Intravaginal brachytherapy in FIGO stage I low-risk endometrial cancer: a controlled randomized study.

The purpose of the study was to compare postoperative vaginal irradiation with surgery alone in low-risk International Federation of Gynecology and Obstetrics (FIGO) stage IA-IB endometrial carcinoma. The study was a prospective, randomized trial of 645 evaluable low-risk endometrial carcinoma patients from 6 European gynecologic cancer centers. All tumors were in FIGO stage IA-IB, of endometrioid histological type, and FIGO grade 1-2. High-dose-rate afterloading equipments (iridium [Ir] 192 or cobalt [co] 60) were used at 5 centers, and low-dose-rate (LDR) afterloading equipment (cesium [Cs] 137) at 1 center. Perspex vaginal applicators or ovoids were normally used, and the dose was specified at 5 mm from the surface of the applicator. Three to 6 fractions (3.0-8.0 Gy) were given, and the overall treatment time was 4 to 15 days. A total of 319 patients were treated with surgery plus vaginal irradiation (treatment group), and 326 patients with surgery alone (control group).Twenty-six recurrences (4.0%) were recorded in the complete series. The locoregional recurrence rate was 2.6%, whereas distant metastases occurred in 1.4%. The rate of vaginal recurrences was 1.2% in the treatment group versus 3.1% in the control group. The difference was not statistically significant (P = 0.114). Side effects were few and mild (grade 1-2). Dysuria, frequency, and incontinence were slightly more common after vaginal irradiation (2.8% vs 0.6%, respectively). Late intestinal problems were few and similar in the 2 groups. The conclusions were that the impact of postoperative brachytherapy on even the locoregional recurrence rate seems to be limited in patients with low-risk endometrial carcinoma. The overall recurrence rate and survival were similar in the 2 groups.

Clinical and histopathologic factors related to prognosis in primary squamous cell carcinoma of the vagina.

The goal of this retrospective study concerning primary carcinoma of the vagina (PCV) was to analyze clinical and histopathologic prognostic factors in one of the largest known material, which comprised 314 patients. PCV is a rare disease, and the majority of published studies are based on small materials; therefore, the established knowledge concerning prognostic factors is insufficient. Routine treatment is based on irradiation with risk for undertreatment or overtreatment, which leads to unnecessary complications in the absence of prognostic factors. The overall 5-year disease-specific survival rate in this study was 45% and in stage I 75%. In the univariate statistical analysis, several factors correlated significantly with disease-specific survival. However, in the multivariate analysis, there were only three factors that independently could predict poor survival-high age at diagnosis, large tumors (> or =4 cm), and advanced stage. Common background factors with no prognostic significance were prior hysterectomy, other gynecological malignancies, and pelvic irradiation. In conclusion, this study has elucidated three strong prognostic factors that might be considered in the choice of therapy and also for modification of the FIGO guidelines. Increased knowledge concerning complementary biologic markers to discriminate between low- and high malignant tumors is however of great importance.

Expression of DNA damage response proteins and complete remission after radiotherapy of stage IB-IIA of cervical cancer.

The primary aim of this study was to investigate if the expression of the DNA damage identifying protein DNA-PKcs known to be involved in DNA repair after treatment with ionising radiation can be used as a predictive marker for radiotherapy (RT) response in cervical cancer. Formalin-fixed primary tumour biopsies from 109 patients with cervical cancer, FIGO-stage IB-IIA, treated with preoperative brachytherapy followed by radical surgery were analysed by immunohistochemistry. In addition, correlation studies between early pathological tumour response to radiation and expression of Ku86, Ku70, Mdm-2, p53 and p21 in primary tumours were also performed. We found that tumour-transformed tissue shows positive immunostaining of DNA-PKcs, Ku86 and Ku70, while non-neoplastic squamous epithelium and tumour-free cervix glands show negative immunoreactivity. Expression of DNA-PKcs positively correlated with both Ku86 and Ku70, and a statistically significant correlation between the Ku subunits was also found. After RT, 85 patients demonstrated pathologic complete remission (pCR), whereas 24 patients had residual tumour in the surgical specimen (non-pCR). The main finding of our study is that there was no correlation between the outcome of RT and the expression of DNA-PK subunits. Positive p53 tumours were significantly more common among non-pCR cases than in patients with pCR (P=0.031). Expression of p21 and Mdm-2 did not correlate with the outcome of RT.

Primary carcinoma of the vagina: factors influencing the age at diagnosis. The Radiumhemmet series 1956-96.

The objective to this retrospective study of 341 cases of primary carcinoma of vagina (PCV) diagnosed between 1956 and 1996 was to find whether epidemiological, clinical, and histopathological variables were related to the age at diagnosis of patients with PCV. The univariate statistical analysis showed that younger age at diagnosis significantly correlated with a history of cervical dysplasia, hysterectomy, gynecological infections, and tumors located in the upper part of the vagina, whereas older age at diagnosis significantly correlated with late menarche and exophytically growing tumors. In the multivariate regression analysis, the remaining independent predictors were a history of cervical dysplasia and age at menarche. Further, parity >/=4 as well as nulliparity, smoking, and unstable marital status were more common among patients with PCV than among those in the general Swedish female population. This study indicates that the etiology of vaginal carcinoma may be age related. In young patients, the disease seems to be etiologically related to cervical neoplasia and thus human papillomavirus (HPV) dependent. However, in the most common age group, the older patients, there might be another (probably non-HPV-related) etiology associated with hormonal factors and trauma to the vagina.

Laminin-5 gamma2-chain expression and DNA ploidy as predictors of prognosis in endometrial carcinoma.

Expression of the laminin-5 gamma2-chain in carcinoma cells has been implicated in tumor invasion. The aim was to investigate the expression and prognostic significance of the ln-5 gamma2-chain compared with clinicopathological factors and tumor cell DNA ploidy in endometrial carcinoma. Histological specimens from 80 endometrial carcinomas were examined with respect to immunohistochemical ln-5 gamma2-chain expression and correlated to the clinicopathological characteristics, DNA ploidy, and survival. Sixty-eight of 80 investigated cases were judged to be positive for the ln-5 gamma2-chain. Ln-5 gamma2-chain did not show any correlation to stage, histopathological subtype, grade, and DNA ploidy. In univariate analyses, advanced stage (p < 0.001), nonendometrioid carcinoma (p = 0.030), low grade (p < 0.001), aneuploid tumors (p < 0.001), and ln-5 gamma2-chain expression (p = 0.017) were highly associated with poor survival. Aneuploid tumors in combination with strong ln-5 gamma2-chain expression were significant predictors (p < 0.001) of poor prognosis. In multivariate analyses including stage, histopathological subgroup, grade, DNA ploidy, and ln-5 gamma2-chain expression, all lost their significant prognostic information except for stage (p < 0.001) and grade (p < 0.05). Ln-5 gamma2-chain expression and DNA ploidy both as a single parameter and in combination were demonstrated to be signifi- cant prognostic factors in univariate analysis. However, stage and grade provided more useful clinical information beyond histopathological subgroup, DNA ploidy, and ln-5 gamma2-chain expression. The results also indicate that ln-5 gamma2-chain expression is upregulated during the progression of endometrial carcinoma.

Pathologic complete remission after preoperative intracavitary radiotherapy of cervical cancer stage Ib and IIa is a strong prognostic factor for long-term survival: analysis of the Radiumhemmet data 1989-1991.

The purpose of this study was to evaluate the treatment results of preoperative brachytherapy and the prognostic value of pathologic complete remission after preoperative intracavitary irradiation in patients with stage Ib and IIa cervical carcinoma in relation to recurrence rate and survival. The clinical records of 185 patients with stage Ib (129 patients) and IIa (56 patients) cervical carcinoma, consecutively admitted to Radiumhemmet from January 1989 to December 1991 were reviewed. The median follow-up time was 71 months. In 121 patients the treatment consisted of uterovaginal intracavitary irradiation, according to the Stockholm technique, followed by surgery. Tumor remission assessed in the surgical specimen was classified as pathologic complete remission (pCR) if no microscopic tumor was found or incomplete pathologic remission (non-pCR) if microscopic residual tumor was found. Postoperative external beam radiation was added to cases with metastases in pelvic nodes or residual tumor in the resection margins. The disease-specific 5-year survival was 87% and 75% for stage Ib and IIa, respectively, for the patient population treated with preoperative intracavitary radiotherapy and surgery. After intracavitary radiation, 79% of the patients obtained pCR of the primary tumor. Five-year survival in those with pCR was 95%, compared with 46% in those with non-pCR (P < 0.0001). Patients with pCR and no lymph node metastases had a 98% 5-year survival as compared to a 5-year survival of 64% in patients with non-pCR and node negativity (P < 0.0001). Locoregional relapses were diagnosed in 2% of the patients with pCR compared to 54% in patients with non-pCR (P < 0.0001). Multivariate analysis revealed non-pCR (RR = 6.42) and node positivity (RR = 4.59) as nonfavorable factors for survival, while tumor size was not found to be of independent significance for survival. Pathologic complete remission after intracavitary irradiation is a strong favorable prognostic factor in node-negative patients. The combination of preoperative intracavitary radiotherapy and surgery results in a high cure rate and aids in identifying patients at risk for relapse who might be subject to adjuvant therapy.

Nuclear DNA content, proliferative activity, and p53 expression related to clinical and histopathologic features in endometrial carcinoma.

The purpose of this study was to evaluate the prognostic impact of image cytometry DNA ploidy, MIB-1, and p53 in relation to clinicopathologic variables in 376 consecutive patients with endometrial carcinoma stages I-IV. Following primary treatment 358 patients were considered tumor-free. Relapses and tumor-specific deaths of these patients were noted. Image cytometry DNA ploidy (n = 340) and expression of MIB-1 (n = 318) and p53 (n = 323) were studied. In univariate analysis, stage (P < 0.001), histopathologic subtype (P < 0.001), degree of differentiation (P < 0.001), HRT (P = 0.034), DNA ploidy (P < 0.001), and p53 (P < 0.001) were significant predictors of relapse. Patient age showed that the estimated mean risk of relapse increases with nearly 64% per decade in life (P 0.003), and the MIB-1 expression with 21% per 10-unit increment (P 0.004). In multivariate analysis, degree of differentiation, MIB-1, and p53 lost their prognostic capability. However, after stage and histopathologic subtype, image cytometry DNA ploidy was the strongest predictor of outcome and was of value in predicting the risk for relapse. The combination of DNA ploidy, MIB-1, and p53 expression was an even stronger predictor of relapse-free survival than the individual prognostic factors.

Cancer of the vagina: Laminin-5gamma2 chain expression and prognosis.

The purpose of this experiment was to investigate the expression and the prognostic impact of the gamma2 subchain of laminin-5 in vaginal malignancies. The outcome of the rare disease primary carcinoma of the vagina is poor and little is known about prognostic markers. The gamma2 chain of laminin-5, an epithelial basement membrane protein, is thought to play a crucial role in tumor cell adhesion, migration, and proliferation, and may thus be an additive potential marker. Archival, paraffin-embedded sections were stained immunohistochemically with an antibody against the gamma2 chain of human laminin-5 protein. The material consisted of 59 cases of primary vaginal malignancies, subdivided into short- and long-time survivors. All invasive malignancies of epithelial origin were positively stained with the antibody against the gamma2 chain. High expression of the gamma2 chain correlated significantly in an univariate analysis with short-time survival (P = 0.041), but in the multivariate analysis only age and tumor size were independent prognostic factors. A significant intercorrelation between large tumors and high gamma2 chain immunoreactivity was found (P = 0.003). These results indicate that laminin-5gamma2 subchain expression in primary vaginal carcinomas is of prognostic impact. However, in a multivariate analysis only patient age and tumor size had independent prognostic value.

Cisplatin administration to gynecologic cancer patients. Long-term effects on hearing.

BACKGROUND: Cisplatin is known to create an acute dose-related ototoxic effect. There are unanswered questions regarding the long term effect of cisplatin on hearing in gynecologic cancer patients. METHODS: A retrospective review of 59 to 115 months' duration was performed on 184 women with gynecologic cancer who were treated with cisplatin-based chemotherapy between 1982 and 1986. Twenty-six of 40 survivors were again tested audiometrically with the same audiologic equipment. RESULTS: Fourteen patients (54%) had significantly progressive hearing loss (> or = 15 decibels) at long term follow-up compared with the posttreatment control. These changes were generally small and restricted to three frequencies or fewer in one of the patient's ears. The changes corresponded to the expected age effect upon hearing. Only 2 patients (8%) showed more severe hearing threshold changes. The hearing loss in one of the two patients might represent degenerative changes induced by cisplatin treatment, whereas in the other patient the etiologic background to the hearing loss remains unknown. CONCLUSIONS: This study does not provide any strong evidence for a delayed ototoxic effect of cisplatin that should influence therapeutic strategy. Patients who receive moderate dose cisplatin therapy, 50 mg/m2 per body surface area every 4 weeks, have a negligible long term risk of a drug-induced social hearing handicap.

Doxorubicin-melphalan with and without cisplatin in advanced ovarian cancer--ten-year survival results from a prospective randomized study by the Swedish Cooperative Ovarian Cancer Study Group.

In a controlled prospective randomized study the regimen doxorubicin (A) 40 mg/m2 + melphalan (M) 0.4 mg/kg was compared with A + M + cisplatin (C) 50 mg/m2 given every four weeks in advanced ovarian cancer, FIGO stage III or IV and with serous or anaplastic histology. From 1981 to 1983, 300 patients entered the study and 295 patients were evaluable for response, toxicity and long-term survival. All patients were followed for at least 10 years. The majority of patients had large residual tumours >2 cm. Patients treated with MAC had a higher response rate compared with patients treated with MA (76% vs. 50%, p < 0.01) and treatment with MAC resulted in significantly more pathological complete responders than MA. There was a significant difference in median duration of response (19 months vs. 13 months, p < 0.006) and in median survival time (26 months vs. 19 months, p = 0.05). After 5- and 10 years a significant difference in progression-free and overall survival was found. The independent prognostic factors in this study were residual tumour after primary surgery, treatment with MAC, tumour grade, ascites, and stage. Objective and subjective side effects were significantly worse with MAC, although tolerable. In conclusion, this study shows that incorporating C into MA improves the duration of progression-free survival and overall survival in women with incompletely resected Stage III or Stage IV ovarian epithelial cancer. A 5- and 10-year survival of 25% and 18%, respectively, is impressive.

An open, randomized study to compare the efficacy and tolerability of tropisetron with that of a metoclopramide-containing antiemetic cocktail in the prevention of cisplatin-induced emesis.

In a prospective randomized study comprising 66 women treated for gynecologic malignancies with cisplatin-containing chemotherapy, the new 5-hydroxytryptamine3 (5-HT3) receptor antagonist tropisetron (Navoban, Sandoz Pharma Ltd.) was compared with a metoclopramide cocktail for the prevention of nausea and emesis. All patients were chemotherapy-naive. Two consecutive courses (including the 1st week posttherapy) were studied. The cisplatin doses were in the range of 50-75 mg/m2, and the regimens also contained doxorubicin, teniposide, etoposide, vincristine, and bleomycin. Complete protection against nausea during the first 24 h (course 1) was achieved in 76% of the tropisetron group and in 85% of the metoclopramide group. Emesis was prevented in 82% of the patients in both groups. During the whole 6-day period, full emetic protection was achieved in 30% and 18% of the patients in the two groups. On days 3-4 of course 1, tropisetron was superior to metoclopramide. The overall tolerability of the tropisetron was excellent or good in 94% of patients, a rate higher than that observed for the metoclopramide regimen (75%). The most common side effects for the latter regimen were sedation (82%) and extrapyramidal reactions (21%). The only significant adverse event recorded after treatment with tropisetron was headache of slight or moderate grade.

Hexamethylmelamine as second-line therapy in platin-resistant ovarian cancer.

A total of 61 patients with recurrent or persistent clinically measurable platin-resistant epithelial ovarian carcinoma were treated with 260 mg/m2 oral hexamethylmelamine daily for 14 days, repeated at 4-week intervals. Platin resistance was defined as progression or stable disease during cis- or carboplatin treatment (used alone or in combination with other drugs), or relapse within 6 months after the end of that therapy. Fifty patients were evaluable for response and 57 for toxicity. The objective response rate was 14% (3 complete and 4 partial responses). The response rate was higher in patients with relapse within 6 months than in patients with progression or stable disease on platin-based therapy. This observation underscores the importance of defining response and time to progression after first-line chemotherapy. The median duration of response was 8 months and the median survival in responding patients was 9+ months versus 5 months for patients with progression on hexamethylmelamine. Nausea and vomiting requiring antiemetic treatment occurred in 8 (14%) patients and reversible peripheral neuropathy in 3 patients. Two patients developed agitation, insomnia, and depression during hexamethylmelamine therapy. In conclusion, the 14% objective response rate and the occurrence of complete responses with oral hexamethylmelamine treatment in a group of ovarian cancer patients with true platin resistance are noteworthy.

Prognostic flow cytometric information in cervical squamous cell carcinoma: a multivariate analysis of 307 patients.

In a prospective study of 307 patients with invasive squamous cell carcinoma of the uterine cervix, the prognostic impact of flow cytometric parameters (ploidy level and the fraction of S-phase cells) and clinical variables was evaluated using univariate and multivariate analyses (Cox model). Mean follow-up time as 39 (4-84) months. A total of 93 patients died from their disease during the follow-up. The S-phase fraction was evaluable in 242 cases. By means of univariate models, lethality rate was found to increase significantly with increasing age, postmenopausal status, advancing stage, and increasing S-phase fraction. In a multivariate analysis of the clinical variables of age, stage, and grade, only clinical stage was prognostic. The inclusion of ploidy level in the analysis gave no additive prognostic information. In a multivariate analysis including all variables mentioned above, stage was the strongest predictor of survival. S-phase fraction was significantly related to survival both when studied as a continuous variable (P = 0.006) and when studied as a categorized variable (10, 15, 20% as cutoff points), and in this special analysis ploidy level was of prognostic interest with a poorer survival for near-diploid cases. The outcome was poorer with increasing age. The prognostic impact of the S-phase fraction remained highly significant in separate analyses of the clinically interesting stages Ib-IIb (P less than 0.001). We conclude that measurement of the S-phase fraction is of prognostic interest and may be used for the identification of high-risk patients within a given stage, whereas ploidy level yields little information.

DNA ploidy, morphometry, and nuclear grade as prognostic factors in endometrial carcinoma.

In a retrospective analysis of 106 cases of endometrial carcinoma stages I-IV (FIGO), the prognostic value of DNA ploidy and nuclear morphometry of tumor cells was evaluated and compared with that of conventional clinical and histopathologic parameters. Paraffin-embedded tumor tissue from the original curettage specimens was used. A flow cytometric technique was employed to distinguish diploid from aneuploid tumors. It was not possible to estimate S-phase rates by this method. Eight different nucleus-related morphometric parameters were computed from representative tumor regions on the original slides. All histologic specimens were reviewed by on the pathologist and graded according to FIGO; nuclear grade was determined separately. Tumor stage, depth of myometrial infiltration, and nuclear grade were the most important prognostic factors with regard to tumor-related survival. DNA ploidy and nuclear morphometry did not add significant prognostic information that could be used to distinguish high-risk and low-risk populations with endometrial carcinomas. The simple nuclear grading system should be further evaluated in prospective studies and compared with DNA analysis and nuclear morphometry performed on fresh-frozen tissue.

Intracavitary irradiation of endometrial carcinoma stage I by a high dose-rate afterloading technique.

Intracavitary irradiation was administered to 366 patients with endometrial carcinoma stage I by a high dose-rate afterloading method using 60Co sources (bulb technique). In 275 cases hysterectomy and bilateral salpingo-oophorectomy were performed 6 weeks later and in 91 cases dilation and curettage was used to verify tumor eradication. In 58% of the hysterectomy specimens no residual carcinoma was detected at the histopathologic evaluation. In the group treated with radiotherapy alone 74% showed no carcinoma remnants in the curettings 3 months after therapy. The effect of the fractionation dose was evaluated in relation to the outcome of the histopathologic examination. The proportion of specimens with no residual carcinoma increased from 27% for the 5 Gy per fraction group to 78% for the 10 Gy per fraction group. Recurrences were recorded in 13% in the hysterectomy group and in 29% in the group treated with radiotherapy alone. The 5-year corrected survival rate for the combination-treated group was 88% and for the group treated with radiotherapy alone 72%. If the dose per fraction is specified in the range of 5 to 8 Gy the high dose-rate afterloading technique seems safe with a tumor control rate and a frequency of radiation reactions comparable to the manual radium method.

Misonidazole combined with radiotherapy in the treatment of carcinoma of the uterine cervix.

Between April 1979 and January 1982, 331 patients were included in a study to establish whether misonidazole (MISO) had any effect as an adjuvant to radiotherapy in the treatment of squamous cell carcinoma of the uterine cervix (FIGO Stage IIb, III, and IVa). Patients were randomized to receive either MISO (12 g/m2 applied within 6 weeks) or placebo. This was given in conjunction with each institution's normal radiotherapy schedule and thus varied with regard to external and intracavitary irradiation. The analysis was performed based on patients' status at January 1986, with all patients observed for at least 4 years. One hundred and sixty-four patients received MISO and 167 placebo. Compliance to radiotherapy was good and MISO was well tolerated. The overall rates for MISO vs. placebo were as follows: local tumour control, 50 vs. 54%; disease-free survival, 47 vs. 46%, and crude survival, 39 vs. 45%. A similar lack of MISO effect was found in the individual stages. However, patients in all stages with hemoglobin concentrations below 7 mmol/l had a significantly lower local control probability (overall 24 vs. 47%), whereas the incidence of distant metastases was unaffected. We conclude that the addition of MISO did not influence the radiation response in advanced uterine carcinoma. The reasons for this ineffectiveness are yet to be clarified.

VM-26-vincristine-cisplatin combination chemotherapy in the treatment of primary advanced and recurrent endometrial carcinoma.

A chemotherapeutic combination consisting of VM-26-vincristine-cisplatin was used to treat 44 consecutive patients with primary advanced or recurrent endometrial carcinomas. Nine complete remissions (20.5%) and 14 partial remissions (31.8%) were recorded. The median duration of remission in responders was 8 months (range 1-35). The responding patients had significantly longer survival than nonresponders. The median duration of survival in the complete series was 7 months. The response rates and survival times were the same for primary advanced tumors and recurrences, regardless of sites. Peripheral neuropathy, secondary anemia, and nausea were the most common side effects. The drug combination was well tolerated, and its efficacy is comparable to that of other more toxic chemotherapy regimens.

Preoperative intracavitary irradiation of endometrial carcinoma stage I by a high dose rate afterloading technique.

Preoperative intracavitary irradiation was administered to 366 patients with endometrial carcinoma stage I by a high dose rate afterloading method using 60Co sources (bulb-technique). In 275 cases hysterectomy and bilateral salpingo-oophorectomy were performed 6 weeks later and in 91 cases dilation and curettage was used to verify tumor eradication. In 58% of the hysterectomy specimens no residual carcinoma was detected at the histopathologic evaluation. In the group treated with radiotherapy alone 74% showed no carcinoma remnants in the curettings 3 months after therapy. The effect of the fractionation dose was evaluated in relation to the outcome of the histopathologic examination of the hysterectomy and curettage specimens. The proportion of specimens with no residual carcinoma increased from 27% for the 5 Gy per fraction group to 78% for the 10 Gy per fraction group. Recurrences were recorded in 13% in the hysterectomy group and in 29% in the group treated with radiotherapy alone. The nuclear grade of the tumor and the age of the patient were the most important risk factors for tumor recurrence. The 5-year crude survival rate for the combination-treated group was 84% and for the group treated with radiotherapy alone 47%. The corresponding corrected survival rates were 88 and 72% respectively. Serious late radiation reactions were noted in 6.6%. The significant risk factors for radiation reactions were dose per fraction and the age of the patient.