Randomized trial comparing two combination chemotherapy regimens (CHAP-5 v CP) in advanced ovarian carcinoma.

One hundred ninety-one patients with advanced epithelial ovarian carcinoma were treated with either a combination of doxorubicin and a five-day course of cisplatin alternating with cyclophosphamide and hexamethylmelamine orally for 14 days (CHAP-5) or cyclophosphamide and cisplatin both administered intravenously (IV) on a single day at 3-week intervals (CP). At a median follow-up time of 45 months, treatment with each of these combinations resulted in the same remission rates (80% and 74%, respectively) and exactly the same progression-free survival and overall survival (median, 26 months). Despite adequate hydration, more renal toxicity was encountered in the CP-treated patients than in those who received CHAP-5. Disabling neurotoxicity and severe myelosuppression were encountered more frequently in the patients treated with CHAP-5. Because the toxicity was lower and CP treatment required shorter hospitalization, the single-day regimen was considered preferable for future use. The Karnofsky index was the only independent predictor for response, whereas both this index and the size of residual tumor before chemotherapy were predictive of survival. After correcting for other prognostic factors, it was determined that tumor size associated with improved survival was less than 1 cm. The site of metastases in International Federation of Gynecology and Obstetrics (FIGO) stage IV patients did not influence survival within this category. The results of this study confirm our previous findings that patients with microscopic remnants at second-look have a survival similar to that of patients who are histopathologically free of disease. This makes the significance of so-called pathologically confirmed complete remission questionable. The survival benefit of debulking surgery performed during chemotherapy seems only minimal for patients in whom debulking has already been attempted before treatment. Like others, we have found the CP regimen to have a good therapeutic index.

Carboplatin and cyclophosphamide salvage therapy for ovarian cancer patients relapsing after cisplatin combination chemotherapy.

30 ovarian cancer patients with a relapse after prior cisplatin combination chemotherapy were treated in a phase II study with cyclophosphamide 100 mg/m2 orally on days 1-7 and carboplatin 300 mg/m2 intravenously on day 8. Treatment was well tolerated. The major side-effect was thrombocytopenia. 28 patients were evaluable for response. The response was 5 CRs (18%), 4 PRs (14%) 15 SDs (53%) and 4 PDs (14%), for an overall response rate of 32%. The overall progression-free survival lasted from 2 to 23 months, median 8 months. Overall survival ranged from 2 to 35+ months, median 12 months. Patients with a therapy-free interval of more than 1 year showed a higher response rate (46%) than patients with a shorter therapy-free interval (20%). It is concluded that platinum containing second-line chemotherapy, after treatment that already contained cisplatin, is only warranted to palliate symptoms.

Long-term survival in ovarian cancer. Mature data from The Netherlands Joint Study Group for Ovarian Cancer.

In two studies initiated in 1979 and 1981, 377 patients were treated for advanced epithelial ovarian cancer. In the first study patients were randomly assigned to receive Hexa-CAF (hexamethylmelamine, cyclophosphamide, methotrexate, 5-fluorouracil) or CHAP-5 (cyclophosphamide, hexamethylmelamine, doxorubicin, cisplatin for 5 days) and in the second study to receive CHAP-5 or CP (cyclophosphamide, cisplatin on 1 day). Patients who did not respond to Hexa-CAF were offered subsequent treatment that included cisplatin. Median follow-up of patients in the first study was 9.5 years and in the second study 7.7 years. At 10 years 9% of the patients initially treated with Hexa-CAF and 21% of patients assigned to CHAP-5 were alive. Among the 10-year survivors treated with Hexa-CAF, 50% had experienced progressive disease but were alive as a result of retreatment with a cisplatin regimen. The survival curves of both studies revealed that approximately 60% of the patients who reached a complete remission were alive at 5 years and 40% at 10 years. Patients with microscopic disease at second-look had a less favourable outlook: 35% survived 5 years. Not recognised at first publication of both studies was the influence of tumour grade on survival. Before 5 years of follow-up, the good prognosis of grade 1 tumours (well differentiated) could not be detected. About 50% of patients with grade 1 tumours were alive at 5 and 30% at 10 years while these survival rates were halved for the other grades. Combination chemotherapy with cisplatin can enhance survival by more than 10% at 5 and 10 years compared with the best treatment of the precisplatin era: Hexa-CAF.

The morbidity of treatment for patients with Stage I endometrial cancer: results from a randomized trial.

PURPOSE: To compare the treatment complications for patients with Stage I endometrial cancer treated with surgery and pelvic radiotherapy (RT) or surgery alone in a multicenter randomized trial. METHODS AND MATERIALS: The Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial included patients with endometrial cancer confined to the uterine corpus, either Grade 1 or 2 with more than 50% myometrial invasion, or Grade 2 or 3 with less than 50% myometrial invasion. Surgery consisted of an abdominal hysterectomy and oophorectomy, without lymphadenectomy. After surgery, patients were randomized to receive pelvic RT (46 Gy), or no further treatment. A total of 715 patients were randomized. Treatment complications were graded using the French-Italian glossary. RESULTS: The analysis was done at a median follow-up duration of 60 months. 691 patients were evaluable. Five-year actuarial rates of late complications (Grades 1-4) were 26% in the RT group and 4% in the control group (p < 0.0001). Most were Grade 1 complications, with 5-year rates of 17% in the RT group and 4% in the control group. All severe (Grade 3-4) complications were observed in the RT group (3%). Most complications were of the gastrointestinal tract. The symptoms resolved after some years in 50% of the patients. Grade 1-2 genitourinary complications occurred in 8% of the RT patients, and 4% of the controls. Bone complications occurred in 4 RT patients (1%). Seven patients (2%) discontinued their RT due to acute RT-related symptoms. Patients with acute morbidity had an increased risk of late RT complications (p = 0.001). The 4-field box technique was associated with a lower risk of late complications (p = 0.06). CONCLUSION: Pelvic RT increases the morbidity of treatment in Stage I endometrial cancer. In the PORTEC trial, severe complications occurred in 3% of treated patients, and over 20% experienced mild (mostly Grade 1) symptoms. Patients with acute RT-related morbidity had an increased risk of late complications. As pelvic RT in Stage I endometrial carcinoma was shown to significantly reduce the rate of locoregional recurrence, but without a survival benefit, its use in the adjuvant setting requires careful patient selection (treating those at increased risk of relapse), and the use of treatment schemes with the lowest risk of morbidity.

The pedicled omentoplasty, a simple and effective surgical technique to acquire a safe pelvic radiation field; theoretical and practical aspects.

A substantial number of patients need radiotherapy after surgery for pelvic malignancy. Approximately 15% of them will experience radiation enteritis. After omentoplasty, reduction of irradiated bowel volume may be obtained. We evaluated the pedicled omentoplasty during gynaecologic surgery as a technique to improve safe irradiation of the pelvic region.

Choriocarcinoma in mother and child, identified by immunoenzyme histochemistry.

A case of metastic choriocarcinoma after term pregnancy, with tumor localization in the kidney of a hydropic stillborn infant, is presented. The primary tumor was found in a scraping four weeks after delivery. The identity and nature of the malignant growth in mother and child were substantiated by identical immunohistochemical patterns for gonadotropin activity. Because of a positive Kleihauer test it was assumed that massive feto-maternal transfusion had caused the hydrops and intrauterine death. Now, four and a half months after starting methotrexate therapy, the mother seems to be free of tumor. Plasma human chorionic gonadotropin titers have decreased to normal.

Metastasectomy, a feasible treatment in selected cases with gynecologic malignancy.

We present the course of six gynecological patients who underwent surgical intervention because of a solitary metastasis. After a considerable follow-up period five patients are alive without evidence of disease and with a good quality of life. Metastasectomy should play a role in the management of gynecologic malignancies.

The omentoplasty: a neglected ally in gynecologic surgery.

Although the omentum is extensively used in general, reconstructive and thoracic surgery as a pedicled omentoplasty, little information exists about the utility of such a procedure in general and radical gynecologic surgery. In this paper we review the properties of the omentum which may be useful in gynecologic surgery. The omentum is highly vasculated and rich in thromboplastin, an excellent property for treating difficult to handle abdominal or pelvic abscesses and for inducing hemostasis. Furthermore, it appears that the omentum has a trophical effect on the surrounding tissue, making it very useful in reconstruction procedures. Moreover, elevating the small intestines out of the true pelvis paves the way for high dose (brachy)radiotherapy with less radiation enteritis. The technique of the pedicled omentoplasty is straightforward and takes 20-30 min extra operating time. We use pedicled omentoplasty for covering large operating fields instead of reperitonealization, to prevent radiation enteritis, as a matrix for grafting, to treat serious intraperitoneal infections and to facilitate hemostasis. Our experience of 48 omentoplasty procedures in gynecology is described.

Ovarian cysts, cytology and histology: a conflicting story.

Ovarian cysts from 27 selected patients were examined cytologically as well as histologically. The aspirates were obtained by means of ultrasound or laparoscopy. Cytological examination in 17 of the cases did not show malignancy, but histological examination demonstrated malignancy in 5 of these patients. The fluid of the other 10 cysts indicated malignancy, which was confirmed histologically in only 4 cases. From this study we conclude that cytological examination has little to offer in diagnosing the true nature of ovarian cysts.

Results of curettage for postmenopausal vaginal bleeding in women treated with tamoxifen and megestrol acetate for progressive metastatic breast carcinoma.

Tamoxifen and megestrol acetate are used as a hormonal treatment for metastatic breast carcinoma. It is suggested that the use of tamoxifen may induce endometrial cancer. In this article we describe nine patients under hormonal treatment for metastatic breast cancer with, firstly, tamoxifen and, later, megestrol acetate. These nine patients all had symptoms of postmenopausal vaginal blood loss during therapy with megestrol acetate, an indication to perform a diagnostic dilatation and curettage. By histopathological examination the curettings showed a decidualized stroma with an infiltration of lymphocytes, some plasma cells and many eosinophils. In none of the patients was atypical hyperplasia or malignancy found. The dilatation and curettage had also a therapeutic effect, since only one of the patients still had complaints, while the other eight did not complain of postmenopausal bleeding again. We review the literature and discuss the value of a diagnostic dilatation and curettage.

Cryosurgical treatment of cervical intraepithelial neoplasia (CIN III) in 102 patients.

Results of cryosurgical treatment in 102 patients with a histologically confirmed diagnosis of severe dysplasia or carcinoma in situ of the uterine cervix (CIN III) are presented. The colposcopic evaluation performed in all patients required full visualization of the squamocolumnar junction. In 95 of the 102 patients no significant cytological abnormalities were found during the follow-up period, which amounts to a success rate of 93%. In seven patients (7%) treatment was considered to have failed because cervical smears persistently suggested CIN II or III. In five of them this was in all probability due to a residual lesion, since the abnormal smears occurred within 12 weeks after cryosurgery. It is concluded that in selected cases cryosurgery is a safe alternative for conisation in the treatment of CIN III. However, thorough colposcopic expertise is essential for adequate preoperative screening, as is careful selection of patients, and the latter may result in the withholding of cryosurgical therapy from 30% of patients with CIN III.

Reasons for incomplete surgical staging in early ovarian carcinoma.

The completeness and associated morbidity of surgical staging in 86 patients with early ovarian carcinoma were analyzed. According to strict criteria for completeness of the procedure established before the onset of the study, surgical staging after one or two laparotomies was complete in only 53% of cases. Initial staging in a peripheral hospital was complete in only 15% of patients. Intraoperative complications occurred in between 8 and 15% of patients and included injury of the vena cava (5), small bowel injury (2), myocardial infarction (1), transection of the ureter (1), and splenic rupture (1). The most frequently omitted staging steps were biopsy of the paracolic gutter, biopsy of the pelvic peritoneum, and sampling of retroperitoneal lymph nodes. Reasons for incomplete surgical staging were divided into factors associated with increased risk of difficulty of the procedure and lack of knowledge of the sites at risk for ovarian cancer metastases. It was found that both phenomena should be held responsible to the same extent for the large number of incomplete surgical staging procedures. The conclusion was made that either gynecologists should be better educated in the staging of ovarian cancer or a more efficient patient referral policy should be considered.

Results of decentralized in-vitro fertilization treatment with transport and satellite clinics.

The results of in-vitro fertilization (IVF) treatments carried out in a university IVF centre are compared with those obtained following 15-40 min transportation of oocytes from a transport IVF clinic to the central IVF laboratory of the university centre. Moreover, treatment results following monitoring of ovarian stimulation in satellite clinics, combined with ovum retrieval at the transport clinic and transport of oocytes to the central IVF laboratory, are described. In a total of 5540 IVF treatment cycles, 24-26% of viable pregnancies per embryo transfer were found in the three groups. Comparison of results, obtained with the three different treatment modalities, showed no negative influences of transporting oocytes from transport clinic to IVF laboratory and of monitoring ovarian stimulation in satellite clinics. It is concluded that decentralization of the clinical phase of IVF treatment is possible. This leads to a more optimal use of existing laboratory facilities in large urban areas. It is stressed that good communication between satellite clinic, transport clinic and IVF laboratory is necessary for a decentralized IVF programme. To obtain good quality assurance, both the satellite clinic and the transport clinic must adhere to the same protocol.

EMG profiles of ACL-deficient patients during walking: the influence of mild fatigue.

The purpose of this study was to determine muscle activities after ACL rupture during walking and running and to investigate the influence of mild fatigue (10 min walking) on these activities. A group of 12 patients with ACL-ruptures was compared with a control group (healthy volunteers) of 15 persons. Linear envelopes of EMG-activity from vastus medialis, vastus lateralis, biceps femoris and medial hamstrings were measured. Patients and control persons walked on a treadmill at speeds of 1.2 m/s (samples at t = 2 min and t = 12 min) and 2.8 m/s i.e. running (sample at t = 15 min). The patient group showed significantly lower muscle activities of vastus lateralis (p < 0.001) and medial hamstrings (p < 0.05) for both the injured and uninjured leg during running compared to the control group. After 10 minutes walking, the mean-EMG of biceps femoris (p < 0.05) and medial hamstrings (p < 0.01) decreased as did the activity time of biceps femoris (p < 0.05), medial hamstrings (p < 0.01) and vastus medialis (p < 0.001) for the injured leg of the patient group. Control persons showed no significant changes. Thus, mild fatigue did effect only the EMG-pattern of the patients. Patients with ACL-ruptures should be trained not only on strength and stabilisation, but also on endurance. A decrease in hamstrings activity during walking might be a sensitive measure for evaluation of the rehabilitation process, as those muscles may be able to substitute ACL-deficiency.

Malignant leiomyomatosis peritonealis disseminata.

Leiomyomatosis peritonealis disseminata is a rare condition characterized by the presence of multiple intraabdominal nodules that consist of benign smooth muscle. We found 42 documented cases in the literature. Malignant degeneration appears to be extremely rare. We describe the second case with proved malignancy.

High tissue factor concentration in the omentum, a possible cause of its hemostatic properties.

The hemostatic properties of the pedicled omentoplasty turned out to be helpful in difficult hemorrhages in extensive surgery. As suggested by others, a high concentration of tissue factor (TF) in the omentum could be responsible for this favourable property. The authors investigated the nature of that property in 11 patients who underwent laparotomy. In omentum and striated muscle (controls) the TF-concentrations in both tissues were estimated by the ELISA method. A significant difference between TF-concentration in omentum and striated muscle could be demonstrated.

Watch and wait after careful surgical treatment and staging in well-differentiated early ovarian cancer.

Patients with well-differentiated epithelial ovarian cancer Stages Ia, Ib, Ic, and IIa (FIGO 1976) were observed after surgical treatment without adjuvant therapy. Careful surgical staging was required, and the extent of the staging procedure was assessed in each individual patient. There were 107 patients entered in the study by nine Dutch oncology centers. Of these 107, 21 did not fulfill all of the inlet criteria of the study and were excluded. Central pathologic review was performed in the remaining 86 cases, revealing that there was borderline tumor in seven patients, moderately or poorly differentiated tumor in nine patients, and tumor of nonepithelial histologic cell type in one patient. In two cases, no material for histologic review was available. After exclusion of these 19 cases, 67 patients were further analyzed. None of these 67 patients was lost during the follow-up period that ranged from 19 to 99 months (mean, 50 months). Tumor recurrence was found in four patients after 11, 25, 34, and 34 months of follow-up, all of whom died shortly after diagnosis of the recurrence without satisfactory response to secondary treatment. For the patients who underwent the most extensive staging procedure, disease-free 5-year survival was 100%. For the patients who were inaccurately staged, disease-free 5-year survival was 88%. It was concluded that well-differentiated early stage (Ia-IIa) ovarian cancer carries an excellent prognosis after surgical treatment and complete surgical staging, with the possible exception of patients with Stage Ic disease with malignant peritoneal washings. Furthermore, it was considered that the application of more objective and consistent ways of assessing tumor grade should be encouraged. Surgical staging should be regarded as the golden standard in defining subsets of low-risk patients and should be included and clearly defined in future trials on early ovarian cancer.

The effect of debulking surgery after induction chemotherapy on the prognosis in advanced epithelial ovarian cancer. Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer.

BACKGROUND: Although the value of primary cytoreductive surgery for epithelial ovarian cancer is beyond doubt, the value of debulking surgery after induction chemotherapy has not yet been defined. In this randomized study we investigated the effect on survival of debulking surgery. METHODS: Eligible patients had residual lesions measuring more than 1 cm in diameter after primary surgery. After three cycles of cyclophosphamide and cisplatin, these patients were randomly assigned to undergo either debulking surgery or no surgery, followed by further cycles of cyclophosphamide and cisplatin. The study end points were progression-free and overall survival. At surgery 65 percent of the patients had lesions measuring more than 1 cm. In 45 percent of this group, the lesions were reduced surgically to less than 1 cm. RESULTS: Of the 319 patients who underwent randomization, 278 could be evaluated (140 patients who underwent surgery and 138 patients who did not). Progression-free and overall survival were both significantly longer in the group that underwent surgery (P = 0.01). The difference in median survival was six months. The survival rate at two years was 56 percent for the group that underwent surgery and 46 percent for the group that did not. In the multivariate analysis, debulking surgery was an independent prognostic factor (P = 0.012). Overall, after adjustment for all other prognostic factors, surgery reduced the risk of death by 33 percent (95 percent confidence interval, 10 to 50 percent; P = 0.008). Surgery was not associated with death or severe morbidity. CONCLUSIONS: Debulking surgery significantly lengthened progression-free and overall survival. The risk of death was reduced by one third, after adjustment for a variety of prognostic factors.