Prognostic factors in locally advanced carcinoma of the cervix treated with radiation therapy.
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Carcinoma↗
Biomedical subjects
F B Stehman
Publications and source records attributed to F B Stehman.
Carcinoma of the cervix treated with chemotherapy and radiation therapy. Cooperative studies in the Gynecologic Oncology Group.
Since its inception in 1970, the Gynecologic Oncology Group (GOG) has pursued a series of Phase II and III cooperative clinical investigations of the combination of cytotoxic chemotherapy and radiation therapy for patients with locally advanced carcinoma of the cervix. After an initial randomized trial indicated that hydroxyurea was superior to placebo, subsequent studies have evaluated whether the hypoxic sensitizer, misonidazole, or the combination of cisplatin with infusional 5-fluorouracil were superior to hydroxyurea. Other studies have evaluated concurrent chemotherapy with extended field radiation for patients with metastatic disease in their paraaortic nodes. The GOG will continue to attempt to identify and develop superior adjuncts to radiation therapy for this patient population.
Antineoplastic Combined Chemotherapy Protocols↗
Blood transfusion and the risk of recurrence in squamous carcinoma of the vulva.
OBJECTIVE: Our purpose was to determine if postoperative transfusion increases the risk of recurrence in patients who have undergone operation for squamous carcinoma of the vulva. STUDY DESIGN: Data from 154 patients with squamous carcinoma of the vulva treated at Indiana University Medical Center from 1974 through 1988 were retrospectively analyzed to determine the influence of postoperative transfusion on recurrence risk. Patients were evaluated for International Federation of Gynecology and Obstetrics stage, lesion size, lesion depth, grade, patient age, number of transfusions, and recurrence with chi 2 analysis, Fisher's exact test, and the Student t test where appropriate. RESULTS: Transfusions were given to 57 patients (37%) with a mean of 2.2 units delivered (range 1 to 5 units). Transfused patients differed significantly from those not transfused in that they had more advanced stage (p = 0.002), more positive nodes (p = 0.03), and higher grade lesions (p = 0.03), and they were older (p = 0.005). Recurrences developed in 25 patients (16.2%). Recurrences were more common in those with positive nodes (10-39, 25.6%) than in those with negative nodes (8/99, 8%), (p = 0.01). Only nodal status was predictive of recurrence in this series. Transfused patients had a 14% (8/57) rate of recurrence, whereas the recurrence risk was 17.5% (17/97) in those not transfused (p = 0.65). CONCLUSIONS: We have been unable to confirm that postoperative transfusions increase the risk of recurrence in patients with squamous carcinoma of the vulva.
Adult↗
Hydroxyurea versus misonidazole with radiation in cervical carcinoma: long-term follow-up of a Gynecologic Oncology Group trial.
PURPOSE: Long-term follow-up data of a randomized trial that compared hydroxyurea and the hypoxic-cell radiosensitizer to misonidazole as adjuncts to standard radiation therapy in locally advanced carcinoma of the cervix are reported. PATIENTS AND METHODS: Three hundred eight women were entered, and all 294 eligible patients are assessable as randomized. Eighty-one percent of patients have been monitored for 5 years or to death. RESULTS: There was an advantage for hydroxyurea in progression-free interval and survival (P = .05 and P = .066, respectively). There was no significant difference in the distribution of sites of failure between the regimens. For the 39% of patients with stages III to IVA disease, the advantage in progression-free interval for hydroxyurea was significant (47.8% v 33.6%). More leukopenia occurred on the hydroxyurea regimen than on the misonidazole regimen. CONCLUSION: In summary, these data provide stronger evidence than our previous analysis that hydroxyurea is superior to misonidazole as an adjunct to radiation therapy. For patients with locally advanced carcinoma of the cervix, hydroxyurea continues to be the adjunct of choice with radiation.
Adult↗
Inhibition by tiazofurin of inosine 5'-phosphate dehydrogenase (IMP DH) activity in extracts of ovarian carcinomas.
Cancer cells have an increased ability to synthesize GTP (guanosine triphosphate) because of increased activity of IMP DH (inosine 5'-phosphate dehydrogenase, EC 1.1.1.205). Because IMP DH activity is rate limiting for de novo biosynthesis of GTP, this enzyme was suggested as a sensitive target for chemotherapy. Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) is converted in the cells into the active metabolite, TAD, (thiazole-4-carboxamide adenine dinucleotide) which potently inhibits IMP DH activity. By adding TAD to tissue extracts one can determine the extent of inhibition of IMP DH. We applied the IMP DH assay method to extracts of normal ovaries (N = 11) and epithelial ovarian carcinomas (N = 10). The IMP DH activity (mean +/- SE) in ovarian carcinoma was 21.1 +/- 5.8 which was markedly higher than that observed in normal ovaries (2.9 +/- 0.7 nmol/hr/mg protein) (P < 0.05%). The inhibition by TAD of IMP DH activity in ovarian carcinomas (N = 4) was 81%. The results indicate that IMP DH activity is elevated sevenfold in ovarian carcinomas as compared to normal ovary and can be inhibited by exposure to tiazofurin (TAD). Similar high IMP DH activity and inhibition of the activity by TAD was observed in patients with chronic granulocytic leukemia in blast crisis among whom 70 to 80% remissions were reported. Since there is increased IMP DH activity in human ovarian carcinomas and in OVCAR-5 cells and tiazofurin and TAD inhibit IMP DH activity of these cells and the proliferation of human ovarian carcinoma xenografts in the mouse, tiazofurin may merit serious consideration for a Phase II trial for patients with recurrent/refractory epithelial ovarian carcinoma.
Adenocarcinoma↗
Groin dissection versus groin radiation in carcinoma of the vulva: a Gynecologic Oncology Group study.
PURPOSE: The objective of this study was to determine if groin radiation was superior to and less morbid than groin dissection. METHODS AND MATERIALS: Members of the Gynecologic Oncology Group randomized 58 patients with squamous carcinoma of the vulva and nonsuspicious (N0-1) inguinal nodes to receive either groin dissection or groin radiation, each in conjunction with radical vulvectomy. Radiation therapy consisted of a dose of 50 Gray given in daily 200 centiGray fractions to a depth of 3 cm below the anterior skin surface. RESULTS: The study was closed prematurely when interim monitoring revealed an excessive number of groin relapses on the groin radiation regimen. Metastatic involvement of the groin nodes was projected to occur in 24% of patients based on this Group's previous experience. On the groin dissection regimen, there were 5/25 (20.0%) patients with positive groin nodes. These patients received post-operative radiation. There were five groin relapses among the 27 (18.5%) patients on the groin radiation regimen and none on the groin dissection regimen. The groin dissection regimen had significantly better progression-free interval (p = 0.03) and survival (p = 0.04). CONCLUSION: Radiation of the intact groins as given in this study is significantly inferior to groin dissection in patients with squamous carcinoma of the vulva and N0-1 nodes.
Adult↗
Recurrent squamous carcinoma of the vulva.
OBJECTIVE: This study reviews experience at Indiana University with recurrent squamous carcinoma of the vulva over an 18-year period from 1971 to 1989. The pattern of recurrence, time interval to recurrence, and efficacy of salvage therapy are evaluated in the context of the primary tumor. STUDY DESIGN: This is a retrospective study of 40 patients, 21 of whom underwent primary therapy for invasive squamous carcinoma of the vulva at Indiana University. RESULTS: Vulvar recurrences were observed in 17 patients (43%), the groin was involved in 12 (30%), whereas pelvic and distant recurrences were observed in 2 (5%) and 9 (22.5%) patients, respectively. Salvage surgery and/or radiotherapy were successful in 25 patients (62.5%) alive from 1 to 144 months (median 8 months) from secondary therapy. Survival after retreatment varied significantly by site of recurrence (p = 0.002), tumor grade (p = 0.009), and interval to recurrence (p < 0.001). Best outcomes were in patients with initial stage I or II disease (International Federation of Gynecology and Obstetrics), grade 1 tumors, local failure, and interval to relapse of > 16 months' duration. Two of 12 patients with groin recurrences were salvaged with surgery and radiotherapy. CONCLUSION: Long-term follow-up of patients with vulvar cancer and careful restaging at the time of recurrence are mandatory. Although local and nodal recurrences may be controlled with surgery and/or radiotherapy, regional recurrences are usually fatal.
Adult↗
Immunohistochemical study of HER-2/neu, epidermal growth factor receptor, and steroid receptor expression in normal and malignant endometrium.
HER-2/neu oncogene protein, epidermal growth factor receptor, progesterone receptor, and estrogen receptor were examined immunohistochemically in specimens of normal and neoplastic endometrium. Tissues obtained at the time of hysterectomy were snap-frozen at liquid nitrogen temperature and serially sectioned at 4 microns. Normal endometrial epithelial cells stained with anti-epidermal growth factor receptor and anti-HER-2/neu with intensities graded from 0 to 3+. Of the 49 endometrial malignancies studied, seven (14%) contained tissue exhibiting HER-2/neu staining in excess (4+) of any of the normal tissues or the other 42 cancer specimens. Expression of both HER-2/neu and steroid receptors was heterogeneous within these seven tumors. To examine this heterogeneity more closely, sections of these and other tumors were double-stained for HER-2/neu and progesterone receptor. It was found that the cells exhibiting 4+ HER-2/neu staining were progesterone receptor-negative. Conversely, cells that were progesterone receptor-positive within the same specimen exhibited HER-2/neu immunostaining equal to or less than 3+. All specimens containing 4+ HER-2/neu tissue were graded 1 or 2 adenocarcinomas, stage I. Thus, there is an inverse relationship between overexpression of HER-2/neu and progesterone receptor in endometrial cancer. On the other hand, overexpression of HER-2/neu in endometrial cancer does not seem to be related to loss of other differentiated characteristics. The prognostic value of these observations awaits continued study.
Biomarkers, Tumor↗
Concurrent chemoradiation in carcinoma of the uterine cervix.
Carcinoma of the cervix is most commonly treated with radiotherapy when the disease is locally advanced. Tumor bulk often limits the efficacy of this therapy, as does the tolerance of adjacent healthy tissue. Cytotoxic chemotherapeutic agents have been used with concomitant radiotherapy. Extensive data are available on dose and schedule tolerance for cisplatin, 5-fluorouracil, and a number of combination regimens. Phase III data that confirm any advantage in terms of local control, disease-free survival, or overall survival have been published only for hydroxyurea. Hydroxyurea, an S-phase-specific inhibitor of ribonucleotide reductase, lacks single-agent activity against metastatic, squamous cell cervical cancer. Further studies are required before agents other than hydroxyurea can be considered standard therapy with concomitant radiotherapy for locally advanced carcinoma of the cervix.
Cisplatin↗
Early stage I carcinoma of the vulva treated with ipsilateral superficial inguinal lymphadenectomy and modified radical hemivulvectomy: a prospective study of the Gynecologic Oncology Group.
Although cure rates are high, the morbidity of radical operation for carcinoma of the vulva is substantial. Between 1983-1989, member institutions of the Gynecologic Oncology Group entered 155 patients in a prospective evaluation of modified radical hemivulvectomy and ipsilateral inguinal lymphadenecctomy for clinical stage I vulvar cancer. Only patients with neoplastic thickness of 5 mm or less, without vascular space invasion, and negative inguinal lymph nodes were eligible for this study. There have been 19 recurrences and seven deaths from disease among the 121 eligible and evaluable patients. Patients whose disease recurred on the vulva were frequently (eight of ten patients) salvaged by further operation. Five of the seven deaths due to cancer occurred among patients whose first recurrence was in the groin. Acute and long-term morbidity as well as hospital stay were each less than in the Group's previous experience in a comparable patient population treated with radical vulvectomy and bilateral inguinal-femoral lymphadenectomy. There was a significantly increased risk of recurrence but not death when compared with these same historic controls. Modified radical hemivulvectomy and ipsilateral inguinal lymphadenectomy is an alternative to traditional radical operation for these selected patients with stage I carcinoma of the vulva. The number of patients who experienced recurrence in the operated groin is of concern and may be attributable to the decision to leave the femoral nodes intact.
Adult↗
Experience with hydroxyurea as a radiosensitizer in carcinoma of the cervix.
Since 1968, hydroxyurea has been used as a radiosensitizer in combination modality treatments for carcinoma of the cervix. The drug has shown an advantage over placebo in several randomized trials. Although hydroxyurea is given orally on an outpatient basis, it has not gained widespread acceptance. Previous reports are reviewed and possible future uses are discussed.
Animals↗
Carcinoma of the cervix treated with radiation therapy. I. A multi-variate analysis of prognostic variables in the Gynecologic Oncology Group.
Between 1977 and 1985, the Gynecologic Oncology Group (GOG) conducted three clinical trials in locally advanced carcinoma of the cervix, clinical Stages I to IVA as classified by the International Federation of Gynecology and Obstetrics (FIGO). All 626 patients had primary carcinoma of the cervix and underwent operative assessment of the para-aortic (PA) lymph nodes. Patients received standardized external radiation therapy to the pelvis or to the pelvis and PA lymph nodes followed by one or two brachytherapy applications. To date, no statistically significant differences in progression-free interval (PFI) or survival time have been identified between the randomization treatment arms on any of these studies. Basic similarities among these studies led us to pool these data to identify patient characteristics and tumor characteristics associated with an increased risk of treatment failure. Multi-variate analysis showed patient age, performance status (PS), PA lymph node status, tumor size, and pelvic node status to be significantly associated with PFI. When modeling for survival, all these factors and clinical stage and bilateral extension were significant.
Adult↗
Trends in the operative management of invasive squamous carcinoma of the vulva at Indiana University, 1974 to 1988.
From January 1974 to March 1988, 150 patients with primary invasive squamous cell carcinoma of the vulva underwent surgery at Indiana University. There has been a trend toward more conservative surgical management of this disease. To determine the impact of this trend on clinical outcome, cases were divided into three groups according to date of operation: group I, 1974 to 1978; group II, 1979 to 1983; and group III, 1984 to 1988. Overall, 80 patients had en bloc radical vulvectomy and groin dissection, 20 had modified radical vulvectomy and bilateral groin dissection through three separate incisions, and 36 had modified radical vulvectomy and unilateral superficial groin dissection. Fourteen patients had other operations. Forty-two patients (27.3%) had radiotherapy in addition to surgery. Among the three groups, there were no differences when mean age, International Federation of Gynecology and Obstetrics stage distribution (1988 system), mean lesion size, mean depth of invasion, or grade distribution were compared. A significant trend toward more conservative surgical therapy was observed. En bloc radical vulvectomy was performed in 77.4% of group I patients, 71.1% of group II patients, and 35.8% of group III patients (p less than 0.001). Mean days of hospitalization were also reduced significantly. Group I had a mean stay of 30 days, group II had a mean stay of 23 days, and group III had a mean stay of 11 days (p less than 0.001). Mean operative blood loss (group I, 754.8 ml; group II, 620.0 ml; group III, 393.6 ml; p = 0.03), mean units of blood transfused (group I, 1.4 units; group II, 1.3 units; group III, 0.4 units; p less than 0.01), and mean hours of operating time (group I, 3.7 hours; group II, 3.7 hours; group III, 3.2 hours; p = 0.02) were also reduced.
Adult↗
Teniposide (VM-26) in patients with non-squamous-cell carcinoma of the cervix. A phase II trial of the Gynecologic Oncology Group.
Twenty-three evaluable patients with non-squamous-cell carcinoma of the cervix were treated with teniposide 100 mg/m2 per week administered as a 30-60 min infusion. Escalations of 20 mg/m2 per week to a maximum dose of 160 mg/m2 were performed in patients without toxicity. Thirteen of the 23 patients had no prior chemotherapy. One patient had a partial response (95% confidence intervals for response less than or equal to 19%). Toxicity was minimal. Seven patients had white blood cell counts of less than 2,000/mm3 but only one had less than 1,000/mm3. No patients had platelet counts less than 50,000/mm3, and no bleeding or septic episodes were noted. Two patients had mild nausea and seven had mild nausea and vomiting. Teniposide displays no major activity in patients with non-squamous-cell cervical cancer.
Adult↗
Features associated with survival and disease-free survival in early endometrial cancer.
Age, clinical stage, histologic grade, depth of myometrial penetration, adnexal status, peritoneal cytology, and progesterone and estrogen receptor status were available for 139 patients with clinical stage IA, IB, or II endometrial adenocarcinoma who had therapy at Indiana University Hospital or St. Vincent Hospital in Indianapolis. These features were analyzed for their association with survival and disease-free survival. Patients treated at Indiana University Hospital were similar to those from St. Vincent Hospital when comparisons were made by chi 2 test for age, clinical stage, grade, adnexal metastases, peritoneal cytologic results, progesterone receptor status, or estrogen receptor status. However, patients treated at Indiana University Hospital had lesions that were deeper (p = 0.03) than those treated at St. Vincent Hospital. Survival differences were observed for patients with progesterone receptor-rich versus progesterone receptor-poor tumors (p = 0.004), grades 1 and 2 versus grade 3 lesions (p = 0.013), and malignant versus benign peritoneal cytologic results (p = 0.01). Differences in disease-free survival were observed for those patients with adnexal metastases versus those with no adnexal disease (p = 0.002), those with estrogen receptor-rich versus estrogen receptor-poor tumors, outer third myometrial invasion (p = 0.002), and patients with clinical stage I versus clinical stage II disease (p = 0.03). A stepwise Cox proportional hazards model was constructed to determine correlates of disease-free survival. In the final model, grade (p = 0.0002), peritoneal cytologic results (p = 0.0002), progesterone receptor status (p = 0.004), and age as a continuous variable (p = 0.008) were most closely associated with disease-free survival.
Adenocarcinoma↗
A prospective surgical pathological study of stage I squamous carcinoma of the cervix: a Gynecologic Oncology Group Study.
Thirty-three institutions collaborating in the Gynecologic Oncology Group gathered surgical and pathological data on 1125 patients with primary, previously untreated, histologically confirmed stage I cervical carcinoma with more than 3 mm of invasion who were selected to undergo radical hysterectomy and paraaortic and pelvic lymphadenectomy. Of the 940 eligible, evaluable patients, 732 had squamous carcinoma. Of the study group, 87 (12%) did not undergo radical hysterectomy because of gross disease beyond the uterus or microscopic aortic node involvement documented at exploratory laparotomy. Among the 645 patients undergoing pelvic and paraaortic lymphadenectomy and radical hysterectomy, five risk factors were significantly associated with microscopic pelvic lymph node metastasis: depth of invasion (P = 0.0001), parametrial involvement (P = 0.0001), capillary-lymphatic space invasion (P = 0.0001), tumor grade (P = 0.01), and gross versus occult primary tumor (P = 0.009). The factors identified as independent risk factors for pelvic lymph node metastasis by multivariate analysis were capillary-lymphatic space involvement (P less than 0.0001), depth of invasion (P less than 0.0001), parametrial involvement (P = 0.0005), and age (P = 0.02). The model was used to predict the chance of a patient having nodal metastasis for any combination of risk factors.
Adult↗
DNA content as a prognostic index in gestational trophoblastic neoplasia.
Hydatidiform mole will progress to malignant gestational trophoblastic neoplasia (GTN) in some cases. Aneuploidy and high proliferative activity are associated with malignant tumors. Molar pregnancy tissue was considered a precursor to malignant GTN, and was studied retrospectively using paraffin-embedded tissue to determine whether aneuploidy or proliferative rates measured on molar tissue could predict a malignant course. Tissues from 51 complete hydatidiform moles were analyzed for nuclear DNA content by flow cytometric techniques. A chart review identified the clinical course after evacuation of the mole. A satisfactory DNA histogram was generated in 40 cases. Of the 40 patients, 22 (55%) had spontaneous resolution, and 18 patients (45%) required treatment for persistent GTN. The molar tissue was found to be euploid in 27 cases and aneuploid in 13 cases. Eight of the twenty-seven euploid cases (30%) required treatment after evacuation, whereas 10 of the 13 aneuploid cases (77%) required treatment after molar evacuation. Proliferative index (PI) was compared with treatment requirements. Average PI was 0.11 +/- 0.10 for the treatment group and 0.08 +/- 0.06 for the spontaneous resolution group. The correlation of clinical course with ploidy was significant (P less than 0.01). The association with proliferative index was not (P greater than 0.05). Aneuploidy, therefore, identifies a high-risk group of molar pregnancies, and may represent those that have undergone one stage of malignant transformation.
DNA, Neoplasm↗