Weekly AUC2 carboplatin in acquired platinum-resistant ovarian cancer with or without oral phenoxodiol, a sensitizer of platinum cytotoxicity: the phase III OVATURE multicenter randomized study.

BACKGROUND: Platinum-resistant ovarian cancer (PROC) constitutes a therapeutic dilemma with limited efficacy from traditional cytotoxic agents. Based on prior data suggesting that scheduling alterations of platinum would increase activity, the aim of the present study was to assess the potential therapeutic benefit of phenoxodiol (PXD), a novel biomodulator shown to have chemoresistance reversing potential, when combined with weekly AUC2-carboplatin in PROC patients. PATIENTS AND METHODS: A multicenter randomized double-blind placebo controlled phase-III-study was conducted to compare oral PXD plus AUC2-carboplatin (group 1) versus placebo plus AUC2-carboplatin (group 2) weekly in PROC patients. The primary end point was progression-free-survival (PFS). Secondary objectives included overall survival (OS), response rates, duration of response and quality of life. RESULTS: The study was terminated early 14 April 2009, after recruitment of 142 patients due to feasibility and recruitment challenges. A total of 142 patients were randomized. The groups were well balanced in terms of important baseline characteristics. The median PFS for group 1 was 15.4 weeks [95% confidence interval (CI) 11.1-21.0] versus 20.1 weeks for group 2 (95% CI = 13.1-33.4); P = 0.3. The objective response rate and median survival in group 1 versus group 2 was 0% versus 1% and 38.3 weeks (95% CI 32.0-45.3) versus 45.7 weeks (95% CI 35.6-58.0), respectively. PXD appeared to be well tolerated. The main reason for dose modification in both groups was hematologic toxicity. CONCLUSIONS: Orally delivered PXD showed no evidence of clinical activity, when combined with weekly AUC2-carboplatin in PROC. In addition, single-agent weekly AUC2-carboplatin appeared to be inactive by response criteria in a homogenously defined population of PROC. This has implications for the design of future studies.

Phase II randomized study of trabectedin given as two different every 3 weeks dose schedules (1.5 mg/m2 24 h or 1.3 mg/m2 3 h) to patients with relapsed, platinum-sensitive, advanced ovarian cancer.

BACKGROUND: This randomized, open-label, phase II clinical trial evaluated the optimal regimen of trabectedin administered every 3 weeks in patients with platinum-sensitive, relapsed, advanced ovarian cancer (AOC). PATIENTS AND METHODS: Patients previously treated with less than two or two previous chemotherapy lines were randomized to receive trabectedin 1.5 mg/m(2) 24 h (arm A, n = 54) or 1.3 mg/m(2) 3 h (arm B, n = 53). Objective response rate (ORR) per RECIST was the primary efficacy end point. Toxic effects were graded according to the National Cancer Institute-Common Toxicity Criteria v. 2.0. RESULTS: ORR was 38.9% [95% confidence interval (CI) 25.9% to 53.1%; arm A] and 35.8% (95% CI 23.1% to 50.2%; arm B) (intention-to-treat primary analysis). Median time to progression was 6.2 months (95% CI 5.3-8.6 months; arm A) and 6.8 months (95% CI 4.6-7.4 months; arm B). Frequent severe adverse events were nausea/vomiting (24%, arm A; 15%, arm B) and fatigue (15%, arm A; 10%, arm B). Common severe laboratory abnormalities were transient, noncumulative neutropenia (55%, arm A; 37%, arm B) and transaminase increases (alanine aminotransferase, 55%, arm A; 59%, arm B). CONCLUSIONS: Both every-3-weeks trabectedin regimes, 1.5 mg/m(2) 24 h and 1.3 mg/m(2) 3 h, were active and reasonably well tolerated in AOC platinum-sensitive patients. Trabectedin every-3-weeks has promising activity and deserves to be further evaluated in relapsed AOC.

The value of tumor marker and cytokine analysis for the assessment of regional lymph node status in cervical cancer patients.

The aim of the study was to evaluate the utility of the measurements of the circulating tumor markers, squamous cell carcinoma antigen (SCCA), CA125, carcinoembryonic antigen (CEA), cytokeratin fragment 19 (CYFRA 21.1), and the cytokines, interleukin-6 and vascular endothelial growth factor (VEGF), to estimate regional lymph node involvement in patients with cervical cancer. The study comprised 182 untreated patients with cervical cancer. The regional lymph node status was assessed either by the postsurgical histopathologic examination or by the computed tomography (CT). Concentrations of SCCA, CEA, and CA125 were determined using the Abbott Instruments system, of CYFRA 21.1 by the Roche kits, and of IL-6 and VEGF by the ELISA of R&D Systems (Minneapolis, MN). For the statistical analyses, Mann-Whitney U test and chi(2) test were applied. Serum levels of SCCA, CEA, CA125, CYFRA 21.1, IL-6, and VEGF were measured in patients with specified pelvic and para-aortic lymph node status. SCCA, CA125, and IL-6 levels were found to be significantly higher in patients with lymph node metastases than in those with no lymph node involvement. Also, the percentage of patients with simultaneously elevated concentrations of SCCA and CA125 or SCCA and IL-6 differed depending on the lymph node status and was significantly higher in the series of patients with lymph node metastases. Simultaneous assessment of serum levels of SCCA and CA125 or SCCA and IL-6 in patients with cervical cancer may be useful for the regional lymph node evaluation, especially in patients with advanced stages, when the lymph nodes are examined only by CT, with no histologic confirmation.

Results of chemotherapy for pulmonary metastases of carcinoma of the cervix in patients after primary surgical and radiotherapeutic management.

The purpose of this study was to evaluate the results of chemotherapy of pulmonary metastases from invasive carcinoma of the cervix, which were detected after a disease-free period after initial treatment with surgery or radiotherapy. Fifty patients with radiologically proven pulmonary metastases were treated with chemotherapy. All patients received a platinum-5-fluorouracil (PF) program: cisplatin 75 mg/m(2) and 5-fluorouracil 800 mg/m(2) every 4 weeks. The overall 1- and 3-year survival after PF chemotherapy was 62% and 17.6%, respectively. The progression-free survival at 1 and 3 years was 36.7% and 14.3%, respectively. There were 6 (12%) complete responses and 17 (34%) partial responses. Hematologic tolerance was acceptable. Third degree and fourth degree leukopenia was diagnosed in four (8%) and six (12%) patients, respectively. Three individuals had third degree thrombocytopenia. In the multivariate analysis, the following prognostic factors were associated with poor survival: time to recurrence after primary treatment (P= 0.002), number of lung metastases (P= 0.016), and progression during chemotherapy (P= 0.001). We conclude that PF regimen is a safe and reasonably effective chemotherapy in the management of patients with pulmonary metastases after primary treatment for invasive carcinoma of the cervix who do not qualify for surgical metastasectomy.

The evaluation of intra- and postoperative complications related to debulking surgery with bowel resection in patients with FIGO stage III-IV ovarian cancer.

The surgical treatment of advanced ovarian cancer is based on the maximal debulking with widening the operation range to the infiltrated organs. The aims are as follows: (1) the assessment of the quantity and quality of intra- and postoperative complications in patients with advanced ovarian cancer in which partial bowel resection was performed and (2) the evaluation of intra- and postoperative complications related to surgery with bowel resection and anastomosis, compared to Hartmann's procedure. The analysis of debulking procedures with intestinal resection and postoperative period in 39 ovarian cancer patients, FIGO stage III-IV, was performed. During 39 operations, the most frequent type of resection was the sigmoidectomy or proctosigmoidectomy (29 patients). In the remaining patients, left- and right-side hemicolectomy or partial enterectomy was done. Twenty-four anastomosis and 15 Hartmann's procedures were performed. There were no differences between surgery with anastomosis and Hartmann's procedure in aspect of quantity of complications, blood loss, and the time of surgery. There were no statistically significant differences in overall survival and progression-free survival in both groups. We conclude that the percentage of complications related to debulking surgery with intestinal resection in advanced ovarian cancer patients might be accepted. The quantity of complications related to surgery with anastomosis and to Hartmann's procedure is similar. If possible, the surgery with anastomosis should be performed.

Comparison of the results of surgical treatment using laparoscopy and laparotomy in patients with endometrial cancer.

The objective of the current study was to compare the results of surgical treatment in endometrial cancer with the use of laparoscopy and the traditional approach of laparotomy. Our goal was to evaluate and compare the morbidity, recurrence rate, and disease-free survival in both groups. This article is a retrospective study. A chart review of 45 patients treated by laparoscopy between 1994 and 2002 and 136 patients treated by laparotomy between 2001 and 2002 was performed. Disease-free survival in both groups was evaluated with the Kaplan-Meier method and was compared using the log-rank test. The rate of recidive was 6% in the laparoscopy group and 13% in the laparotomy group. There was no statistically significant difference in disease-free survival and recidive rate between the laparoscopy and laparotomy groups. Laparoscopic management in endometrial cancer does not worsen the prognosis, and the disease-free survival is similar to that resulting from the traditional approach. The benefits of minimal invasive surgery are quicker postoperative recovery, shorter hospital stay, and no wound complications.

Analysis of the treatment of ovarian cancer patients with neo-adjuvant chemotherapy--preliminary results.

INTRODUCTION: Primary surgery and adjuvant chemotherapy is the standard treatment in ovarian cancer patients. Neo-adjuvant chemotherapy is one of the treatment modes in patients with a poor general condition or advanced disease, not adjustable for primary surgery. The purpose of this study was to evaluate if the efficacy of this new option of therapy is comparable to the standard method. MATERIALS AND METHODS: 319 ovarian cancer patients, FIGO Stage III and IV, have been analyzed. Within this group, 50 women were treated with neo-adjuvant chemotherapy. 18 patients were operated after three cycles of neo-adjuvant chemotherapy, and 32 patients--after six cycles. Results of treatment were evaluated, including disease-free survival, and number of complications. Factors that may influence the treatment results were also analyzed. RESULTS: Median disease-free survival in the group treated with adjuvant chemotherapy (group 3), and operated on after three cycles of neo-adjuvant chemotherapy (group 1), were 19 and 20 months, respectively. For the group operated on after six cycles of neo-adjuvant chemotherapy (group 2), median disease-free survival was 15 months (p = 0.27). The following factors have been found to influence treatment results: optimal cytoreduction and tumor grading. There was no difference in complication rates among the three analyzed groups.

Nijmegen breakage syndrome gene (NBS1) alterations and its protein (nibrin) expression in human ovarian tumours.

We looked for NBS1 gene (602667) alterations and changes in nibrin expression in 162 human gynaecological tumours, mostly ovarian. Exons 6-8 and 10 of the NBS1 gene were evaluated by the SSCP and direct sequencing method. Nibrin expression was detected immunohistochemically with the use of the p95NBS1 (Ab-1) antibody. The 657del5 mutation (Slavic mutation) was found in two of 117 carcinomas studied (1.7%) - in both cases it was present in the germline; one of these tumours showed loss of heterozygosity (LOH) for the 657del5 mutation and loss of nibrin expression. We have found three types of novel germline intron variants: (1) two concomitant transitions (G to A) at bases 14009 and 14256; (2) C to T transition at base 13998; (3) G to C transversion at base 20035. Among the carcinomas studied, the intron variants were associated with a clear cell histological type (p = 0.004). Our results may suggest that NBS1 gene alterations contribute to the development of rare ovarian carcinomas. LOH for 657del5 in tumour tissue may support the hypothesis that the NBS1 gene functions as a tumour suppressor.

[Evaluation of the value of hysteroscopy or doppler ultrasonography for monitoring treatment effects of radiotherapy in patients with cervix carcinoma]. / Ocena wartosci histeroskopii oraz ultrasonografii dopplerowskiej dla monitorowania efektów leczenia wylaczna radioterapia u chorych na raka trzonu macicy.

The aim of this study was to investigate the useful of colour flow doppler (CDF) and hysteroscopy to determine the endometrium status in endometrial cancer patients who were treated by radiotherapy alone. The study group comprised 33 patients. There were hysteroscopy and CDF performed in obligatory regular periods. High useful of hysteroscopy was confirmed. It appeared 89% of sensitivity and 91% of specificity. CDF sensitivity was 69% and specificity 75%. Absence of the flow signal in endometrial tissue was correlated with no of malignant pathology in uterus. Pulsatility and resistance indexes in CDF were not characterised for histopathology status of endometrium.

[Granulosa cell tumor--the assessment of some clinical and therapeutic parameters as prognostic factors]. / Ziarniszczak jajnika--ocena wybranych czynników klinicznych i terapeutycznych w ich prognostycznym znaczeniu.

The results of the clinical and therapeutic factors in prognostic mean was presented. 48 cases of granulosa cell tumours treated from 1984 to 1994 in Oncology Centre in Warsaw were analysed. In investigated group 13 patients died, but only 8 because of relapse of the tumour. Among all analysed patients, 79% have reached 5 years free survival period. Tumour rupture, FIGO stage and incidence of irregular bleeding before recognition of the tumour had significant prognostic value. There were surprising that relative risk of relapse between patients stage I and II were similar (1.0 vs 1.01). The relative risk between I and III stage had strong prognostic difference. Additional operation after no radical surgery did not influence on better prognosis, but followed radiotherapy increase treatment results.

[Adenocarcinoma of the cervix--stage IB: results of treatment and prognostic factors]. / Rak gruczolowy szyjki macicy w stopniu IB--wyniki leczenia i analiza czynników prognostycznych.

The study presents the results of treatment of 63 women with stage IB adenocarcinoma of the cervix. The treatment consist of radical Wertheim-Meigs hysterectomy with adjuvant brachytherapy or external beam irradiation. A statistical analysis with Kaplan-Meier and cox model was conducted to assess the influence of selected prognostic factors on survival. After 5-year long follow-up 73.4% of patients were alive without recurrence. The results of univariate analysis showed that metastatic pelvic nodes, cervical tumor size of more than 4 cm and the presence of microscopic parametrial infiltration had a statistically significant negative influence on survival. In a multivariate analysis tumor size of more than 4 cm and microscopic parametrial involvement had an independent negative impact on survival (relative risk of death--12.1 and 15.7).

[Primary vaginal and uterine melanoma--a case of long term survival after local excision and vaginal brachytherapy]. / Pierwotny czerniak pochwy i macicy--przypadek wieloletniego przezycia po pierwotnym leczeniu operacyjnym i brachyterapii.

This report presents the case of long term survival of primary vaginal melanoma treated by local excision and vaginal brachytherapy. A unique histopathological pattern of preinvasive vaginal melanoma is also described. A review of the literature revealed 22 long term survivals after treatment of malignant melanoma of the vagina, and only 4 surviving more than 10 years. In general the prognosis in women with these malignancy is poor regardless of type of surgery. Depth of infiltration seems to be the only important prognostic factor influencing the survival.

Nuclear grading of endometrial cancer harbors heterogenous prognostic groups as detected by proliferation activity.

OBJECTIVE: Nuclear grading, in addition to the histopathological result of every tumor, is responsible for consecutive treatment designs. Ki-S5 is the monoclonal antibody against a formalin-resistant epitope of the Ki-67 antigen and can be determined in paraffin-embedded samples. The aim of the study was a comparative analysis of the nuclear grading of endometrial cancer and the proliferation marker Ki-S5. METHODS: In 126 specimens of endometrial cancer the proliferation activity of the monoclonal antibody Ki-S5 was determined (streptavidin-biotin-complex method) in correlation to nuclear grading. In the group of grade 2, stages Ib and Ic andenocarcinomas, proliferation rates were compared to recurrence rates. RESULTS: Divergent proliferation rates resulted. Adenoacanthomas showed a relatively low proliferation rate (<28%). For the andenosquamous carcinomas the proliferation rate ranged between 28-43%. The largest group of adenocarcinomas showed proliferation rates from 5-74%. A clear dependency between increasing proliferation rates and decreasing differentiation (nuclear grading 2-3) was observed. In the small group of patients with andenocarcinomas, nuclear grading G2 stages Ib and Ic, 38 suffered no recurrence after 6-10 years. However, the six patients with proliferation rates of over 35% all suffered a recurrence. CONCLUSIONS: The results emphasize the need to differentiate G2 tumors, depending on their proliferation rate, into low risk (KiS5<35%) and high risk cases (Ki-S5>35%).

Cervical verrucous carcinoma involving endometrium. Case report.

A case report of verrucous carcinoma of the cervix is presented. Verrucous carcinoma is a rare variant of squamous cell carcinoma with distinct clinical and histopathologic features, with a favorable prognosis. A 32-year-old woman had an abdominal hysterectomy with bilateral ovary transposition. Intravaginal brachytherapy using cesium 137 in a total dose of 60 Gy 0.5 cm from the vaginal layer was performed. Five year disease-free follow-up was observed. Macro- and microscopic examination of the tissue after hysterectomy was performed. The full thickness of the tumor is necessary for histopathological assessment. The cytology or superficial and simple biopsy may be misdiagnosed. The differentiating diagnosis among condyloma acuminata, verrucous carcinoma and invasive squamous cell carcinoma was analysed.

[Clinical usefulness of color doppler flow examination during treatment of gestational trophoblastic disease]. / Ocena przydatnosci klinicznej badan przeplywów naczyniowych z uzyciem kolorowego Dopplera u chorych leczonych z powodu ciazowej choroby trofoblastycznej.

Neovascularisation is the integral part of tumor development. Presence and type of pathological vascularisation can be used in therapy monitoring and follow up. The value of beta HCG and pulsatility index (PI) and resistance index (RI) in 14 women treated for nonmetastatic persistent trophoblastic disease (NMTD) were been compared. There was statistical, significant correlation between dropped BHCG level and increased value of RI. No correlation between BHCG blood concentration and values of PI was observed. In summary it should be stated that color Doppler ultrasonography is useful method in monitoring patients with NMTD.

Endoscopic lymphadenectomy and LAVH in the treatment of endometrial cancer.

This article describes the results of two and half years experience in laparoscopic treatment of patients with endometrial cancer stage I and II. Between January 1994 and October 1996, 25 patients were treated by laparoscopy procedures. All of them had performed LAVH and pelvic lymphadenectomy. The technique of the laparoscopic procedure was accurately described. No operative complications were observed and blood loss did not exceed 250 ml. In 7 patients (27.8%) nodal metastases were found. Mean 14 (range 7-25) lymph nodes were removed. After surgery some patients required radiotherapy. Up to now all patients are free of disease. We believe that laparoscopic assisted surgical staging of stage I and II endometrial cancer is an attractive alternative to the traditional surgical laparotomy approach.

The assessment of value of transvaginal ultrasound for monitoring of gestational trophoblastic disease treatment.

Thirtysix patients with persistent gestational trophoblastic disease were analysed in The Clinic of Cancer of Female Reproductive System. Using transvaginal USG, the volume of pathological foci within myometrium, diametre of theca lutein ovarian cysts and uterus length before, during and after the treatment were registred. In order to check the effectiveness of USG examination in the monitoring of GTD treatment particular USG factors were compared with hCG level. On 28 patients (77.7%) in USG examination pathological changes in uterus and ovaries were seen. The relation between hCG level and tumor volume, uterus length and theca lutein ovarian cysts was stated. That proves the usefulness of transvaginal USG examination in the monitoring of treatment of patients with persistent gestational trophoblastic disease.

Evaluation of the hormonal function and features of the ultrasound picture of transposed ovary in cervical cancer patients after surgery and pelvic irradiation.

Conventional surgical methods for treatment of invasive cervical cancer inevitably lead to castration. In young women premature cessation of ovarian function may lead to serious short term and long term complications. The preservation of ovarian function if possible is crucial to improving quality of life. 48 patients with Ia and Ib carcinoma of the cervix entered this study. All patients were treated by Wertheim's radical hysterectomy with ovarian transposition. Some of them had adjuvant radiotherapy. It appears that radical surgery even with postoperative brachytherapy has not had adverse effect on ovarian function. It has been found that depletion of ovarian function might be expected in patients treated by external beam irradiation if the distance between the upper margin of the inlet field and the transposed ovary was less than 3 cm. In 91% cases, in USG examinations distinct reduction of transposed ovary echostructure were found.

Clinical value of transvaginal, sonographically guided fine needle aspiration biopsy of parametria in recurrent cervical carcinoma.

Forty four patients with a clinically suspected relapse of cervical carcinoma were evaluated with transvaginal sonographically guided fine-needle aspiration biopsy (FNAB) of parametria in the Gynaecological Department of the Institute of Oncology, Warsaw, Poland. Sonographical scans and FNAB results were compared with subsequent clinical course (41 cases) and surgery (3 cases). Of the total of 56 aspiration biopsies 50 specimens were of cytological value. Overall diagnostic accuracy of FNAB was 82%, specificity and positive predictive value 100%, sensitivity 61% and negative predictive value 75%. As regards sonography the accuracy rate was 77%, the sensitivity as well as negative predictive value were 100%, specificity was 62% with false positive rate 23%. The definitive diagnosis of recurrence was obtained by FNAB in 13 out of 18 cases and in 8 of these radiotherapy was instituted. The negative FNAB correctly rules out the recurrent disease in 22 of 26 cases. In all cases with relapse parametrial lesions were detected on ultrasound scans. The Authors have found that sonographically guided FNAB of parametria is a useful diagnostic tool in imaging and biopsying of parametrial masses. As the conjunction of two complementary diagnostic methods this technique is an excellent tool for obtaining the cytologic verification of recurrence, especially in doubtful cases, when post-therapeutic pelvic fibrosis is present. It is also a quick, safe technique, well accepted by the patient.

The value of transvaginal ultrasonography (TVS) in the assessment of myometrial and cervical invasion in corpus uterine neoplasma.

62 women with histologically proven corpus uteri neoplasia were examined to estimate accuracy, sensitivity and specificity of TVS in assessing myometrial invasion and cervical involvement of the disease. Incorrect ultrasound interpretation were found in 9 cases (14.5%). Accuracy rate was 88.7% in myometrial infiltration and 93.5% in cervical invasion. The sensitivity of TVS in detecting the level of myometrial invasion was 96% and in cervical spread was the same. The specificity of this method in proper estimation the myometrial infiltration was 91% and in cervical involvement 95%. Concomitant myomas and primary radiotherapy may increase difficulties in determining the spread of neoplasia. All these facts have convinced us that TVS is of great value in gyneacological oncologic practice and deserves even wider application.