Weekly topotecan and cisplatin (TOPOCIS) as neo-adjuvant chemotherapy for locally-advanced squamous cervical carcinoma: Results of a phase II multicentric study.

OBJECTIVES: The aim of this phase II multicentric study was to evaluate the efficacy and toxicity of neo-adjuvant chemotherapy with weekly topotecan and cisplatin in locally-advanced squamous cervical cancer. PATIENTS AND METHODS: From November 2008 to January 2011, 92 patients met the inclusion criteria and were enrolled. Eligibility criteria were: squamous or adenosquamous cervical cancer; clinical stages IB2, IIA, IIB; Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)≤ 2; neutrophils ≥1500/µL; platelets ≥100,000/µL, normal renal and liver function. Treatment consisted of six courses of weekly topotecan (2mg/m(2)) and cisplatin (40 mg/m(2)). All responsive and stable patients were submitted to radical surgery, while progressed cases underwent definitive radiotherapy±chemotherapy. Primary end-point was evaluation of efficacy and toxicity. All patients are evaluable for toxicity and efficacy. RESULTS: Ninety-six percent of patients completed the six planned courses of chemotherapy, and 95% of courses were administered at a full dose and without interruption or delay. Mean age was 49 years (35-64 years). FIGO Stage distribution was 30 IB2, 13 IIA and 49 IIB. Treatment was well tolerated and no death occurred. G3-G4 haematological toxicity was observed in 28% of patients (5% out of cycles). Support therapies (blood transfusions and/or erythropoietin and/or Granocyte-Colony Stimulating Factor) were given to 24% of patients. Clinical response rate was 77%. The nine progressed cases were irradiated, while the remaining 83 patients were submitted to radical surgery. An overall pathologic response was observed in 67% of patients, with an optimal response rate of 32% and a disease downstage in 57% of patients. Nodal metastases occurred in 36% of patients. Adjuvant therapy (radiotherapy and or chemotherapy) was prescribed in 55% of patients, because of lymph node metastases, parametrial or vaginal involvement or cut-through margins. Median follow-up was 18 months: 76% of patients are alive and free from recurrence, 24% of patients relapsed and 13% died. CONCLUSIONS: Weekly topotecan and cisplatin showed an acceptable toxicity profile; the promising response rate warrants further investigation.

Clinical and pharmacological phase I evaluation of Exherin (ADH-1), a selective anti-N-cadherin peptide in patients with N-cadherin-expressing solid tumours.

BACKGROUND: Upregulation of N-cadherin promotes dysregulated cell growth, motility, invasiveness, plus maintenance of vascular stability and is associated with cancer progression in several human tumour types. N-cadherin is expressed also on tumour cells and the anti-N-cadherin cyclic pentapeptide ADH-1, tested in the present study, can exert a direct antitumour effect. PATIENTS AND METHODS: Adult patients with advanced solid malignancies expressing N-cadherin on tumour biopsies carried out in the previous 12 months received escalating i.v. doses of ADH-1 given weekly (initially for 3 of 4 weeks, then every week). Plasma pharmacokinetics (PK) was studied at cycle 1. Blood flow changes were assessed after first dosing in all patients treated in the initial regimen. RESULTS: In all, 129 patients were screened, 65 (50%) were N-cadherin positive, and 30 were enrolled. The doses ranged from 150 to 2400 mg/m(2); no maximum tolerated dose was reached. Treatment was well tolerated with asthenia as the most frequent adverse event. Two patients with ovarian cancer showed prolonged disease stabilisation while one patient with fallopian tube carcinoma achieved a mixed response. PK was linear in the range of doses tested. CONCLUSION: ADH-1 is the first anti-N-cadherin compound tested in humans. In N-cadherin-positive patients, ADH-1 showed an acceptable toxicity profile, linear PK and hints of antitumour activity in gynaecological cancers.

Randomised trial of drains versus no drains following radical hysterectomy and pelvic lymph node dissection: a European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group (EORTC-GCG) study in 234 patients.

Drainage, following radical hysterectomy and pelvic lymph node dissection to prevent postoperative lymphocyst formation and surgical morbidity, is controversial. To study the clinical significance of drainage, 253 patients were registered and 234 patients were randomised into two arms. In one arm (n=117) postoperative drainage was performed, in the other arm (n=117) no drains were inserted. In both arms closure of the peritoneum of the operating field was omitted. The main exclusion criteria were blood loss of more than 3000 ml during surgery or persistent oozing at the end of the operation. Clinical and ultrasound or CT-scan evaluation was done at one and 12 months postoperatively. The median follow-up amounted to 13.3 months. No difference in the incidence of postoperative lymphocyst formation or postoperative complications was found between the two study arms. The late (12 months) incidence of symptomatic lymphocysts was 3.4% (drains: 5.9%; no drains: 0.9%). The difference showed a p-value of 0.06 in Fisher's Exact test. The operating time was related to the occurrence of postoperative lymphocyst formation. It was concluded that drains can be safely omitted following radical hysterectomy and pelvic node dissection without pelvic reperitonisation in patients without excessive bleeding during or oozing at the end of surgery.

Cytoreduction combined with intraperitoneal hyperthermic perfusion chemotherapy in advanced/recurrent ovarian cancer patients: The experience of National Cancer Institute of Milan.

AIMS: We report the effects of cytoreductive surgery (CRS) and intraperitoneal hyperthermic perfusion (IPHP) in the treatment of advanced/recurrent epithelial ovarian cancer (EOC) on survival, morbidity and mortality. PATIENTS: Forty EOC patients were studied. Median age was 52.5 years (range: 30-68) and median follow-up 26.1 months (range: 0.3-117.6). Most patients presented advanced disease (stage III/IV). Previous systemic chemotherapy included cisplatin-based, taxol-based or taxol/platinum containing regimens. RESULTS: After the CRS, 33 patients presented no macroscopic residual disease. Five-year overall survival was 15%; the mean overall and progression-free survivals were 41.4 and 23.9 months, respectively. The morbidity, toxicity and mortality rates were 5%, 15% and 0%, respectively. CONCLUSION: Our results suggest that CRS + IPHP merits further evaluation by a formal prospective trial.

'State of the art' of radical hysterectomy; current practice in European oncology centres.

Quality control of medical performance requires adequate 'state-of-the-art' data and this is currently not uniformly defined for radical hysterectomy. We have used data from a randomised multicentre clinical trial examining the clinical significance of surgical drains following radical hysterectomy (European Organisation for Research and Treatment of Cancer (EORTC)-55962). Although the study was not designed to analyse the quality of the surgical procedure per se, surgical data during and after the operation were carefully noted. A total of 234 patients from 12 European institutes were included in the study. We reported on the clinical and surgical characteristics, the radicality of surgery and short- and long-term complications of radical hysterectomy: median duration of surgery: 240 min; median number of nodes removed: 26; lymph node metastases: 22%; post-operative mortality: <1%; urinary tract infection: 42%; deep venous thrombosis: 3%; fistula: 2%. The data from our study provides an honest and realistic picture of the current practice of radical hysterectomy among European oncology centres and may be considered as the 'standard of care' in this part of the world.

Cisplatin, doxorubicin and ifosfamide in carcinosarcoma of the female genital tract. A phase II study of the European Organization for Research and Treatment of Cancer Gynaecological Cancer Group (EORTC 55923).

Carcinosarcomas of the female genital tract are highly malignant tumours composed of carcinomatous and sarcomatous elements. In the past, these tumours were frequently treated as sarcomas. However, a number of arguments, including the sensitivity of these tumours to platinum-based chemotherapy, suggest that these tumours behave more like poorly differentiated carcinomas. The European Organization for Research and Treatment of Cancer (EORTC) Gynaecological Cancer Group therefore decided to perform a prospective phase II study in patients with advanced or metastatic carcinosarcoma with an approach such as that used in gynaecological carcinomas. Eligible patients could have primary or recurrent disease, but prior radiotherapy or chemotherapy was not allowed. The treatment plan recommended upfront debulking, followed by chemotherapy with cisplatin, ifosfamide and doxorubicin. Patients who could be debulked to non-measurable disease remained eligible for the study, but the response assessment was restricted to patients who had measurable disease before the start of chemotherapy. A total of 48 patients (39 primary disease, 9 recurrent disease) were registered, 41 of them being eligible. In 9 patients, all macroscopic lesions could be removed, 32 patients were left with residual disease and were assessable for response. The overall response rate was 56%: a complete response (CR) was observed in 11 (34%) patients and partial response (PR) in 7 (22%) patients. No change occurred in 5 patients and progression in 2 patients. In 7 patients, response could not be assessed. Median survival for all of the 41 eligible patients was 26 months. Severe leucopenia and thrombocytopenia were common and necessitated dose reductions or delays in 60% of patients. From a clinical point of view, the most severe non-haematological toxicity was renal dysfunction, and one patient died of this complication in the absence of disease progression. The results of this study are in-line with the hypothesis that carcinosarcomas are chemosensitive, in particular for the currently investigated regimen. The treatment also included upfront cytoreduction when feasible. Considering the observed toxicities, alternative platinum-based regimens with more favourable toxicity profiles should be explored.

Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer Group.

BACKGROUND: Combination chemotherapy yields better response rates which do not always lead to a survival advantage. The aim of this study was to investigate whether the reported differences in the efficacy and toxicity of monotherapy with doxorubicin (DOX) versus combination therapy with cisplatin (CDDP) in endometrial adenocarcinoma lead to significant advantage in favour of the combination. PATIENTS AND METHODS: Eligible patients had histologically-proven advanced and/or recurrent endometrial adenocarcinoma and were chemo-naïve. Treatment consisted of either DOX 60 mg/m(2) alone or CDDP 50 mg/m2 added to DOX 60 mg/m2, every 4 weeks. RESULTS: A total of 177 patients were entered and median follow-up is 7.1 years. The combination DOX-CDDP was more toxic than DOX alone. Haematological toxicity consisted mainly of white blood cell toxicity grade 3 and 4 (55% versus 30%). Non-haematological toxicity consisted mainly of grade 3 and 4 alopecia (72% versus 65%) and nausea/vomiting (36 % versus 12%). The combination DOX-CDDP provided a significantly higher response rate than single agent DOX (P <0.001). Thirty-nine patients (43%) responded on DOX-CDDP [13 complete responses (CRs) and 26 partial responses (PRs)], versus 15 patients (17%) on DOX alone (8 CR and 7 PR). The median overall survival (OS) was 9 months in the DOX-CDDP arm versus 7 months in the DOX alone arm (Wilcoxon P = 0.0654). Regression analysis showed that WHO performance status was statistically significant as a prognostic factor for survival, and stratifying for this factor, treatment effect reaches significance (hazard ratio = 1.46, 95% confidence interval 1.05-2.03, P = 0.024). CONCLUSIONS: In comparison to single agent DOX, the combination of DOX-CDDP results in higher but acceptable toxicity. The response rate produced is significantly higher, and a modest survival benefit is achieved with this combination regimen, especially in patients with a good performance status.

Phase II study of a combination of cyclophosphamide, adriamycin and cisplatin in advanced fallopian tube carcinoma. An EORTC gynecological cancer group study. European Organization for Research and Treatment of Cancer.

OBJECTIVE: To investigate the clinical activity and toxicity of a combination chemotherapy consisting of cyclophosphamide (C), adriamycin (A) and cisplatin (P) for patients with primary adenocarcinoma of the Fallopian tube having FIGO stage III-IV disease. METHODS: The CAP-regimen consisted of cyclophosphamide 600 mg/m2, adriamycin 45 mg/m2, and cisplatin 50 mg/m2 administered intravenously on day one every 28 days. RESULTS: Twenty-four eligible patients with histologically-confirmed Fallopian tube adenocarcinoma were entered in the trial. Fourteen patients had FIGO stage III, and ten had stage IV disease. The median number of CAP cycles was six. Ten patients had a complete and six had a partial response (response rate: 67%, 95% confidence limits: 45-84%). WHO grade III-IV side-effects included haematological toxicity, nausea/vomiting and alopecia. Furthermore, mild signs of cisplatin-related peripheral neurotoxicity were observed. At a median follow-up of 40 months, nine patients were alive and 15 had died due to malignant disease. The median time to progression was 13 months for all patients. The median overall survival was 24 months and the 1-, 3- and 5-year survival and their 95% confidence limits were 73% (54-92%), 25% (4-46%) and 19% (0-38%), respectively. CONCLUSION: The present data confirm the therapeutic activity of the CAP-regimen in primary Fallopian tube adenocarcinoma. The response rate is moderate and the toxicity profile is acceptable.

A phase II study of high-dose epirubicin in ovarian cancer patients previously treated with cisplatin. EORTC Gynecological Cancer Cooperative Group.

BACKGROUND: In vitro data demonstrated a dose-response relationship for doxorubicin in ovarian cancer cell lines. However, this dose-response question for anthracyclines has never been adequately addressed in ovarian cancer patients. A phase I study with epirubicin gave support to these in vitro findings and recommended a dose of 150 mg/m2 for phase II testing. PATIENTS AND METHODS: The present report concerns the final analysis of an EORTC-Gynecological Cancer Cooperative Group (GCCG) phase II study of high-dose epirubicin (HDE) in cisplatin-pretreated patients with epithelial ovarian cancer. A total of 100 eligible patients were included; 34 had progressed during first-line therapy (group 1), 17 had persistent disease after first-line therapy (group 2) and 49 had relapsed following an initial response to first-line therapy (group 3). All patients had measurable or evaluable disease, were aged < 75 years, had a WHO performance status 0-2, had adequate vital organ function and gave consent. Epirubicin was administered by rapid i.v. infusion at a dose of 150 mg/m2 and given at three-week intervals. Escalation to 180 mg/m2 was to be carried out if white blood cell nadir count was > 2.0 x 10(9)/l and platelet nadir count was > 75 x 10(9)/l. RESULTS: A total of 361 HDE treatment cycles were administered, the median number per patient being 4. Of the 85 patients who received at least two cycles of protocol treatment, 26 (31%) did not have any dose modification, 23 (26%) had dose reduction, while 36 (43%) had the dose increased to 180 mg/m2, at least for one cycle. The response rate in all eligible patients was 20% (95% confidence interval 13%-30%), 15% in group 1, 12% in group 2 and 27% in group 3. Patients with a cisplatin-free interval of > 12 months responded in 41%. The median duration of response was nine months (range 19 weeks to 3 years). Main toxicities were myelosuppression (leucopenia, neutropenia), nausea, vomiting, alopecia and mucositis. There were three cases of excessive toxicity leading to early discontinuation of HDE treatment and in one patient this contributed to death. No serious cardiotoxicity was recorded. CONCLUSIONS: It is concluded that HDE is active in platinum-pretreated patients with epithelial ovarian cancer and should be further studied in first-line in combination with paclitaxel and a platinum compound.

Microlaparoscopy: a new approach to the reassessment of ovarian cancer patients.

BACKGROUND: The purpose of the work was to determine the feasibility and accuracy of microlaparoscopy as diagnostic method for the reassessment of ovarian cancer patients. METHODS: Eight patients scheduled for second-look laparoscopy who had undergone primary surgery for ovarian cancer followed by 6 cycles of chemotherapy were included in the study. Microlaparoscopy was performed using a 2.8 mm laparoscope followed by conventional 10-mm laparoscopy. Three additional 5-mm ancillary trocars were inserted to perform intraabdominal biopsies. Pelvic washings were performed in all cases. RESULTS: Microlaparoscopy was feasible in all cases and as accurate as conventional laparoscopy in seven cases. In one case the procedure was terminated before conventional laparoscopy because of positive biopsies at frozen section examination. There were no intra-operative complications related to microlaparoscopy. The median time from skin incision to the removal of the microlaparoscope was 47 minutes (range 30-70). CONCLUSION: Microlaparoscopy seems to be a safe, accurate, minimally invasive method and therefore we suggest its use as primary approach to the reassessment of ovarian cancer patients.

Clinical value of intraoperative gross examination in endometrial cancer.

We present the largest multicenter study evaluating whether intraoperative visual estimation can accurately assess the depth of myometrial invasion in patients with endometrial cancer. The study population consisted of 403 consecutive women who underwent total hysterectomy for endometrial cancer. After the uterus was removed, a visual estimate of depth of gross myometrial invasion was recorded. The uterus was opened, the endometrial cavity was inspected, and one or more full-thickness incisions were made through the tumor, myometrium, and serosa. An intraoperative estimation of gross myometrial invasion was made and classified as more or less than 50% of the uterine wall. Gross visual estimation accurately identified the microscopic myometrial invasion in 85.3% (344/403) of cases. Sensitivity, specificity, and positive and negative predictive values of gross estimation in determining a microscopic myometrial invasion greater than 50% were 73.0, 92.5, 85.0, and 85.5%, respectively. Among patients in whom the myometrial invasion was underestimated at gross examination the tumoral invasion was limited to the inner two thirds of the myometrium in 45% (18/40) of cases and the distance from the tumor-myometrial junction to the uterine serosa was greater than 3 mm in 65% (26/40) of cases. We conclude that gross estimation of myometrial invasion is a reliable and inexpensive method for evaluating the invasiveness of uterine carcinomas and that deciding to perform an extensive surgical staging upon gross estimation will be in accordance with the final histopathologic report in about 9 of 10 cases.

Endometrial thickness in tamoxifen-treated patients: an independent predictor of endometrial disease.

OBJECTIVE: To assess the independent contribution of transvaginal ultrasound in identifying women at risk for endometrial disorders, and determine whether a cutoff value identifies women who need endometrial histologic assessment. METHODS: Postmenopausal women with breast cancer who were receiving tamoxifen, with ultrasonographic endometrial thickness greater than 4 mm or vaginal bleeding, had hysteroscopy with selective endometrial biopsies. Endometrial thickness, duration of tamoxifen therapy, and endometrial histology were studied. Parametric and nonparametric tests and logistic regression and receiver operating characteristic curves were used for statistical analysis. RESULTS: The study population consisted of 163 women, 46 with vaginal bleeding. The proportion of women with abnormal histologic findings was greater among those with endometrial thicknesses exceeding 9 mm compared with those with endometrial thicknesses 9 mm or less (60% versus 6.1%, P < .001) and among women who received tamoxifen for more than 27 months than those who received it for less time (46% versus 16%, P < .005). Logistic regression showed that endometrial thickness greater than 9 mm and vaginal bleeding were independent predictors of abnormal findings at hysteroscopy. CONCLUSION: In women taking tamoxifen, sonographic endometrial thickness exceeding 9 mm and the presence of vaginal bleeding are independent predictors of endometrial disease. If either exists, hysteroscopy and biopsy should be done.

The clinical predictivity of biomarkers of stage III-IV epithelial ovarian cancer in a prospective randomized treatment protocol.

BACKGROUND: The aim of this study was to define the clinical relevance of functional biomarkers, prospectively assessed in a randomized clinical protocol, in patients with Stage III-IV epithelial ovarian cancer. The protocol compared cisplatin with polychemotherapy that included cisplatin and cyclophosphamide. METHODS: In a subset of 168 patients with invasive epithelial ovarian cancer cell proliferation was determined by the 3H-thymidine labeling index, DNA ploidy was assessed by flow cytometry, and the expression of p53, bcl-2, and glutathione S-transferase-pi (GST-pi) was evaluated by immunohistochemistry using the antibodies PAb1801, anti-bcl-2, and GST-pi, respectively. RESULTS: Cell proliferation, DNA ploidy, and the expression of p53, bcl-2, and GST-pi were generally unrelated to one another and unrelated to clinicopathologic features, except for an association between DNA ploidy and the rate of cell proliferation. All biologic variables except bcl-2 were slightly related to tumor grade. DNA ploidy emerged as a predictor of clinical complete response and 3-year overall survival, regardless of treatment type or residual disease. Conversely, except for a favorable outcome for patients with tumors not expressing bcl-2 who were treated with cisplatin, no definitive patterns of predictivity for short term or long term clinical outcomes were observed for the other biomarkers studied. CONCLUSIONS: DNA ploidy appears to be the most clinically relevant biomarker for epithelial ovarian cancer. More information is needed to understand the role of the other markers studied in this tumor type.

Nonclosure of peritoneum at radical abdominal hysterectomy and pelvic node dissection: a randomized study.

OBJECTIVE: To compare closure and nonclosure of the peritoneum at radical abdominal hysterectomy and pelvic node dissection with respect to postoperative morbidity. METHODS: Women with uterine cancer who underwent radical abdominal hysterectomy and node dissection type II or III of Piver-Rutledge were assigned randomly to have a standard closure of pelvic and parietal peritoneum and placement of a T-shaped suction drain or to have the peritoneum left open but the vagina closed and two abdominal drains placed. Adjuvant radiotherapy was given to patients with risk factors. The postoperative incidence of lymphocysts (within 8 weeks from the operation and after 1 year) and infection-related and non-infection-related complications were analyzed. RESULTS: One hundred twenty subjects were enrolled, of whom 59 had peritoneal closure and 61 did not. Both groups were similar with regard to age, weight, nodes removed, nodal metastases, operative time, type of surgery, need for transfusion, and incidence of postoperative radiotherapy. The median follow-up was 36 months (range 11-72). Eleven patients died, four because of treatment-related complications. The amount of drainage was significantly higher in the closed group than in the unclosed group (median 740 mL, range 50-5980 versus median 340 mL, range 40-4000; P < .005). The incidence of asymptomatic lymphocysts was similar in the closed and open groups at 2 weeks (17 of 59 versus 15 of 6, respectively), at 8 weeks (eight of 56 versus ten of 61, respectively), and after 1 year (one of 21 versus four of 22, respectively). No difference was found between closed and open groups in terms of symptomatic lymphocysts (one of 59 versus two of 61, respectively), wound and pelvic infection (seven of 59 versus 11 of 61, respectively), febrile morbidity (two of 59 versus 11 of 61, respectively), and obstruction (zero of 59 versus one of 61, respectively). CONCLUSION: Nonclosure of the peritoneum at radical abdominal hysterectomy and node dissection is not hazardous and is not associated with an increased incidence of infection- or adhesion-related complications.

Weekly cisplatin given for 2 months versus cisplatin plus cyclophosphamide given for 5 months after cytoreductive surgery for advanced ovarian cancer.

PURPOSE: To compare the efficacy of a treatment with cisplatin plus cyclophosphamide given for 5 months and a short treatment with cisplatin alone in advanced ovarian cancer, we conducted a multicenter randomized clinical trial. PATIENTS AND METHODS: Eligibility criteria were as follows: first diagnosis of histologically confirmed invasive epithelial ovarian cancer of International Federation of Gynecology and Obstetric (FIGO) stage III-IV, age younger than 75 years, and Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. Within 28 days of cytoreductive surgery, eligible women were randomly assigned treatment with weekly cisplatin 50 mg/m2 for nine courses or cisplatin 75 mg/m2 plus cyclophosphamide 750 mg/m2 every 21 days for six courses. RESULTS: A total of 607 women were entered onto the study. There was no difference in the response to treatment. Pathologic complete response (CR) was documented in 63 of the weekly cisplatin cases and 70 of the cisplatin plus cyclophosphamide group (chi 1(2) = 1.43; P = .23). The median follow-up time was 3 years. There were 151 and 148 deaths in the weekly cisplatin and cyclophosphamide plus cisplatin arms, respectively. Survival curves were similar in the two groups, with a 3-year percent survival estimate of 44.1 (SE = 3.4) in the weekly cisplatin and 44.6 (SE = 3.4) in the cisplatin plus cyclophosphamide group (log-rank test chi 1(2) = 0.004; P = .96). CONCLUSION: This study found that 2-month monochemotherapy treatment with cisplatin was as effective as 5-month polychemotherapy including cisplatin at a similar doses but different dose-intensity plus cyclophosphamide.

A phase I-II trial of fixed-dose carboplatin and escalating paclitaxel in advanced ovarian cancer.

We conducted a phase I-II study with escalating paclitaxel doses plus carboplatin at a fixed dose for previously untreated patients with advanced ovarian cancer in order to define the maximum tolerated dose. Eligible for the study were women with a histologically confirmed diagnosis of ovarian cancer stage III-IV according to the FIGO classification. In the first phase of the study, 6 patients were allocated escalating paclitaxel doses with fixed-dose carboplatin in order to establish the maximum tolerated dose. The starting dose of paclitaxel was 150 mg/m2 given after carboplatin (300 mg/m2) every 4 weeks for a total of six courses. The paclitaxel dose step was 25 mg/m2 up to 250 mg/m2. The study then progressed to a phase II trial using the maximum tolerated paclitaxel dosage reached during the escalating dose phase. A total of 27 patients entered phase I and 23 phase II. Neurotoxicity was observed in 47 patients (94%; 29 grade 1, 17 grade 2, 1 grade 3, according to the WHO classification). The intensity of neurotoxicity tended to be dose related: out of the 15 patients who received < or = 200 mg paclitaxel, a total of 14 grade 1, but no grade 2 or 3 neurotoxicities, were observed. The frequency of grade 1, 2 and 3 neurotoxicity was 15, 17 and 1, respectively, in the 35 women who received > or = 225 paclitaxel +300 mg carboplatin. There was no clear relationship between median WBC and platelet nadir and dose level. Among other toxicities, alopecia was observed in all 50 cases, hypersensitivity in two (4%) and myalgia in 41 (82%; 34 grade 1 and 7 grade 2). These frequencies tended to increase with the dose, but the relationship was not statistically significant. The overall response rate was 78% (39/50) with a complete response rate of 62% (31/50). In conclusion, this study suggests that carboplatin and paclitaxel can be administered safely to patients with advanced ovarian carcinoma. The maximum dose reached was 250 mg/m2 paclitaxel and 300 mg/m2 for carboplatin, but from a clinical point of view the maximum paclitaxel dose we would consider safe is 225 mg/m2.

Determinants of response to a cisplatin-based regimen as neoadjuvant chemotherapy in stage IB-IIB invasive cervical cancer.

The response rate and the determinants of response to a cisplatin-based regimen of neodjuvant chemotherapy (NACT) in women with a histologically confirmed first-diagnosis of invasive bulky stage IB-IIB cervical cancer are analyzed. A total of 79 cases were treated with cisplatin (40 mg/m2) each 7 days for seven courses. During the first, fourth, and seventh cycles, ifosfamide (3.5 g/m2) was given by infusion for 24 hr. At the end of the seven cycles, 51 had a partial response (64.5%) and 4 a complete pathological response (5.1%). The overall 24-month cumulative survival was 80%, being 93% in responders and 43% in nonresponders (log-rank test, P < 0.05). With respect to the 66 subjects for whom pretreatment status of pelvic lymph nodes was available, complete or partial response was obtained in 35 of 42 subjects with negative pelvic lymph nodes at computed tomography, but in only 13 of 24 with positive lymph nodes. The corresponding odds ratios of response was 0.2 for women with positive status in comparison with those with negative status (95% confidence interval, 0.1-0.4). With respect to the 66 women who underwent surgery after NACT, of the 24 women with pretreatment positive lymph nodal status, 15 had positive nodes at surgery, but in 9 cases the histological analysis of nodes showed negative findings. Positive nodes at surgery were observed in 2 of the 42 subjects with negative nodes before treatment.

Octreotide in the management of bowel obstruction in terminal ovarian cancer.

Intestinal obstruction is a common and distressing clinical complication in ovarian cancer. The aim of our study was to assess vomit control in terminal ovarian cancer patients with inoperable gastrointestinal obstruction, using a symptomatic pharmacological treatment with octreotide which obviates the need for nasogastric tube placement. We studied 13 patients, all of whom had advanced ovarian cancer FIGO stage IIIc. Seven patients were treated in the Gynecology Department of S. Raffaele Hospital, at the University of Milan, and 6 were managed in the University of Varese Hospital. Octreotide was administered at doses starting with 0.3 up to 0.6 mg (mean 0.44 mg) a day by subcutaneous bolus or continuous infusion. Octreotide controlled vomiting in all cases to grade 0 on the WHO emesis scale. Complete relief of symptoms was achieved within 3.07 days (range 1-6 days). Vomiting stopped within 2-3 days of starting treatment in most patients. In 8 patients with a nasogastric tube, drainage decreased from 2000 to under 100 ml/day after the start of octreotide treatment. No side effects were reported. All patients died with minimal distress or pain.

Survival of women with advanced ovarian cancer and complete pathologic response at second-look laparotomy.

BACKGROUND: The purpose of the study was to analyze the determinants of long term survival in women with advanced ovarian cancer and negative second-look laparotomy. METHODS: A series of 140 advanced (Stage III-IV) ovarian cancer patients (median age, 54 years; range, 22-74 years) with negative second-look laparotomy after primary surgery and chemotherapy is included in the analysis. At first diagnosis, all patients were treated with radical or debulking surgery. After primary surgery, the patients were treated with a chemotherapy regimen based on cisplatin or carboplatin alone or in combination with other drugs. All second-look laparotomies were performed 6-8 months after first surgery. RESULTS: The overall survival rates were 76% at 3 years, 66% at 5 years, and 51% at 8 years. The corresponding rates for disease free survival were 57, 50, and 43%, respectively. Survival rates were better for women with a residual tumor 1 cm or less after primary surgery. The 5-year probability of survival was 78% in this group, compared with 55% in women with a residual tumor more than 1 cm (log rank test, P < 0.05). Survival rates for women with tumor Grade 3 tended to be worse than Grades 1-2, but the difference was only of borderline statistical significance. No relationship emerged between survival and age, histotype, and presence of ascites at diagnosis. Women with a residual tumor 1 cm or less and positive lymph nodes had a 66% 5-year probability of survival, compared with 85% for women with a residual tumor 1 cm or less and negative lymph nodes. This difference was significant (log rank test, P = 0.05). The 5-year survival probabilities were 47 and 58%, respectively, in women with a residual tumor more than 1 cm and positive or negative lymph nodes. CONCLUSIONS: This analysis shows a favorable long term survival rate for women with advanced ovarian cancer and complete pathologic response after debulking surgery and postoperative chemotherapy. It further suggests that lymph nodal status is a prognostic factor for women with minimal residual tumor after surgery.