodes for p16 by deletion mapping, a PCR-based methylation assay and PCR-SSCP, revealed that deletions and transcriptional silencing by methylation might represent the main mechanisms of CDKN2/p16(INK4A) inactivation in breast carcinomas. The results of deletion mapping also suggest that another TSG(s) may reside at the 9p21-22 area particularly at the D9S162 loci and that co-deletion of this putative gene with CDKN2/p16(INK4A) may play a role in breast carcinogenesis. In addition, microsatellite instability (MI), a marker of replication error phenotype (RER+), was observed with a frequency of 16% in the area examined and was inversely related with loss of heterozygosity (LOH). Interestingly, most cases with MI at the region encoding for p16 were aggregated in a subgroup of breast carcinomas with no other obvious genetic and/or epigenetic CDKN2/p16(INK4A) alterations. We speculate that there is an additional mechanism of CDKN2/p16(INK4A) inactivation. The relationship of p16 protein level pRb, status, the p16-pRb combined immunoprofiles, and the microsatellite alterations detected at the 9p21-22 locus with the patients' clinicopathological parameters revealed two significant correlations: one between normal pRb expression and lymph node involvement (p = 0.0263), and the other between microsatellite alterations (LOH and or MI) and tumor size (p = 9.2 x 10(-3)). In view of the heterogenous nature of breast cancer, we suggest that in a significant proportion of breast carcinomas, deregulation of the p16-pRb pathway in association with another, as-yet unidentified, TSG(s) of the 9p21-22 region may play a role in initiating or progressing the oncogenic procedure, while in other subgroups, alternative molecules may play this role.

Hypersensitivity reactions to carboplatin administration are common but not always severe: a 10-year experience.

We have retrospectively evaluated and characterized the hypersensitivity reactions associated with carboplatin administration in ovarian cancer patients treated mainly on an outpatient basis at the Laikon Hospital from 1988 to 1998. A total of 240 patients, who had never been exposed to platinum compounds previously, received carboplatin plus cyclophosphamide (n = 58) or paclitaxel (n = 136) intravenously, and intraperitoneal carboplatin plus intravenous cyclophosphamide (n = 46). The median number of carboplatin courses was 6 (range 3-12) and 5 (range 4-6) for the intravenous and intraperitoneal treatment regimens, respectively. Thirty-two of 194 patients (16%) who were on intravenous carboplatin treatment developed symptoms compatible with a hypersensitivity reaction to carboplatin, that was always verified by manifestation of at least similar symptoms on rechallenging. In contrast, in the group of 46 patients on intraperitoneal carboplatin treatment, no hypersensitivity reaction was ever noticed. Hypersensitivity reactions always occurred after administration of the first 4 intravenous courses of carboplatin; 4, 19, 4, and 5 reactions occurred at the 5th, 6th, 7th, and 8th courses, respectively. These reactions could be distinguished in: (a) mild hypersensitivity reactions in 20 of 194 patients, which manifested as itching (20 patients) and small area erythema plus erythema of the palms and soles (12 patients), occurring either during intravenous injection when most of the drug scheduled had been administered, or within 3 days, and (b) in severe reactions in 12 of 194 patients, which manifested acutely as itching, diffuse erythroderma, rigor, facial swelling, throat and chest tightness, tachycardia (12 patients) and bronchospasm (2 patients), and hypertension or hypotension in 8 and 4 patients, respectively. With appropriate symptomatic management, discontinuation of carboplatin treatment was not required in patients with mild hypersensitivity reactions, but none of the 12 patients with severe reactions was able to receive a full subsequent dose of carboplatin on rechallenging. However, in 4 of these 12 patients carboplatin was replaced by cisplatin, which was given for 4-6 courses without side effects. These findings indicate that although hypersensitivity reactions are common in general, occurring in almost 1 of every 6 patients treated intravenously with carboplatin, their clinical picture is variable, leading to discontinuation of treatment in only 6% of patients. This is not the case when the intraperitoneal route of carboplatin administration is used when indicated.

A comparative study of intraperitoneal carboplatin versus intravenous carboplatin with intravenous cyclophosphamide in both arms as initial chemotherapy for stage III ovarian cancer.

Cisplatin (C) or carboplatin (CBP) plus cyclophosphamide (CTX) was until recently considered standard chemotherapy for advanced ovarian cancer (OC). Attempts to maximize platinum and its analog activity against OC include its administration directly into the peritoneal cavity. In the past we have shown that intraperitoneal (IP) CBP administration is a safe and effective treatment for OC [Polyzos et al: Proc Am Assoc Cancer Res 1990;31: 1120]. In the present study we aimed to compare the effectiveness and toxicity of CBP administration either intravenously (IV) or IP plus CTX IV. Since 1990, 90 evaluable patients with stage III OC were prospectively randomized to receive CBP 350 mg/m2 IV or IP plus CTX 600 mg/m2 IV (in both groups) every 3-4 weeks for six courses. The randomization incorporated stratification according to performance status and the amount of residual tumor (maximum diameter 2 cm). Clinical assessment was performed with abdominal CT and serum CA-125. Responses were observed in 33/46 = 72% (95/CI 56.5-84.0) of the IV group and in 33/44 = 75% (95/CI 59.7-86.8) of the IP group with 48 and 45% clinical complete responses, respectively. Times to progression were 19 months (8-62+) for the IV group and 18 (6-72+) for the IP group. Median survivals were: 25 months (6-80+) and 26 months (6-72+), respectively. Significantly more patients in the IV group than in the IP group had grade 3 or higher leukopenia (p < 0. 01) and grade 3 thrombocytopenia (p < 0.09). Morbidity due to infectious complications in the IP group was minimal. It seems that IP CBP is equally effective to IV administration in terms of response and survival with less myelotoxicity. The favorable results on survival demonstrated in studies with IP C administration in patients with small volume disease [Alberts et al: N Engl J Med 1996;335:1950-1965] could not be repeated in the present study applying CBP in patients with variable tumor size and a relatively small number of patients. The likelihood that patients with large volume disease would benefit from a regional approach compared to systemic administration is small and this explains the inability to detect a difference between the two arms.