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.

Lymphokine-activated killer activity of tumor-associated and peripheral blood lymphocytes isolated from patients with ascites ovarian tumors.

Peripheral blood lymphocytes (PBLs) and tumor-associated lymphocytes (TALs) were isolated from 36 patients with advanced ovarian adenocarcinoma and peritoneal effusions for study of lymphokine-activated killer activity. PBLs and TALs cultured in vitro for 3-5 days in the presence of interleukin-2 (IL-2, supernatant of the MLA 144 gibbon cell line, or human recombinant IL-2) expressed higher levels of cytotoxicity as compared to cells cultured in medium alone, against natural killer (NK)-susceptible (K562) or NK-resistant targets (Daudi and the human ovarian carcinoma cell line SW626). When ovarian tumor cells, freshly isolated from carcinomatous ascites or surgical specimens, were used as target cells in the cytotoxicity assay, 8 of 14 PBLs and 5 of 7 TAL preparations lysed the autologous tumor after treatment with IL-2, while no spontaneous reactivity was observed in any of the 14 patients tested. Although levels of lysis were usually relatively low, these data demonstrate that PBLs and TALs from ovarian cancer patients (TALs usually exhibiting low NK activity) when stimulated in vitro by IL-2 acquire some cytotoxic potential against the autologous tumor.

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.

'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.

Response to second-line weekly cisplatin chemotherapy in ovarian cancer previously treated with a cisplatin- or carboplatin-based regimen.

Response to a second-line weekly cisplatin chemotherapy in ovarian cancer previously treated with cisplatin- or carboplatin-based regimens was analysed in a clinical series observed between 1984 and 1991. Women who achieved pathological complete response or pathological optimal partial remission after first-line cisplatin- or carboplatin-based regimens were treated at recurrence or progression, occurring at least 4 months after first-line treatment, with second-line chemotherapy. A total of 72 women were included in the analysis. Second-line chemotherapy regimens were: cisplatin 1 mg/kg weekly for seven courses plus epirubicin 70 mg/m2 intravenously (i.v.) every 3 weeks for three courses (28 subjects), cisplatin 1 mg/kg plus etoposide 90 mg/m2 i.v. weekly for a total of seven courses (11 subjects) and cisplatin 1 mg/kg weekly for nine courses plus carboplatin 250 mg/m2 every 3 weeks for three courses (33 subjects). Of the 72 women, 22 (31%, 14 clinical, 8 pathological) had a complete response and 28 (39%), a partial response (24 clinical, 4 pathological). The 24-month cumulative survival probability was 63% in women with complete response, 32% in those who had partial response, but all the 22 non-responders died within 24 months from diagnosis of recurrence (log rank test P < 0.05). The frequency of complete response and partial response increased with the interval between first diagnosis and recurrence: among the 33 women who had recurrent disease to < 18 months from first diagnosis, complete response or partial response was obtained in 20 (61%) subjects, this figure was 67% (14 out of 21 women) among subjects who had recurrent disease between 18 and < 36 months from first diagnosis and 89% (16/18) among those who had recurrence > or = 36 months. In comparison with women who had recurrence 4- < 18 months from first diagnosis, the OR of response was 1.3 (95% CI 0.4-4.1) for those who had recurrence between 18 and < 36 and 5.2 (95% CI 1.1-24.3) for those who had recurrence > or = 36 months from surgery (chi 1(2) trend p < 0.05). Survival rate after the end of second line chemotherapy for women who relapsed 4- < 18 months, 18- < 36 or 36 months or more after surgery were, respectively, 24, 20 and 67% (log rank test, P < 0.05). Age at first diagnosis, histology, stage, and grading of the disease at first diagnosis and site of recurrence were not associated with response to second-line therapy.

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.

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.

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.

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.

DNA-ploidy and proliferative activity in uterine-tumors - an in-vivo study using bromodeoxyuridine and flow-cytometry.

We have studied the DNA ploidy and the proliferative activity in 102 patients with endometrial and cervical carcinoma, by flow cytometry. Samples were excised 1 hour after bromodeoxyuridine (BrdU, 250 mg/) e.v. infusion and fixed in 70% ethanol. Nuclear DNA content and BrdU incorporation, were simultaneously determined to obtain ploidy (DNA index) and proliferative activity (BrdU-labeling index, LI). No acute toxicity or side effects related to BrdU injection were recorded. The overall feasibility of the determinations was higher than 90% (93/102). Twenty-two out of 59 (37.2%) endometrial neoplasms and 23 out of 34 (67.6%) cervical neoplasms were aneuploid, with a median DNA-index of the aneuploid peak of 1.3 and 1.4, respectively. Overall median BrdU LIs were 4.8% and 7.2%. Proliferative activity was found to be higher in aneuploid tumors (p<.05). DNA ploidy and/or BrdU-LI were not significantly related either with the clinical stage or the histopathologic grading in either tumor type. The BrdU in vivo administration coupled with bivariate FCM for measurement is a simple method that can be performed in clinical settings to better evaluate the prognostic significance of proliferative parameters in gynecological tumors.

The biological tumor markers' myopia: a model with CA 125 and second-look in ovarian cancer.

Preoperative CA 125 levels were measured in 36 patients with advanced epithelial ovarian carcinoma in clinical response undergoing a second-look operation. All the patients had positive levels (greater than 35 U/ml) of this tumor marker at diagnosis. The correlation between antigen levels and disease status at surgery revealed a sensitivity of this assay of 0.55 (only 11/20 patients still with tumor had positive levels) and a specificity of 0.94 (15/16 patients with no tumor had less than 35 U/ml). The predictive value of a positive test was 0.92. This method unfortunately proved unable to recognize microscopic residual tumor burden, less than 0.5 cm.

Preliminary study on serum levels of mucinous like cancer antigen (MCA) in patients with breast disease: comparison with CEA.

MCA (mucinous-like cancer antigen) can be measured in the biological fluids of patients by means of a solid phase enzyme immunoassay. This study describes the results of MCA determination in sera of 230 patients with benign (99) and malignant (131) breast diseases. MCA levels were significantly higher in breast cancer patients than in non cancer patients and in healthy subjects (p less than 0.001). MCA concentrations tended to increase as the stage of the disease advanced. The 95th percentile of MCA value distribution in normal subjects showed a diagnostic sensitivity in breast cancer patients of 16.3% at stage I, 26.2% at stages II-III and 52% at stage IV. In a group of 118 cancer patients, MCA and CEA were tested simultaneously. The diagnostic sensitivity and specificity of MCA and CEA assays was very similar; nevertheless the association of the two tests showed 11 cases with high levels of MCA and low levels of CEA and 9 patients with high levels of CEA and low levels of MCA. Seventy-four out of 118 patients were negative for both markers and in 22 out of 118 patients markers were positive. The new marker MCA appeared to correlate with breast cancer and gave different information complementary to CEA.

CA 125 reliability in predicting ovarian cancer recurrence.

The predictive value of CA 125 assay for recurrence in ovarian cancer patients in follow-up was analyzed in a study from April 1984 through June 1987. Forty-two patients with no evidence of disease (NED), with positive antigen levels at diagnosis and negative at the end of active treatment, were considered eligible for the analysis. Median follow-up time was 16 months (range, 5-34). Outcome analysis revealed 19 cases still NED: 16 had normal CA 125 levels (less than 35 U/ml). The 3 patients with positive antigen titers were intensively investigated with no evidence of recurrence. Twenty-three cases had disease recurrence: 13 of them had elevated marker levels prior to relapse diagnosis, with a median lead time of 5 months (range, 2-13). In contrast, 10 patients had positive titers at or soon after the recurrence. Test sensitivity was therefore 56% and specificity 84%. Predictive value for recurrence of elevated CA 125 levels was 0.81.

Thyroid function in gestational trophoblastic tumors.

Thyroid function was assessed in a total of 15 cases, 7 of whom had choriocarcinoma and 8 hydatidiform mole, by measuring free T3, free T4, thyroxin-binding globulin (TBG), basal thyroid-stimulating hormone (TSH) and after the thyrotropin-releasing hormone test (delta TSH). Free T3, free T4 and TBG were investigated in the same number of healthy women within the first three months of pregnancy. Only 13.4% of the cases presented elevated levels of free T3 and T4 and TBG; TSH and delta TSH were within normal limits. Both thyroid hormones and TBG returned to within normal limits when beta-human chorionic gonadotropin became undetectable. One patient was found to be hypothyroid. Comparison with the control group showed no significant differences except in TBG levels, which were higher in controls. A significant, direct correlation was found between levels of free T3 and T4 and TBG and the pattern of human chorionic gonadotropin.

Analysis of 309 cases after hydatidiform mole: different follow-up program according to biologic behavior.

Between 1976 and 1985, at the Obstetrics and Gynecology Department of Milan University, a total of 309 cases of hydatidiform mole, 223 complete moles and 86 partial moles, were monitored with the assay of beta-human chorionic gonadotropin, following a postmolar biochemical surveillance program. Spontaneous remission of the disease occurred in 287 (92.9%) patients. Marker levels were undetectable in 80.4% of cases within 60 days after evacuation of the mole and in 19.6% between 61 and 140 days. There were 22 (7.1%) patients diagnosed as having gestational trophoblastic tumors (GTT) and treated with chemotherapy: 20 were complete moles and 2 partial moles. Considering these data, the authors suggest different follow-up times for partial and complete moles and confirm the necessity of selection criteria in a diagnosis of GTT.

The role of cytoreduction in ovarian cancer.

Whether or not cytoreduction improves the outlook of ovarian cancer patients is not yet clear from data from Literature. Maybe not the successful procedure itself, but the favourable tumor characteristics of these tumors determine the prognosis. New studies are necessary to define the role of surgery in the overall management of ovarian cancer more precisely. In this article a Dutch study is presented, to answer the question about the influence of attempted cytoreductive surgery prior to, during chemotherapy on survival time and remission rates. All patients are treated with either combination chemotherapy and/or an attempt to cytoreduction prior to or during chemotherapy. With this strategy ethical problems concerning undertreatment are avoided. The study is currently activated but it is too early to draw any conclusions.

High-dose epirubicin in platinum-pretreated patients with ovarian carcinoma: the EORTC-GCCG experience.

BACKGROUND: A dose-response relationship for doxorubicin in ovarian cancer (OC) cell lines has been demonstrated in vitro. However, this has never been carefully addressed in the clinic. These data and the more favourable toxicity profile of the anthracycline analogue epirubicin were reasons to study high-dose epirubicin (HDE) in OC patients who relapsed on/after platinum-based chemotherapy. This was done both in a phase I/II feasibility study (n = 27; HDE dose 120-200 mg/m2 q3 weeks) and a still ongoing straightforward phase II study (n = 91; HDE dose 150-180 mg/m2 q 3 weeks). RESULTS: Responses were observed at all dose levels. Overall 24 of the 118 patients responded (20%), which is much higher than reported with lower doses (7% with doses of 60-110 mg/m2). The most important side effects were myelosuppression, alopecia, nausea and vomiting and mucositis. CONCLUSION: HDE is tolerable and has activity in second-line after platinum-based chemotherapy in OC patients.

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.