Phase I trial of escalating doses of paclitaxel combined with fixed doses of cisplatin and doxorubicin in advanced endometrial cancer and other gynecologic malignancies: a Gynecologic Oncology Group study.

PURPOSE: The primary objective of this phase I trial was to determine the feasibility of administering a combination of paclitaxel, cisplatin, and doxorubicin with or without granulocyte colony-stimulating factor (G-CSF) in patients with advanced endometrial and other gynecologic cancers. PATIENTS AND METHODS: Patients were chemotherapy-naive. Doxorubicin was administered as a brief infusion, paclitaxel for 3 hours, and cisplatin for 60 minutes. Treatments were repeated every 3 weeks. For most dose levels, the cisplatin and doxorubicin were fixed at 60 mg/m(2) and 45 mg/m(2), whereas the paclitaxel was escalated in successive cohorts from 90 to 250 mg/m(2). Patients who had received previous radiotherapy to the whole pelvis were escalated separately from those who had not. RESULTS: Eighty patients received 320 cycles of therapy. When G-CSF was not used, myelosuppression prevented escalation beyond the starting dose for patients with or without previous pelvic radiotherapy. When G-CSF was added, neurotoxicity became dose-limiting for both groups. Ten patients were removed from the study for asymptomatic declines in ejection fraction, but no symptomatic congestive heart failure was observed. Major antitumor responses occurred in 46% of patients (six of 13) with measurable endometrial carcinoma and 50% of patients (eight of 16) with measurable cervical carcinoma. CONCLUSION: The combination of paclitaxel, doxorubicin, and cisplatin at relevant single-agent doses is active and feasible with the addition of G-CSF. A regimen of cisplatin 60 mg/m(2), doxorubicin 45 mg/m(2), and paclitaxel 160 mg/m(2) with G-CSF support is recommended for further testing.

The HRAS1 minisatellite locus and risk of ovarian cancer.

Approximately 10% of ovarian cancers are due to mutations in highly penetrant inherited cancer susceptibility genes. The highly polymorphic HRAS1 minisatellite locus, located just downstream from the proto-oncogene H-ras-1 on chromosome 11p, consists of four common progenitor alleles and several dozen rare alleles, which apparently derive from mutations of the progenitors. Mutant alleles of this locus represent a major risk factor for cancers of the breast, colorectum, and bladder, and it was found that BRCAI mutation carriers with at least one rare HRAS1 allele have a greater risk of ovarian cancer than BRCA1 carriers with only common HRAS1 alleles. There are no conclusive studies of HRAS1 alleles in sporadic epithelial ovarian cancer. A case-control study of HRAS1 alleles was performed on DNA from 136 Caucasian patients with ovarian cancer and 108 cancer-free controls using conventional (Southern blot) and PCR-based methods to determine the frequency of rare HRAS1 alleles. Odds ratios (ORs) were estimated using unconditional logistic regression methods. A single degree of freedom test was used to assess the significance of linear trend across categories of increasing exposure. A statistically significant association between rare HRAS1 alleles and risk of ovarian cancer was observed [OR, 1.70; 95% confidence interval (CI), 1.03-2.80; P = 0.04]. Having only one rare allele was associated with a relative risk of 1.66 (95% CI, 0.91-3.01), whereas having two rare alleles increased the relative risk to 2.86 (95% CI, 0.75-10.94; trend P = 0.03). Analysis of HRAS1 allele types by the age of the case at diagnosis revealed that younger cases (<45 years) had a borderline statistically significant increased association with rare HRAS1 alleles compared to older cases (> or = 0 years; OR, 1.89; 95% CI, 0.90-3.98; P = 0.09). Rare HRAS1 alleles contribute to ovarian cancer predisposition in the general population. Thus, the HRAS1-variable number of tandem repeats locus may function as a modifier of ovarian cancer risk in both sporadic and hereditary ovarian cancer.

Masculinizing granulosa cell tumor of the ovary in a postmenopausal woman. A case report.

BACKGROUND: A total of 32 cases of virilizing granulosa cell tumors of the ovary have been reported. The current case has some unique features not previously reported. CASE: A 78-year-old woman presented with symptoms and signs of masculinization. A large, painless abdominal mass was discovered. Exploration revealed the mass to be originating in the left ovary, and surgical resection resulted in prompt reversal of the clinical and biochemical hyperandrogenic manifestations. Morphologic studies demonstrated a homogeneous granulosa cell tumor. CONCLUSION: This is the oldest patient on record with a masculinizing granulosa cell tumor and also the only masculinizing tumor presenting with advanced, stage III disease. Such tumors, although rare, should be considered in the differential diagnosis in postmenopausal women presenting with masculinizing symptoms.

Endometrial cancer: current concepts and management.

Endometrial cancer is the most common pelvic gynecologic cancer in women. Its occurrence is associated with endometrial hyperplasia, unapposed estrogen therapy, and more recently, tamoxifen. The staging uses information obtained at the time of surgery. Hysterectomy continues to be the primary treatment for most patients with endometrial cancer, whereas postoperative radiation therapy is used in the treatment of patients with other than low-risk prognostic factors.

A phase II trial of paclitaxel in patients with advanced or recurrent adenocarcinoma of the endometrium: a Gynecologic Oncology Group study.

OBJECTIVE: To determine the efficacy and toxicity of paclitaxel in advanced or recurrent adenocarcinoma of the endometrium. METHODS: Thirty patients with advanced or recurrent endometrial cancer with measurable disease not previously treated with chemotherapy were treated with paclitaxel, 250 mg/m2, over 24 hr with G-CSF, 5 mcg/kg/day, from Days 2 to 12. The cycle was repeated every 21 days. Patients who had received previous pelvic radiation were treated at an initial paclitaxel dose of 200 mg/m2. Twenty-eight patients were evaluable for response, and 29 patients for toxicity. All patients were Gynecologic Oncology Group performance status 0,1, or 2. RESULTS: Complete responses were observed in 4 (14.3%) and partial responses in 6 patients (21.4%) for a response rate of 35.7%. Severe (grade 3 or 4) leukopenia or thrombocytopenia was seen in 18 and 2 patients, respectively. Grade 3 or 4 gastrointestinal toxicity was seen in 5, neurotoxicity in 3, anemia in 2, and cardiac toxicity in 1 patients. Alopecia was reported in 16 patients. CONCLUSIONS: This dose and schedule of paclitaxel are active in patients with advanced or recurrent adenocarcinoma of the endometrium and should be considered for inclusion in phase III trials.

Prognostic factors for local and distant recurrence in stage I and II cervical carcinoma.

PURPOSE: The effects of tumor size, parametrial involvement, and other variables on treatment outcome for patients with Federation Internationale de Gynecologie et d'Obstetrique (FIGO) Stage I or II cervical carcinoma, as well as treatment complications, were analyzed retrospectively. METHODS AND MATERIALS: Records of 125 patients with FIGO Stage I or II carcinoma of the uterine cervix selected for curative radiotherapy between January 1980 and December 1990 were reviewed. Twelve patients (9.9%) underwent adjuvant extrafascial hysterectomy and 8 patients (6.4%) received chemotherapy. Median age was 55 years. Median follow-up time was 40 months, and minimum follow-up time was 24 months. The data were analyzed for site of first relapse, survival, overall incidence of complications, and incidence of grade 4 complications. RESULTS: The overall 5-year survival was: Stage IA: 100%, Stage IB: 72%, Stage IIA: 90%, and Stage IIB: 72%. The 5-year survival with no evidence of disease (NED) was: Stage IA: 100%, Stage IB: 67%, Stage IIA: 90%, and Stage IIB: 50%. Patients with bulky (> 5 cm) tumors had a shorter overall and NED survival than patients with nonbulky tumors (53% vs. 83%; p = 0.0008 and 44% vs. 78%; p = 0.0001, respectively). Thirty-nine tumor recurrences (39 out of 125 = 31%) occurred and were scored as local (23 out of 125 = 18.3%), if initial failure had a local component, or distant (16 out of 125 = 12.7%), if initial failure was distant only. Patients with bulky (more than 5 cm) tumors (32 out of 125) were more likely to experience a recurrence (18 out of 32 = 56%) than patients with nonbulky tumors (21 out of 93 = 22%; p = 0.0004). The initial site of recurrence was more likely to be local for bulky tumors (14 out of 18 = 78%) than for nonbulky tumors (9 out of 21 = 43%; p = 0.03). The probability of a recurrence increased with the number of involved parametria (none: 20 out of 78 = 25%; one: 12 out of 34 = 35%; two: 7 out of 13 = 54%; p = 0.04 for linear trend), as did the probability that the initial failure was distant rather than local (none: 4 out of 20 = 20%; one: 7 out of 12 = 58%; two: 5 out of 7 = 71%; p = 0.01 for linear trend). Positive lymph nodes, vessel invasion, and low hemoglobin level all correlated with an increased risk of a recurrence (RR 2.41, p = 0.004; RR 2.20, p = 0.01; OR 2.02, p = 0.01, respectively). There were 46 complications among 37 (29%) patients. The incidence of grade 4 complications was 8.8% (11 out of 125). History of pelvic surgery and bulky tumor were significant predictors of a grade 4 complication (p < 0.0001 and 0.021, respectively). Also, a dose rate to point A of > 0.6 Gy/h increased the chance of a grade 4 complication (p = 0.007). CONCLUSION: For patients with FIGO Stage I or II cervical carcinoma, tumor size was more predictive of local recurrence than was overall stage, and the extent of parametrial involvement was strongly predictive of distant recurrence, as was the stage. These findings suggest that tumor size and extent of parametrial involvement should be incorporated into the staging system. Patients with bulky tumors had a shorter survival and were more likely to experience a grade 4 toxicity of therapy. Dose rate to point A of > 0.6 Gy/h was associated with the increased risk of grade 4 complications.

Allelic loss at 7q31.1 in human primary ovarian carcinomas suggests the existence of a tumor suppressor gene.

We studied loss of heterozygosity (LOH) in chromosome 7q in order to determine the location of a putative tumor suppressor gene (TSG) in human epithelial ovarian carcinomas. Samples were obtained from 26 primary ovarian carcinomas at the time of staging laparotomy. Paired normal and tumoral DNAs were used as templates for polymerase chain reaction amplification of a set of 14 (C-A)n microsatellite repeats on 7q21-qter. All the cases studied presented LOH at one or more loci on 7q. Seventy-three percent LOH (in 14 of 19 informative cases) were detected in D7S522 at 7q31.1. The percentages of LOH were normally distributed around microsatellite D7S522 determining a smallest common deleted region of 1 cM. The high incidence of LOH in primary ovarian carcinomas suggests that a TSG relevant to the development of ovarian cancers is present at 7q31.1, confirming our previous functional evidence for a TSG in this region.

Molecular genetic changes associated with ovarian cancer.

Multiple specific chromosomal deletions can be found in human epithelial ovarian cancer by cytogenetic analysis or molecular techniques. Somatic allelic deletion or loss of heterozygosity (LOH) in a tumor is considered circumstantial evidence for the location of tumor suppressor genes. We have examined 27 primary epithelial ovarian tumors for the presence of LOH at 19 polymorphic markers on chromosomes 1, 5, 6, 9, 11, 13, and 17. Markers near the adenomatous polyposis coli (APC) gene at 5q21 showed LOH in 50% (10/20) of informative cases. LOH was seen in 53% (8/15) at the IFNA locus on 9p, another region implicated in other tumors, but not previously associated with ovarian cancer. We observed LOH for markers on 11p15 in 50% (12/24) of ovarian cancer DNAs from informative cases, while only 25% (4/16) at 11q13 and 29% (5/17) at 11q24 showed LOH. Only a portion of distal 11p was deleted in six cases. The incidence of LOH (50%) at HGH (17q22-q24) was greater than that at D17S579 (39%; 17q21), a locus tightly linked to BRCA1. Sixty-four percent (7/11) showed allelic loss at 17p11. LOH was infrequently observed at markers on chromosomes 1, 6, and 13q. Most cases showing LOH were stage III or IV, and most showed LOH at more than one locus. These studies support the concept that multiple genetic loci are involved in ovarian tumorigenesis. Two additional regions thought to harbor genes important in other cancers, 5q21 and 9p21, can now be added to the growing spectrum of molecular alterations seen in ovarian cancer.

Second-look laparotomy in ovarian germ cell tumors: the gynecologic oncology group experience.

The Gynecologic Oncology Group (GOG) experience with second-look laparotomy in malignant ovarian germ cell tumors is reviewed. All patients in this study were enrolled prospectively on one of three protocols that employed relatively brief cisplatin-based chemotherapy after initial surgical staging and cyto-reduction. Forty-five surgical procedures were done in patients who received three courses of cisplatin-based adjuvant therapy after complete tumor resection. Findings were no tumor or mature teratoma in 43; 2 patients had immature teratomas. One of the latter patients received further chemotherapy and one did not. Both of these patients and 44 of the total are disease free. Seventy-two patients were treated with similar chemotherapy for advanced incompletely resected tumor. Forty-eight of these patients did not have teratoma elements in their primary tumor. At surgery, 45 patients had no tumor and 3 had persistent endodermal sinus tumor or embryonal carcinoma. All three of the latter patients are dead despite further treatment. Twenty-four patients had teratoma elements in their primary tumor. Of these patients, 16 had mature teratoma at second-look, which in 7 was bulky or progressive. Fourteen of the total 16 and 6 of the 7 with bulky residual tumor remain disease free after surgical resection. Second-look laparotomy is not necessary in patients completely resected initially or in those patients with advanced tumor that does not contain teratoma. However, enough patients with incompletely resected tumor which initially contains elements of teratoma benefit from the procedure to warrant its general use.

Persistence of gestational trophoblastic disease for longer than 1 year following evacuation of hydatidiform mole.

BACKGROUND: A spontaneous fall in the radioimmunoassay for the beta subunit of hCG to less than 2 mIU/mL documents regression of hydatidiform mole following evacuation of a molar pregnancy. Continued negative hCG levels for the year after evacuation indicates the absence of risk for persistent gestational trophoblastic disease. This report describes an unusual case of recurrent nonmetastatic gestational trophoblastic disease 16 months after initial evacuation. CASE: A 29-year-old woman presented at 19 weeks' gestation with severe preeclampsia and vaginal bleeding. Pelvic ultrasonography demonstrated a molar pregnancy. Pathology following uterine evacuation confirmed a hydatidiform mole. Serial hCG levels fell progressively to less than 2 mIU/mL over the following 25 weeks. She remained compliant with oral contraceptive pills despite having no sexual activity. Sixteen months after uterine evacuation, recurrence of gestational trophoblastic disease was documented by a rising beta-hCG, negative pelvic ultrasound, normal liver function tests, and normal computed tomography of the head. Endometrial curettage showed no chorionic villi or molar tissue. She was treated with five courses of actinomycin D and has remained disease-free for the following 5 years. CONCLUSION: This late recurrence of gestational trophoblastic disease suggests that those with a molar pregnancy may benefit from surveillance beyond 1 year after uterine evacuation.

The efficacy of an automated preparation device for cervical cytology.

A new automated method for collecting and preparing cells for cytologic screening (termed the ThinPrep process) was tested. Four hundred forty-nine specimens prepared by ThinPrep and conventional methods were evaluated. This study compared specimen adequacy and detection of disease with the two methods. For the ThinPrep method, exfoliated cells were collected in suspension, gently dispersed, collected on a polycarbonate filter, and transferred to a glass slide. The ThinPrep method reduced the number of smears that lacked endocervical columnar cells by 24%. Significant improvement with the ThinPrep, versus the conventional method, also was found for detection of low-grade cervical intraepithelial lesions. Thus, the ThinPrep method improved specimen quality and reliability of cytologic detection of cervical neoplasia.

Contextual analysis and intermediate cell markers enhance high-resolution cell image analysis for automated cervical smear diagnosis.

Until now, efforts to automate cervical smear diagnosis have focused on analyzing features of individual cells. In a complex specimen such as that obtained from a cervical scrape, diagnostically significant cells may not be adequately represented or may elude detection by the automated technology. An approach is needed that extracts additional quantitative information from cervical smears beyond what the cell-by-cell approach can provide. A new methodology, contextual analysis, was developed to extract global quantitative information about cells, cell clusters, and background debris. This pilot study was designed to compare the efficacy of contextual analysis with high-resolution, single cell analysis and the analysis of intermediate cell markers. Thirty-four samples prepared as monolayers and stained with the Feulgen-Thionin/Congo Red stain were measured. Contextual analysis alone was able to classify 91% of the smears correctly; single cell analysis classified 94% of the cells correctly; and the intermediate cell analysis correctly identified the smear diagnosis for 84% of the cells. When all three analysis methods were combined into a simple smear level classifier, the overall smear classification accuracy was improved over those obtained using the three methodologies alone.

Uterine thickness determination using real-time ultrasonography: a guide for intracavitary brachytherapy in the treatment of endometrial carcinoma.

Two patients with medically inoperable stage I endometrial carcinoma were treated with intracavitary implants alone using Simon capsules, tandems, and ovoids. In both cases, uterine thickness was measured during the implant procedure by realtime ultrasonography. Tumor doses in both patients were then calculated to the midmyometrium and to the serosal surface of the uterus. These estimates, rather than the usual milligram-hours or points A and B, were used to make treatment decisions.

Ultrasound for diagnosing and preventing malplacement of intrauterine tandems.

Postoperative B-mode ultrasound was used to evaluate final tandem position in 50 consecutive placements (28 patients). In 34% (17 of 50), the tandem was found to be suboptimally positioned; in 24% (12 of 50), it penetrated the myometrium; and in 10% (five of 50), it frankly perforated the uterus. The uterine fundus was the region most commonly perforated, and the anterior myometrium was the site most frequently penetrated. In all cases in which postoperative ultrasound showed malpositioning, the clinical and radiographic assessment indicated proper intracavitary placement. Ultrasound affected clinical management in 42% (21 of 50) of the placements involving 61% (17 of 28) of the patients. To improve tandem placement, we used intraoperative real-time ultrasound to guide 73 consecutive surgical insertions. Ultrasound clearly visualized the procedure, allowing tandems to be positioned with confidence even in the most difficult cases. The immediate feedback from intraoperative ultrasound eliminated malplacements and thus the need for a second anesthesia to reposition the tandem.

Intraoperative real-time ultrasonography during intrauterine tandem placement.

Real-time ultrasound is used in the operating room as an aid in the placement of the intrauterine tandem. This method provides excellent imaging of the ongoing procedure, facilitating final tandem placement in the endometrial cavity even in the most difficult case.