Phase II study of mitomycin-C and cisplatin in disseminated, squamous cell carcinoma of the uterine cervix. A European Organization for Research and Treatment of Cancer (EORTC) Gynecological Cancer Group study.

The aim of this study was to investigate the tumour response rate and toxicity of a combination chemotherapy consisting of mitomycin-C and cisplatin in patients with disseminated squamous-cell carcinoma of the uterine cervix. Chemotherapy consisted of mitomycin, 6 mg/m(2) intravenously (i.v.), and cisplatin, 50 mg/m(2) given i.v., both administered on day 1 of each cycle. The regimen was repeated at 4-weekly intervals. Mitomycin-C/cisplatin were used to treat 33 evaluable patients aged 29-67 years (median: 50 years). All patients except 1 had previously been treated with either surgery, radiation or both. At the initiation of chemotherapy, 8 patients had loco-regional and disseminated disease and 25 women had only distant metastases. The overall response rate was 42% (95% confidence interval (CI): 26-61%). Five complete and nine partial responses were observed with a median duration of response of 7.9 months (95% CI: 3.7-23.5 months). 9 patients had stable disease and 10 developed progressive disease during mitomycin-C/cisplatin-treatment. World Health Organization (WHO) grade III/IV side-effects were documented in 15 women, of whom 10 had gastro-intestinal toxicity, 3 had haematological toxicity, 1 had alopecia and 1 developed an allergic reaction to cisplatin. There were neither drug-related deaths nor severe or irreversible renal or hepatic dysfunction or peripheral neuropathy. The median progression-free survival was 5.0 months (95% CI: 3.6-6.2 months) for all patients and 10.5 months (95% CI: 6.2-15.2 months) for the responders. The median overall survival was 11.2 months (95% CI: 6.5-18.4 months).The mitomycin-C/cisplatin combination showed antitumour activity in the treatment of advanced or recurrent squamous-cell carcinoma of the uterine cervix. The regimen was well tolerated and could be administered on an outpatient basis.

Ovarian cancer: the challenge of local tumor control and its impact on survival.

To achieve better understanding of the factors influencing local control of ovarian cancer, an analysis of failure in early stages of ovarian carcinoma has been carried out. The material consisted of 185 patients diagnosed in early stages; 40 of them failed in their disease, 17 with local recurrence, 23 with distant metastases. The material was analyzed with respect to age, histology, grade, size and surface of the tumor, the surgical procedure and treatment modalities, and the time between treatment and recurrence, and recurrence and death. In the analysis, both the behavior of the ovarian cancer tumor and the pattern of failure was shown to be different for each histological group.

Preoperative radiation therapy in advanced carcinoma of the ovary.

Preoperative radiotherapy in advanced ovarian carcinoma was evaluated. The overall 5-year survival rate in the irradiated group was 27%. When tumour mass remaining after operation was less than 2 cm in diameter, this figure rose to 52%. Comparison was made between those in whom operation became feasible only after preoperative irradiation and patients in advanced stages who were primarily successfully operated to less than 2 cm and with a 5-year survival rate of 44%. Selection of the cases for preoperative radiotherapy is obviously necessary. Fixed, bulky tumours in the pelvis, with or without metastases, may be suitable for preoperative radiotherapy.

Is there place for radiotherapy in the treatment of advanced ovarian cancer?

BACKGROUND AND PURPOSE: Irradiation of advanced ovarian cancer has been performed during the years 1976-1984 with six-field technique. Results of this treatment in a long follow-up have never before been evaluated. MATERIAL AND METHODS: Seventy-five patients with stage IIb-IV of invasive ovarian cancer have been treated with a combination of surgery, radiotherapy and chemotherapy. The results of the treatment were compared with 98 patients treated during the year 1991-1992 with surgery and chemotherapy only. RESULTS: After controlling for the differences in background factors between the groups considered, there was still a significantly better survival rate for the patients treated with radiotherapy. CONCLUSION: The results suggest that the role of radiotherapy in advanced ovarian cancer should be investigated in a prospective randomized trial.

Radiation therapy of ovarian carcinoma: presentation of a six-field technique.

A new technique for radiotherapy in ovarian carcinoma is presented. The aim was to deliver a homogeneous radiation dose to the entire abdominal cavity. The whole abdomen, except for 20% of the upper compartment, received a homogeneous dose of 40 Gy, while 2/3 of the kidneys and the posterior part of the liver received a dose ranging from 40 to 20 Gy. No clinically significant impairment of liver function was seen during follow-up.

Age is not a limiting factor for radical radiotherapy in pelvic malignancies.

BACKGROUND AND PURPOSE: Pelvic radiotherapy (RT) toxicity in the elderly is poorly documented. We developed a study aiming to evaluate whether or not a limit of age could be identified beyond which toxicities in patients receiving pelvic RT were more frequent or more severe. MATERIAL AND METHODS: 1619 patients with pelvic cancers enrolled in nine EORTC trials, RT arms, were retrospectively studied. Patients were split into six age ranges from 50 years to 70 years and over. Survivals and late toxicity occurrence were calculated with the Kaplan-Meier method and comparison between age groups with the logrank test. A trend test was done to examine if chronological age had an impact on acute toxicity occurrence. RESULTS: Survival was comparable in each age group for prostate (P = 0.18), uterus (0.41), anal canal cancer (P = 0.6) and slightly better for the younger group of rectum cancer (P = 0.04). A total of 1722 acute and 514 late grade > or = 1 were recorded. Acute nausea/ vomiting, skin complications and performance status deterioration were significantly more frequent in younger patients. There was no trend toward more aged patients to experience diarrhea (P = 0.149) and after adjustment on RT dose, acute urinary complications were observed equally in each age range (P = 0.32). Eighty percent of patients were free of late complication at 5 years in each age range (P = 0.79). For the grade > 2 late side-effects, a plateau was observed after 1 year at near 9% without any difference (P = 0.06) nor trend (P = 0.13) between age-groups. CONCLUSION: Age per se is not a limiting factor for radical radiotherapy in pelvic malignancies.

Adjunctive radiation therapy in the management of stage I cancer of the endometrium.

One hundred fifty-two patients with stage I, grades 2 and 3 adenocarcinoma of the endometrium, treated in 1972 and 1973 at the Radiumhemmet, are presented. Two uterine packings followed at 4 to 6 weeks by total abdominal hysterectomy and bilateral salpingo-oophorectomy resulted in a 5-year survival of 89%, whereas patients treated primarily with surgery followed by vaginal cylinder irradiation demonstrated 90% survival. Patients in both groups received whole pelvis irradiation postoperatively for deep myometrial invasion (more than 50% invasion by viable tumor). Patients treated with radiation therapy alone had 57% survival. Optimal results in poorly differentiated (grade 3) carcinoma of the endometrium were achieved with preoperative packings (90% survival); only 12% of the patients required external radiation therapy postoperatively.

Combination chemotherapy of advanced ovarian cancer with hexamethylmelamine, cis-Platinum, and doxorubicin after failure of prior therapy.

Forty-nine women received a combination of cis-platinum and hexamethylmelamine (36 also received doxorubicin) for advanced ovarian cancer progressing after therapy that included an alkylating agent or extended field radiation. Twenty-six (53%) had an objective remission that lasted a median of 6 months from start of treatment. Response rate was independent of age, extent of prior therapy, and performance status. A long interval from initial diagnosis to entry, response to therapy, and ambulatory performance predicted improved survival from entry. No patient is surviving free of disease. Myelosuppression and vomiting were moderately severe but tolerable. Azotemia and peripheral neuropathy were infrequent and milk. These drugs have major activity in this poor-risk group and should be studied as part of initial therapy when enhanced efficacy and reduced toxicity are to be expected.

Preoperative evaluation of serum CA 125 levels in patients with primary epithelial ovarian cancer.

Serum CA 125 levels were measured preoperatively in 100 women undergoing diagnostic laparotomy for palpable adnexal masses. All 11 patients with frankly malignant nonmucinous ovarian carcinoma had serum CA 125 levels greater than 35 U/mL and nine of the 11 had serum CA 125 levels greater than 65 U/mL. If patients with mucinous and borderline lesions were included, serum CA 125 was greater than 35 U/mL in 11 of 18 and greater than 65 U/mL in nine of 18 patients. Among 14 individuals with pelvic masses and CA 125 greater than 65 U/mL, 13 had some form of gynecologic malignancy. These results suggest that CA 125 assay can be used as a diagnostic adjunct for discriminating benign from malignant pelvic masses.

Prospective evaluation of serum CA 125 levels for early detection of ovarian cancer.

Detection of ovarian cancer at an early stage should reduce the mortality associated with this disease. Through the Stockholm Population Registry, 5550 apparently healthy women were enrolled in a study designed in part to define the use of the CA 125 radioimmunoassay (RIA) as an initial test for early detection of ovarian cancer. Women whose CA 125 levels were elevated and an equal number of age-matched controls with normal levels were followed by means of pelvic examinations, transabdominal sonography, and serial CA 125 determinations. Of the 175 women with high CA 125 levels, six were found to have ovarian cancer: two each in stages IA, IIB, and IIIC. Of those with normal-range CA 125 levels, three had ovarian cancer as identified through the Swedish Cancer Registry; all three were under 50 years of age. Ovarian cancer was diagnosed on laparotomy in six of the women age 50 or over. Using thresholds of 30 and 35 U/mL, the rates of specificity for the CA 125 RIA were 97 and 98.5%, respectively, for women age 50 or older, and 91 and 94.5%, respectively, for those younger than 50 years of age. Thus, the specificity of the CA 125 RIA is adequate in postmenopausal women to undertake a larger study to determine whether screening using CA 125 influences survival of patients with ovarian cancer.

Ovarian cancer. Early diagnosis and screening.

Late diagnosis is the main reason for the poor outcome of ovarian cancer patients. An attempt to diagnose the disease methods for early diagnosis was recently investigated. The main effort of the study was in finding the role of ultrasonography and CA-125 and their sensitivity and specificity in the screening procedure. The preliminary reports suggest that a mortality study with a large women population has to be done before the usefulness of screening these methods can be established.

Hprt mutations and karyotype abnormalities in T-cell clones from healthy subjects and melphalan-treated ovarian carcinoma patients.

In vivo mutations at the locus for hypoxanthine phosphoribosyl transferase (hprt) were studied in 6-thioguanine (TG)-resistant T-lymphocyte clones from healthy male and female subjects and ovarian carcinoma patients treated with melphalan. Southern blot analysis of 108 clones showed alterations in 14% (4/29) of the clones from healthy males, 4.3% (2/47) of the clones from healthy females and 3.1% (1/32) of the clones from melphalan-treated patients. 2 of the 7 abnormal clones had a total deletion of the hprt gene; the others had partial deletions. Karyotype analysis of 82 clones revealed 1 clonal abnormality in 29 mutant clones from healthy males (3.6%). Loss or structural aberration of 1 X-chromosome occurred in 6% of the clones from healthy females. The frequency of karyotypic abnormalities (excluding those affecting one of the X-chromosomes) was significantly higher in clones from patients (37%) as compared to healthy females (5.9%). No aberration was found to affect the hprt locus at Xq27 in any of the 82 clones studied.

Different types of rupture of the tumor capsule and the impact on survival in early ovarian carcinoma.

The significance of tumor spill in the early stages of ovarian carcinoma has been the subject of controversy. Since rupture of the capsule of the tumor may occur in several different ways, we analyzed all cases of early ovarian cancer treated at Radiumhemmet, Stockholm, Sweden, during the period 1974-1986, in which possible spill of tumor cells was catalogued in different groups. In 247 out of 394 patients (62%) the risk of spill had to be considered. There was no difference in survival between patients whose tumors had intact capsules and patients in whom rupture occurred during surgery-78% and 85%, respectively. On the other hand, a significant difference in survival was found between patients in whom rupture occurred before surgery and those with intraoperative rupture-59% and 85%, respectively. The conclusion can be drawn that manipulation during surgery which results in puncture or rupture does not have a negative influence on the outcome for the patients.

Paget's disease of the vulva: the Radiumhemmet series 1975-1990.

Twenty-eight patients with a diagnosis of 'extramammary Paget's disease of the vulva' were referred to the Radiumhemmet, Karolinska Sjukhuset, Stockholm, during the period 1975-1990. A clinical and histopathologic retrospective review was undertaken. Six patients had associated malignancies (21.4%). The disease was considered primary invasive in three cases, whereas three patients later developed an invasive cancer. Surgery-local resection, hemivulvectomy or vulvectomy-was performed in 24 cases. Twelve patients, in which surgery was supposed to be radical with respect to free margins, had a significantly longer recurrence-free survival than 12 patients in which the surgical margins were dubious.

Prognostic significance of cell cycle proteins and genomic instability in borderline, early and advanced stage ovarian carcinomas.

Disturbed cell cycle-regulating checkpoints and impairment of genomic stability are key events during the genesis and progression of malignant tumors. We analyzed 80 epithelial ovarian tumors of benign (n = 10) and borderline type (n = 18) in addition to carcinomas of early (n = 26) and advanced (n = 26) stages for the expression of Ki67, cyclin A and cyclin E, p21WAF-1, p27KIP-1 and p53 and correlated the results with the clinical course. Genomic instability was assessed by DNA ploidy measurements and, in 35 cases, by comparative genomic hybridization. Overexpression of cyclin A and cyclin E was observed in the majority of invasive carcinomas, only rarely in borderline tumors and in none of the benign tumors. Similarly, high expression of p53 together with undetectable p21 or loss of chromosome arm 17p were frequent events only in adenocarcinomas. Both borderline tumors and adenocarcinomas revealed a high number of chromosomal gains and losses. However, regional chromosomal amplifications were found to occur 13 times more frequently in the adenocarcinomas than in the borderline tumors. The expression pattern of low p27 together with high Ki67 was found to be an independent predictor of poor outcome in invasive carcinomas. The results provide a link between disturbed cell cycle regulatory proteins, chromosomal aberrations and survival in ovarian carcinomas.

Clinical relevance of the CA 125 assay in monitoring of ovarian cancer patients.

CA 125 levels were measured longitudinally during treatment and follow-up of 248 epithelial ovarian cancer patients referred to the Department of Gynecological Oncology at Radiumhemmet, Stockholm, from 1984 to 1986. The aim of the study was to evaluate the value of CA 125 monitoring in clinical practice according to tumor burden at the time of referral to Radiumhemmet, the correlation of CA 125 values to tumor mass at second-look laparotomy, the lead time between increasing CA 125 values and tumor relapse, and the predictivity of normal CA 125 values after completion of first-line therapy. Ninety-one percent (32/35) of patients with a tumor volume greater than 5 cm at referral had elevated CA 125 values; 62% (22/35) with no tumor mass had normal CA 125 values. Elevated CA 125 values greater than 35 U/ml before second-look laparotomy predicted remaining tumors in 77% (15/19) of patients. The mean lead time between increasing CA 125 values and tumor relapse was 3 months. Normal CA 125 values at the end of first-line therapy may predict long survival times.

A phase II study on escalating interferon doses in advanced ovarian carcinoma.

Twenty-four patients with advanced and therapy-resistant ovarian carcinoma were treated with escalating daily doses of human leukocyte interferon (IFN). Doses ranged from 3 X 10(6) to 27 X 10(6) IU/day. Fatigue, fever, thrombocytopenia, and leukopenia were the limiting factors in the escalation of doses. Of nine patients treated for at least 2 months, there were two patients with partial remissions and six with stable disease. Ascites production present in four patients became reduced in three. The level of 2',5'-oligoadenylate synthetase in peripheral blood lymphocytes increased following initiation of IFN therapy. We conclude that IFN-alpha can exert an antitumor effect in some patients with ovarian carcinoma that have previously failed on other therapy regimens.

Human leukocyte interferon therapy for advanced ovarian carcinoma.

Daily intramuscular injections of 3 X 10(6) international units of human leukocyte interferon were given to five patients with advanced ovarian carcinoma, all of whom previously received other forms of treatment. Ascitic fluid production ceases in two out of two patients. According to the criteria specified by Young and DeVita a partial response was observed in one patient and in two other patients the disease was stable for more than 1 year. Side effects of the interferon therapy were relatively mild. The introduction of interferon therapy was followed by an increase in the natural killer cell activity of peripheral blood lymphocytes in all three patients examined. Natural killer cell activity decreased after cessation of interferon therapy in the one patient where this was tested.

Ampicillin versus cefamandole in biliary tract surgery. A prospective, randomized clinical and bacteriological study.

A prospective, randomized study was conducted on 219 surgical patients with biliary tract disease. There were 100 patients undergoing elective biliary surgery, and 119 others with suspected biliary sepsis who were assigned to Prophylactic or Therapeutic clinical categories, then randomized into ampicillin or cefamandole treatment groups. Organisms resistant to the antibiotics given were found less often among patients in the cefamandole groups than among those in the ampicillin groups. No postoperative wound or intra-abdominal sepsis (IAS) occurred in the Prophylactic category. In the Therapeutic category there were two cases (3.2%) of wound and IAS in the ampicillin group and one case (1.8%) of wound infection in the cefamandole group. Overall, cefamandole showed superior coverage in vitro against the biliary flora, but both drugs were equally effective in maintaining a low incidence of postoperative sepsis as well as a minimal number of febrile or total hospital days. The authors suggest that the choice of antimicrobials may not be as critical as effective surgical management in the prevention of septic complications following biliary tract surgery.

A case-control study of oral contraceptive use in women with adenocarcinoma of the uterine cervix.

To evaluate oral contraceptive (OC) use as a possible cause of the changed ratio between adenocarcinoma and squamous cell carcinoma of the uterine cervix a case-control study was performed. The OC use among 23 women with adenocarcinoma of the uterine cervix was compared with that of a matched group of 46 women with squamous cell carcinoma. No differences in percentage of OC use, duration of such use or period of OC use in relation to diagnosis could be demonstrated between the two groups compared.