Biomedical subjects

S K Chambers

Publications and source records attributed to S K Chambers.

At least 19 recordsLinked to original sources

PubMed2004

Patients with uterine papillary serous cancers may benefit from adjuvant platinum-based chemoradiation.

OBJECTIVE: The coexistence of minimal uterine disease and extrauterine metastases is common in patients with uterine papillary serous carcinoma (UPSC). Only complete surgical staging accurately depicts the extent of this disease. The purpose of this study was to evaluate different therapeutic options in surgically staged patients. METHODS: We retrospectively reviewed all patients with UPSC histologically limited in the uterus to the endometrium treated at our institution between 1987 and 2002. RESULTS: Twenty-three (45%) cases were International Federation of Gynecology and Obstetrics (FIGO) stage IA, seven (15%) were stage IIIA, one (2%) was stage IIIC, and nine (18%) stage IV. Additionally, 11 of these 51 patients (21%) were diagnosed with two cancers: a stage IA UPSC and concomitant advanced stage serous cancer of the ovary, fallopian tube, or peritoneum. Stage IA patients with no cancer in the hysterectomy specimen (defined as no residual uterine disease) had no recurrences (n = 10) regardless of treatment. There was a trend toward increased survival in stage IA patients with residual uterine disease who were treated with chemoradiation (concomitant vaginal brachytherapy and platinum-based chemotherapy). There were no recurrences in patients with locoregional disease (stages IA-IIIA) who received chemoradiation. All patients with advanced stage UPSC (stage IIIC or IV or two primary cancers) did poorly regardless of treatment. CONCLUSION: Our findings suggest that stage IA patients with no residual uterine disease may be observed. Stage IA patients with residual uterine disease may benefit from chemoradiation. More effective treatment needs to be identified for advanced stage UPSC.

Aged↗

PubMed2001

The activated macrophage colony-stimulating factor (CSF-1) receptor as a predictor of poor outcome in advanced epithelial ovarian carcinoma.

OBJECTIVE: We have previously shown that the macrophage colony-stimulating factor receptor (CSF-1R) and its ligand, CSF-1, together predict poor prognosis in epithelial ovarian carcinoma. The activated or phosphorylated form of CSF-1R (CSF-1Rphos) has been associated with enhanced invasive and metastatic potential. Our goal is to correlate CSF-1Rphos with known prognostic factors and to determine its role in predicting outcome in advanced ovarian cancer. METHODS: One hundred forty-two primary and forty-seven metastatic epithelial ovarian tumors from 98 patients were immunohistochemically stained using antibodies PY809 and PY723 against their respective tyrosine residues associated with local invasiveness and metastasis. chi2 analysis was used to correlate CSF-1Rphos staining and previously studied prognosticators within each group. Kaplan-Meier curves of survival were comparedusing the log-rank test with significance of P < 0.05. RESULTS: Forty-seven and nine-tenths percent (68/142) of primary tumors and forty-eight and nine-tenths percent (23/47) of metastatic tumors stained positive for PY809 and PY723, respectively. The PY809+ group was strongly associated with CSF-1R (P = 0.015) as was the PY723+ group (P = 0.025) in its respective subset. CSF-1Rphos by itself was not a predictor of survival or disease-free interval (DFI) in either the primary or metastatic group. However, when combined with CSF-1R in the metastatic group, the two together predicted worse survival (P = 0.007) and decreased DFI (P = 0.011). CONCLUSIONS: Phosphorylated tyrosine kinase receptors are detectable in a significant number of ovarian tumors. Staining strongly correlates with CSF-1R. PY723+ metastases coexpressing CSF-1R portend a highly significant decrease in survival and increased risk of recurrence which may serve to identify high-risk ovarian cancer patients.

Antibodies↗

PubMed2000

Cystic pelvic pathology presenting as falsely elevated post-void residual urine measured by portable ultrasound bladder scanning: report of 3 cases and review of the literature.

Dedicated portable ultrasound devices generally offer a rapid, noninvasive, largely operator-independent means of assessing post-void residual urine (PVR) volume. In most published series, PVR measured by portable ultrasound correlates well with catheterized urine volume. We report 3 cases in which follow-up of falsely elevated PVR measurements on ultrasound resulted in comparatively low catheterized volumes. In all 3 cases, the elevated readings were due to cystic ovarian pathology, which was diagnosed by formal radiologic evaluation and ultimately confirmed operatively in 2 cases. Cystic pathology of the pelvis or lower abdomen may present as an elevated PVR on ultrasound and low urine volume on subsequent catheterization and should prompt further evaluation.

Adult↗

PubMed1999

Adenocarcinoma in situ of the cervix: management and outcome.

OBJECTIVE: The aim of this study was to review the management and outcome of patients with adenocarcinoma in situ of the cervix and to evaluate the significance of endocervical cone margin status in these patients. METHODS: A retrospective review of records between January 1988 and December 1996 identified 40 patients with adenocarcinoma in situ on cone biopsy for whom complete information was available. The median follow-up was 38 months. RESULTS: The mean age was 37 years, and the mean parity was 1.3. Fifty-three percent of the patients had prior abnormal cervical cytology. The initial Pap smear that led to the patient's referral was abnormal in 39 (98%). Initial cervical biopsies showed adenocarcinoma in situ and/or glandular dysplasia in 28 (70%), squamous dysplasia in 2 (5%), chronic inflammation in 2 (5%), and no pathologic changes in 2 (5%) patients. Initially no biopsies were performed in 3 (7.5%) patients and the results of 3 (7.5%) biopsies were unknown. Subsequently, all patients had cone biopsies. The endocervical margins were positive for glandular abnormalities in 24% of cold knife cones (CKC), 75% of LEEPs, and 57% of laser cones. The ectocervical margins were positive for squamous and/or glandular abnormalities in 8% of CKCs, 13% of LEEPs, and 57% of laser cones. ECCs above the cone were obtained in 28 patients, and only 1 (3%) was positive. The definitive treatment was hysterectomy in 27, repeat cone in 5, and no additional therapy in 8 patients. The pathology showed residual disease in 44% of treated patients. From 16 cone biopsies with negative margins who had subsequent treatment, there was residual disease in 5 (31%) specimens (1 adenocarcinoma in situ, 1 mild glandular dysplasia, 3 glandular atypia). From 16 cones with positive margins who had subsequent treatment, there was residual disease in 9 (56%) specimens. The patients with negative ECCs above the cone regardless of margin status had residual disease in 58% of treated specimens. CONCLUSION: Women with adenocarcinoma in situ of the uterine cervix had residual disease in 31% of cases with negative margins in cone biopsies and/or with negative ECCs and in 56% of cases with positive endocervical margins. LEEP cones had higher rate of positive endocervical margins (75%) compared to CKC (24%) and laser cone (57%). If maintaining reproductive capacity is desired, we would recommend CKC; however, this does not guarantee absence of the disease.

Adenocarcinoma↗

PubMed1998

Plasminogen activator inhibitor-1 is an independent poor prognostic factor for survival in advanced stage epithelial ovarian cancer patients.

High levels of plasminogen activator inhibitor-1 (PAI-1) in tissue extracts have been associated with poor prognosis in many epithelial cancers. Ovarian cancers contain a higher concentration of PAI-1 than benign ovarian tumors or normal ovaries. Reports, however, on the prognostic value of PAI-1 content in ovarian cancers have been conflicting. We used immunohistochemistry to study the primary and metastatic tissues from 131 epithelial ovarian cancer cases. This group has been previously characterized for the expression of urokinase (uPA), uPA receptor, PAI-2 and macrophage colony-stimulating factor (CSF-1). The intensity and extent of staining for PAI-1 in the tumor epithelium was scored. Kaplan-Meier curves of survival were compared using the log-rank test. The Cox regression model was utilized for multivariate analysis. Approximately 50% of the primary tumors and metastases expressed PAI-1. Among invasive stages III and IV patients, those whose primary tumors expressed PAI-1 had a shorter overall survival. The combination of strong expression of PAI-1 and expression of uPA was a highly significant factor for short disease-free and overall survival. Similar results were seen with the combination of high PAI-1 and low PAI-2 expression. Strong PAI-1 expression was significantly associated with expression of uPA receptor or CSF-I in the tumor epithelium, but not with standard clinical parameters, and was an independent prognostic factor for poor survival on multivariate analysis. Our results show that PAI-1 expression in the primary tumor epithelium is an independent poor prognostic factor for survival, underscoring the tumor protective role of PAI-1 in ovarian cancer biology.

Biomarkers, Tumor↗

PubMed1998

CA 125 may not reflect disease status in patients with uterine serous carcinoma.

BACKGROUND: Although CA 125 level correlates with response to therapy in patients with serous carcinoma of the ovary, the utility of CA 125 in patients with high risk or metastatic endometrial carcinoma has not been established. METHODS: CA 125 was tested as a marker of disease status in patients with endometrial serous carcinoma (SC) undergoing adjuvant chemotherapy. All patients received monthly intravenous chemotherapy with cisplatin, cyclophosphamide, and doxorubicin at standard doses (median number of courses, 6; range, 2-8 courses). Serum CA 125 was measured at diagnosis and before each course. After the completion of chemotherapy, patients were examined every 3 months and the CA 125 level was measured. RESULTS: A total of 220 serum specimens from 15 patients with invasive SC were analyzed. All five patients who died of disease had clinical or radiographic evidence of tumor, which CA 125 elevation did not precede or predict. One patient with advanced disease at staging never had an elevated CA 125 level but died of disseminated disease 14 months after diagnosis. At last follow-up, 3 patients who were without evidence of disease > 36 months from diagnosis had significant false-positive elevations in their CA 125 level (>50 u/mL) lasting 1, 2, and 4 months, respectively, during therapy. The sensitivity for advanced disease was only 57% at presentation. CONCLUSIONS: CA 125 may reflect advanced stage disease and portend a poor prognosis, but may not add information to that gained by history and physical examination, preoperative studies, or surgery that already is mandated by this high risk histology. This circulating marker appears to have limited utility in monitoring the effects of adjuvant therapy for SC, and may not predict recurrence in the absence of other clinical findings.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

Effective treatment of stage I uterine papillary serous carcinoma with high dose-rate vaginal apex radiation (192Ir) and chemotherapy.

PURPOSE: Uterine papillary serous carcinoma (UPSC) is a morphologically distinct variant of endometrial carcinoma that is associated with a poor prognosis, high recurrence rate, frequent clinical understaging, and poor response to salvage treatment. We retrospectively analyzed local control, actuarial overall survival (OS), actuarial disease-free survival (DFS), salvage rate, and complications for patients with Federation International of Gynecology and Obstetrics (FIGO) (1988) Stage I UPSC. METHODS AND MATERIALS: This retrospective analysis describes 38 patients with FIGO Stage I UPSC who were treated with the combinations of radiation therapy, chemotherapy, total abdominal hysterectomy, and bilateral salpingo-oophorectomy (TAH/BSO), with or without a surgical staging procedure. Twenty of 38 patients were treated with a combination of low dose-rate (LDR) uterine/vaginal brachytherapy using 226Ra or 137Cs and conventional whole-abdomen radiation therapy (WART) or whole-pelvic radiation therapy (WPRT). Of 20 patients (10%) in this treatment group, 2 received cisplatin chemotherapy. Eighteen patients were treated with high dose-rate (HDR) vaginal apex brachytherapy using 192Ir with an afterloading device and cisplatin, doxorubicin, and cyclophosphamide (CAP) chemotherapy (5 of 18 patients). Only 6 of 20 UPSC patients treated with combination LDR uterine/vaginal brachytherapy and conventional external beam radiotherapy underwent complete surgical staging, consisting of TAH/BSO, pelvic/para-aortic lymph node sampling, omentectomy, and peritoneal fluid analysis, compared to 15 of 18 patients treated with HDR vaginal apex brachytherapy. RESULTS: The 5-year actuarial OS for patients with complete surgical staging and adjuvant radiation/chemotherapy treatment was 100% vs. 61% for patients without complete staging (p = 0.002). The 5-year actuarial OS for all Stage I UPSC patients treated with postoperative HDR vaginal apex brachytherapy and systemic chemotherapy was 94% (18 patients). The 5-year actuarial OS for Stage I UPSC patients treated with HDR vaginal apex brachytherapy and chemotherapy who underwent complete surgical staging was 100% (15 patients). The 5-year actuarial OS for the 20 Stage I UPSC patients treated with combinations of pre- and postoperative LDR brachytherapy and postop WART was 65%. None of the 6 surgically staged UPSC patients treated with LDR radiation and WART/WPRT developed recurrent disease. For patients with FIGO Stage IA, IB, and IC UPSC who underwent complete surgical staging, the 5-year actuarial DFS by depth of myometrial invasion was 100, 71, and 40%, respectively (p = 0.006). The overall salvage rate for local and distant recurrence was 0%. Complications following HDR vaginal apex brachytherapy included only Radiation Therapy Oncology Group (RTOG) grade 1 and 2 toxicity in 16% of patients. However, complications from patients treated with WART/WPRT, and/or LDR brachytherapy, included RTOG grade 3 and 4 toxicity in 15% of patients. CONCLUSION: Patients with UPSC should undergo complete surgical staging, and completely surgically staged FIGO Stage I UPSC patients can be effectively and safely treated with HDR vaginal apex brachytherapy and chemotherapy. Both OS and DFS of patients with UPSC are dependent on depth of myometrial invasion. The salvage rate for both local and distant UPSC recurrences is extremely poor. Complications from HDR vaginal apex brachytherapy were minimal.

Adult↗

PubMed1998

The gynecologic oncology model: research.

Research in gynecologic oncology has been increasingly emphasized over the last decade. The formal training within this subspecialty has expanded to include quality research, both clinical and laboratory science, as an integral part. There have also been recent major advances in the laboratory and clinical based understanding of the genetics, biology, and treatment of gynecologic cancers. Despite the fiscal constraints of the 1990s that have impacted the ability of the clinician scientist to balance the responsibilities of research, teaching, and patient care, there are ongoing attempts to improve the research environment for physician scientists in this field.

Certification↗

PubMed1997

Expression of plasminogen activator inhibitor-2 in epithelial ovarian cancer: a favorable prognostic factor related to the actions of CSF-1.

In ovarian cancer cells, the macrophage colony-stimulating factor-1 (CSF-1) induces the release of plasminogen activator inhibitor-2 (PAI-2), and high levels of PAI-2 as well as of CSF-1 in ovarian cancer ascites are independently correlated with poor outcome. We now study the effect of CSF-1 on PAI-2 expression in vitro and the significance of cellular PAI-2 expression in vivo. Immunohistochemical detection of PAI-2 was studied in primary and metastatic tissues from 130 epithelial ovarian cancer cases. Kaplan-Meier curves of survival were compared with the results of log-rank test. The Cox regression model was used for multivariate analysis. The effect of CSF-1 on PAI-2 expression in ovarian cancer cells was also examined in vitro. Fifty-eight percent of the primary tumors and 68% of the metastases expressed PAI-2. PAI-2 expression in the metastases of invasive stages III and IV cases was strongly predictive of a prolonged disease-free and overall survival. This finding was associated with low residual disease and was also an independent factor for disease-free survival. In vitro, CSF-1 treatment of ovarian cancer cells resulted in a decrease in cellular staining for PAI-2 while increasing the release of PAI-2 into the conditioned medium. In vivo, we also found an inverse correlation between expression of CSF-1 and that of PAI-2 in the primary tumors. We thus describe the favorable independent prognosis of cellular PAI-2 expression in the metastases of ovarian cancer. Moreover, an inverse correlation was observed between CSF-1 and PAI-2 expression in vivo. This lends support for a primary role of cell-surface (vs. secreted)-mediated events of plasminogen activation in the development of invasive, poor prognostic phenotypes.

Epithelium↗

PubMed1997

Pharmacokinetic and phase I trial of intraperitoneal carboplatin and cyclosporine in refractory ovarian cancer patients.

PURPOSE: The feasibility and pharmacokinetics of cyclosporine (CsA) delivered intraperitoneally (IP) have not been previously explored. We performed a pharmacokinetic study of IP CsA followed by a phase I dose-escalation trial of the combination of IP CsA and carboplatin in refractory ovarian cancer patients. PATIENTS AND METHODS: A pilot study was performed of three patients who received 1, 10, and 20 mg/kg IP CsA alone. Subsequently, a phase I trial of 35 patients was performed between April 1990 and April 1993. Whole-blood and IP fluid CsA concentrations were measured at serial time points. The highest dose delivered IP was 34.6 mg CsA/kg in combination with carboplatin (250 mg/m2 or 300 mg/m2, depending on creatinine clearance), which was not dose-escalated. The area under the concentration-time curve (AUC) for CsA and half-life (T1/2) were calculated. Objective and serologic responses were noted, and toxicity was graded using the National Cancer Institute common toxicity criteria. RESULTS: The feasibility of delivering IP CsA alone was established. We observed a 1,000:1 ratio between IP fluid and blood concentrations at 20 mg CsA/kg. Pharmacokinetic analysis confirmed that at 20 mg CsA/kg, there was an IP fluid-to-blood AUC ratio of 600:1 in favor of peritoneal exposure. At the highest dose delivered, 34.6 mg CsA/kg, the mean IP CsA levels of 1,110 micrograms/ mL were tolerated moderately well and the IP fluid-to-blood ratio of 1,000:1 was maintained. Blood and IP CsA concentrations were analyzed in the presence and absence of IP carboplatin. At 20 mg CsA/kg, there was no difference in either mean blood CsA levels (0.9 microgram/ mL) or mean IP CsA concentrations (1,000 micrograms/mL) obtained in the absence or presence of carboplatin. The most common toxicity in the phase I study was anemia, seen in 66% of patients. Common toxicities at the maximum CsA dose delivered (34.6 mg/kg) were anemia, leukopenia, thrombocytopenia, and hypertension. In this trial, three objective responses (two complete and one partial) were observed for a duration of 3 to 11 months. Control of platinum-resistant ascites was an important feature, noted in five of eight patients. CONCLUSION: We have established the feasibility of delivering IP CsA up to doses of 34.6 mg/kg in conjunction with carboplatin, and the sustaining of IP fluid to blood ratios of 1,000:1. The IP administration of CsA resulted in a favorable ratio of exposure for the peritoneal cavity compared with systemic exposure, indicating a therapeutic advantage of this approach with a significant decrease in systemic toxicity. We recommend that 34.6 mg/ kg of IP CsA be tested as a phase II dose in combination with carboplatin in refractory ovarian cancer patients. This report provides the groundwork for future studies using IP CsA, both as a chemomodulator of platinum and of multidrug resistance.

Antineoplastic Agents↗

PubMed1997

Overexpression of epithelial macrophage colony-stimulating factor (CSF-1) and CSF-1 receptor: a poor prognostic factor in epithelial ovarian cancer, contrasted with a protective effect of stromal CSF-1.

Markedly elevated levels of macrophage colony-stimulating factor (CSF-1) in the serum and ascites of epithelial ovarian cancer patients have been previously associated with a poor prognosis. However, measurements of circulating CSF-1 cannot separate CSF-1 originating in the cancer cell from that originating in stromal macrophage or fibroblast. To study the prognosis related to expression of CSF-1 and its receptor in primary and metastatic ovarian cancers and to compare the significance of epithelial versus stromal CSF-1 expression, an immunohistochemical study of 130 ovarian carcinomas was performed. Twenty-two stage I and II and 108 stage III and IV primary tumors were studied. Metastatic lesions were also studied in 96 of these 130 cases, 90 of which came from those cases with advanced-stage disease. The intensity and extent of staining for CSF-1 in epithelium and stroma and for epithelial CSF-1 receptor was scored. Kaplan-Meier curves of survival were compared with the log-rank test. The Cox regression model was used for multivariate analysis. In the primary tumors, there was strong expression of CSF-1 receptor in 65%, epithelial CSF-1 in 36%, and stromal CSF-1 in 22%. In the metastases, there was strong staining for CSF-1 receptor in 65%, epithelial CSF-1 in 41%, and stromal CSF-1 in 15%; strong staining for both CSF-1 receptor and epithelial CSF-1 was noted in 26% of the cases. When the metastases expressed both CSF-1 receptor and epithelial CSF-1 strongly, a significant decrease in disease-free survival in stage III invasive ovarian cancers was observe (P = 0.043), which was found to be an independent prognostic factor (P = 0.007), with an increased relative risk of recurrence of 2.3-fold. Although strong staining for stromal CSF-1 in the primary tumor was not found to have prognostic value, for all stages and for the subsets of stages III and IV and for stage III alone, the finding of any degree of stromal CSF-1 expression in the ovary was a favorable prognostic factor for disease-free (P = 0.046) and overall (P = 0.015) survival. This finding was associated with younger patients (P = 0.007) and low-grade tumors (P = 0.033) and was not an independent prognostic factor on multivariate analysis. Among the primary tumors, there was a significant association (P = 0.022) between stromal CSF-1 staining and lack of strong coexpression of CSF-1 receptor and epithelial CSF-1; 67 of 94 cases shared these features in the primary tumors. In the metastases of invasive stage III cases, strong staining for stromal CSF-1 was a favorable prognostic factor for overall survival in the absence of strong CSF-1 receptor staining (P = 0.033) and was associated with low-grade tumors (P = 0.0002). We report that strong expression of epithelial CSF-1 along with its receptor in the metastases of ovarian cancer patients appears to be a strong independent poor prognostic factor for outcome. We find that expression of the same cytokine (CSF-1) in the stroma of the primary tumors is associated with low-grade tumors and lack of strong coexpression of CSF-1 receptor and epithelial CSF-1, leading to an improved long-term outcome. This study may help explain the previous observations that elevated levels of CSF-1 in serum and ascites are associated with a worse prognosis in advanced ovarian cancer patients; the results suggest that the source of secreted CSF-1 may largely be the epithelium. The results of this study suggest that paracrine effects of stromal CSF-1 on tumor behavior contrast with those demonstrated when the tumor cell is capable of autocrine intracellular or extracellular interactions between CSF-1 and its receptor.

Age Factors↗

PubMed1996

Malignant uterine smooth muscle tumors: role of etoposide, cisplatin, and doxorubicin (EPA) chemotherapy.

BACKGROUND: Nearly 80% of patients with malignant uterine smooth muscle tumor will suffer local relapse and/or distant metastases after initial surgical resection. There is no convincing evidence that the addition of pelvic radiation improves the outcome. However, adjuvant chemotherapy might be an appropriate therapeutic modality. METHODS: Between 1986 and 1991, 13 consecutive patients with malignant uterine smooth muscle tumors were treated at Yale-New Haven Hospital with a combination chemotherapy containing etoposide 100 mg/M2 on days 1 and 2, cisplatin 50 mg/M2 on day 1, and doxorubicin 50 mg/M2 on day 1, repeated every 28 days. Six patients had Stage I disease, one patient had Stage III disease, and six patients had Stage IV disease. The number of cycles ranged from 2 to 9. RESULTS: The median follow-up was 30 months (range 4-81). The mean overall survival for the group was 43.1 +/- 6.7 months, with the progression-free interval of 25.5 +/- 8.0 months. Of the seven patients with evaluable disease, one patient had complete response and one had partial response (total response rate of 28.6%). Of the six patients treated adjuvantly, three recurred at 9, 33, and 59 months (recurrence rate of 50%). CONCLUSIONS: We conclude that this combination has only modest activity against malignant uterine smooth muscle tumors at the schedule and doses tested.

Adult↗

PubMed1996

Uterine papillary serous carcinoma treated with intraperitoneal cisplatin and intravenous doxorubicin and cyclophosphamide.

This study was designed to evaluate the efficacy of intraperitoneal cisplatin and intravenous doxorubicin and cyclophosphamide in patients with uterine papillary serous carcinoma. Sixteen patients with uterine papillary serous carcinoma underwent complete surgical staging and placement of an intraperitoneal port. Postoperatively, they received cisplatin (100 mg/m2) given intraperitoneally and doxorubicin (50 mg/m2) intravenously and cyclophosphamide (600 mg/m2) intravenously every 4 weeks for 6 cycles. The intraperitoneal ports did not function in 3 patients immediately following surgery. The remaining 13 patients constitute the study group. The patients ranged in age from 37 to 77 years. There were 1 patient with Stage IA, 3 with Stage IB, 2 with Stage IIB, 2 with Stage IIIA, 2 with Stage IIIC, 1 with Stage IVA, and 2 with Stage IVB. At the end of surgery no gross residual disease remained except for 1 patient who had less than 1-cm nodules in the peritoneal cavity. Eleven of the patients underwent 6 cycles of chemotherapy, 1 patient underwent 3 cycles, and 1 patient underwent 1 cycle. A total of 71 cycles of chemotherapy were given. All patients developed alopecia. Two patients developed neutropenic fever, one was treated with antibiotics, the other patient died from urosepsis. One patient had a > 15% decrease in left ventricular ejection fraction which led to a dose reduction of doxorubicin. One patient had a urinary tract infection and one patient developed a port infection which necessitated its removal. Seven patients have died, 1 is alive with disease, and 5 patients are alive with no evidence of disease. Five of the 7 patients with extrauterine disease have died of disease. One is alive with disease and the other is free of disease. The media survival of these patients was 34 months with an overall 3 years survival of only 24.1%. Although the protocol was reasonably well tolerated, the overall survival did not differ from that of a similar group of patients treated at our institution with intravenous chemotherapy. There was a high incidence of dysfunction of the intraperitoneal ports (25%). This approach with intraperitoneal cisplatin presents no therapeutic advantage for these patients.

Adult↗

PubMed1996

Radiation therapy as exclusive treatment for medically inoperable patients with stage I and II endometrioid carcinoma with endometrium.

From 1975 to 1992, 54 patients with clinical Stage I and II endometrioid carcinoma of the endometrium, representing 3.5% of all such patients, were deemed medically inoperable and exclusively received radiation therapy. A cohort of 108 operable patients adjusted for age, clinical stage, and grade served as a control group. The 5-year actuarial cancer-specific survivals for patients with Stage I inoperable, Stage 11 inoperable, Stage I operable, and Stage II operable disease were 80, 85, 98, and 100%. The corresponding 5-year overall survival rates were 30, 24, 88, and 85%. Inoperable patients had a median disease-free interval of 36 months for clinical Stage I and 50 months for Stage II disease versus 74.5 and 77 months for the operable patients (P = 0.001). Inoperable patients with Stage I disease had a median survival of 37 months versus 50 months for Stage II (P = NS), with only 7 (13%) of these patients dying with endometrial cancer. Operable patients had a median survival of 75 and 79 months in Stage I and II, respectively, with 14 patients dying with endometrial carcinoma (13%). Stage I and II inoperable patients had significantly shorter survival than operable patients (P < 0.0001). More deaths from intercurrent disease occurred within the inoperable Stage I group than with the operable group (28 of 32 vs 3 of 15, P < 0.0001). Inoperable patients had a significantly shorter overall survival and more deaths due to intercurrent disease than operable patients (P < 0.0001). However, inoperable patients who did not die from intercurrent disease had a median 5-year survival which approaches that of operable patients. Our study demonstrates that exclusive radiation therapy is a well-tolerated and effective treatment for medically inoperable patients.

Adult↗

PubMed1996

Combination chemotherapy with etoposide, cisplatin, and doxorubicin in mixed müllerian tumors of the adnexa.

Eleven patients with ovarian (9) or fallopian tube (2) mixed müllerian tumors who underwent primary surgery at Yale New Haven Medical Center between 1986 and 1994 were treated with etoposide, cisplatin, and doxorubicin. Responses were observed in three (60%) of five evaluable patients with two complete (40%) and one partial (20%) response. Median survival time was 17 months with an estimated 3-year survival of 18%. Survival may have been improved with earlier stage disease, but survival was not significantly improved with optimal surgical cytoreduction in patients with advanced disease. Four patients required dose reductions for myelosuppression and there was one treatment related death. Toxicity was comparable to other combination chemotherapy regimens. EPA has modest therapeutic activity in ovarian and fallopian tube MMT.

Aged↗

PubMed1996

Parametrial involvement, regardless of nodal status: a poor prognostic factor for cervical cancer.

OBJECTIVE: To evaluate the effect of resection of central disease when the parametria are involved by tumor in high-risk stage I cervical cancer patients. METHODS: Thirty-two patients with high-risk stage I cervical cancer who underwent radical hysterectomy and had pathologic findings of positive lymph nodes (N = 13), positive parametria (N = 7), or both (N = 12) were identified retrospectively. The effects of various histopathologic findings on disease-free interval and survival were evaluated, including the effect of resection of central disease with and without positive nodal disease. Kaplan-Meier survival curves were compared with the log-rang test. Multivariate analyses using a stepwise regression model were performed. RESULTS: Compared with other histologies, adenocarcinoma was associated with a significantly shorter disease-free interval (P = .037). Among patients with parametrial involvement lymph node status did not affect disease-free interval or survival. However, when patients with positive lymph nodes were examined, the additional finding of parametrial positivity significantly worsened both disease-free interval (P = .039) and survival (P = .036). When the 19 patients with positive parametria, regardless of lymph node status, were compared with those with positive lymph nodes alone, the former group had a significantly shorter disease-free interval (P = .038). The tumor recurred in 12 of these 19 patients; all cases involved the pelvis, with a median time to recurrence of 15 months. Multivariate analysis showed that adenocarcinoma histology (P = .038) and parametrial involvement (P = .043) were independent, poor prognostic indicators for disease-free interval. CONCLUSION: Involvement of the parametria, regardless of lymph node status, and adenocarcinoma histology confer a poor prognosis in high-risk patients undergoing radical hysterectomy. Caution should be used when contemplating resection of bulky tumors as part of primary therapy if the parametria appear to be involved by tumor.

Adenocarcinoma↗

PubMed1996

Modulation of platinum sensitivity and resistance by cyclosporin A in refractory ovarian and fallopian tube cancer patients: a phase II study.

Our objective was to assess the activity of cyclosporin A (CsA) used as a chemomodulator of carboplatin in refractory ovarian and fallopian tube cancer patients. Fifty-one patients (47 epithelial ovarian, 1 ovarian mixed mesodermal tumor, and 3 fallopian tube carcinomas) were enrolled in a prospective Phase II trial of CsA and carboplatin. CsA was infused as a loading dose of 10 mg/kg over 5 h, followed by carboplatin infused over 30 min at an AUC of 6 mg/ml x min, then a 24-h continuous infusion of 11.6 mg/kg CsA. The patients received this protocol as second- to sixth-line therapy and had received between 1 and 3 prior platinum-based regimens. Eight patients received more than six cycles every 28 days, 34 patients received three to six cycles; and 9 patients received only one or two cycles. Thirty-eight patients were evaluable for objective response, and in an additional nine patients, CA-125 was the only marker of response. Four patients had no marker of disease. Of evaluable patients, 74% were platinum resistant. There were nine objective responses (one complete and eight partial responses) for an overall response rate in evaluable patients of 24%, with a median duration of response of 7 months (range, 3-38+ months). No responses were seen in patients who had received only one or two cycles of therapy. Among the strictly defined platinum-resistant patients, there was an overall 14% response rate, including one partial response seen after five prior regimens of chemotherapy including paclitaxel, and one ongoing complete response for 38+ months. Among the rest of the patients (those who were potentially platinum sensitive), there was an overall 50+ response rate; four of five responses were seen in patients with a platinum-free interval of <24 months, with only one response seen in a patient with a platinum-free interval of >24 months. Of evaluable patients, 34% had stable disease for a duration of 3-19 months. The most common grade 3 or 4 toxicity, thrombocytopenia, was seen in 22% of the patients. Hypertension, which responded to medications, was seen in 18% of the patients during the CsA infusion. We concluded that this CsA/carboplatin regimen is active in potentially platinum-sensitive patients and compares well with the expected response rate of 30% in patients with a platinum-free interval <24 months who are retreated with platinum. Moreover, this regimen had modest but real activity in platinum-resistant patients.

Adult↗

PubMed1996

Phase I trial of intravenous carboplatin and cyclosporin A in refractory gynecologic cancer patients.

Our objective was to determine the maximum tolerated dose of cyclosporin A (CsA) delivered as a loading dose (LD) and continuous i.v. infusion (CI) in combination with carboplatin in patients with refractory gynecologic cancers. Twenty-nine heavily pretreated patients (25 ovarian epithelial, 2 cervical, and 2 endometrial carcinomas) received 113 cycles of CsA and carboplatin from September 1989 to September 1991. Twenty-four of these 29 carcinomas were strictly defined to be platinum resistant. CsA was administered as a LD escalated from 6 to 10 mg/kg followed by a 24-h CI from 2.5 to 14.5 mg/kg/day. Carboplatin was targeted to an area under the time versus concentration curve (AUC) of 6 mg/ml x min and was not dose escalated. Whole-blood CsA concentrations (fluorescence polarization immunoassay) at the maximum tolerated dose (10 mg/kg LD, 14.5 mg/kg/day CI) ranged from 2.4 to 3.0 microgram/ml over 12 h. Estimated median carboplatin AUC, based on calculated carboplatin clearance, was 7.9 mg/ml x min. The dose-limiting toxicity of the combination of CsA and carboplatin was grade 4 thrombocytopenia. Grade 3 or 4 thrombocytopenia occurred in 35% of the patients, which could be explained by the effects of carboplatin (AUC of 6 mg/ml x min) alone. Overall, neutropenia occurred in 24% of the patients and anemia in 17% of the patients. Grade 3 or 4 nausea or vomiting was noted in 10 and 14% of the patients, respectively. Grade 3 hypertension during CsA administration occurred in 14% of the patients. No grade 3 or 4 nephrotoxicity was seen in this trial. Three objective responses were noted: one complete response (11 months) and one partial response (5 months), both in potentially platinum-sensitive patients with platinum-free intervals of only 9 months each. One platinum-resistant patient had a partial response for 21 months. Five additional patients experienced >75% reduction of CA-125 or a return to a normal CA-125 titer. We concluded that whole-blood CsA concentrations of >3.0 microgram/ml (as seen when CsA is used as a modulator of multidrug resistance) were not achievable in this combination with carboplatin in this population of heavily pretreated gynecologic cancer patients. However, because CsA is used in this trial as a chemosensitizer in platinum-sensitive tumors and as a chemomodulator of platinum resistance, we targeted a CsA concentration of >1.0 microgram/ml, which was achieved. The CsA dose recommended for a Phase II trial of this combination is 10 mg/kg LD and 11.6 mg/kg/day CI, which results in blood CsA concentrations ranging from 1.2 to 1.3 microgram/ml over 12 h. Responses in this population of refractory gynecologic cancer patients are unusual, and these encouraging results form the basis for a Phase II trial of this combination.

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