Adjuvant therapy for early-stage ovarian cancer.
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Combined Modality Therapy↗
Biomedical subjects
J S Berek
Publications and source records attributed to J S Berek.
Phase II study of N-methylformamide (N-MF) (NSC 3051) in patients with advanced epithelial ovarian cancer. A Gynecologic Oncology Group study.
Forty-four patients with advanced, measurable, epithelial carcinoma of the ovary were treated with 97 courses of N-methylformamide (N-MF) at doses ranging from 600-800 mg/m2, intravenously, daily for 5 days every 28 days. Forty-one patients had prior surgery and had received one prior chemotherapy regimen. Only seven patients had received any prior radiation therapy. All patients were Gynecologic Oncology Group (GOG) performance status 0, 1, or 2. Three partial responses were seen. Hematologic adverse effects were extremely rare as predicted by early clinical trials. One major toxicity was a syndrome consisting of some combination of myalgias, arthralgias, pleuritic pain, abdominal pain, peripheral neuropathy, anorexia, lethargy, and declining performance status (pain-lethargy syndrome) that was reversible with discontinuation of the drug. This adverse effect was as common a reason as hepatic toxicity for discontinuation of N-MF. As reported in previous studies with this drug, hepatic toxicity was also common, usually reversible, and also a cause for discontinuation of the drug. The low level of clinical activity and the unpleasant adverse effects in this population of patients with previously treated ovarian cancer makes it unlikely that this drug will play any significant role in treatment of epithelial ovarian cancer.
Adult↗
Management of selected cystic adnexal masses in postmenopausal women by operative laparoscopy: a pilot study.
Twenty-five postmenopausal patients were predicted to have benign masses by screening criteria that included ultrasonographic findings of a cystic adnexal mass less than 10 cm with distinct borders and no evidence of irregular solid parts, thick septa, ascites, or matted bowel, and a normal serum CA 125 value (less than 35 U/ml). All 25 masses were accurately predicted to be benign. The size of the cysts on ultrasonography ranged from 3 to 9 cm with a mean of 5 cm. Twenty-two patients (88%) were successfully managed by operative laparoscopy and adnexectomy. Mean operative time was 70 minutes and mean postoperative hospital stay was 12 hours. Mean time of return to normal activity was 5 days. Three patients required laparotomy. We conclude that removal of these cystic adnexal masses by operative laparoscopy is an acceptable alternative in carefully selected postmenopausal women.
Adnexal Diseases↗
Surgical-pathologic variables predictive of local recurrence in squamous cell carcinoma of the vulva.
One hundred and thirty-five patients with squamous carcinoma of the vulva were treated at UCLA and City of Hope Medical Centers between 1957 and 1985. Sixty-two cases were stage I, 48 stage II, 18 stage III, and 7 stage IV. Twenty-one patients developed a local vulvar recurrence after primary radical resection. Ninety-one patients had a surgical tumor-free margin greater than or equal to 8 mm on tissue section and none had a local vulvar recurrence. Forty-four patients had a margin less than 8 mm; 21 had a local recurrence and 23 did not (P less than 0.0001). Of the 23 patients with a margin less than 8 mm who did not recur locally, 14 remained free of disease, and 9 had either advanced disease, declining health, or short follow-up. Depth of invasion is associated with local recurrence, with a 9.1-mm reference value correctly predicting outcome in 81.5% of cases. Increasing tumor thickness is associated with local recurrence, with a 10-mm reference value predictive of 90% non-recurrence and 33% recurrences. A pushing border pattern is less likely to recur than an infiltrative growth pattern. Lymph-vascular space invasion has a combined predictive accuracy of 81.5%. Increasing keratin and greater than 10 mitoses per 10 high-power fields correlate with local recurrence. Neither clinical tumor size nor coexisting benign vulvar pathology correlates with local recurrence. Fourteen of twenty-one patients with vulvar recurrence died of metastatic disease, four died of intercurrent disease, and three were alive at 32, 68, and 157 months, with 16 recurring in less than 1 year. Surgical margin is the most powerful predictor of local vulvar recurrence. Combining factors in a stepwise logistical regression does not significantly improve this predictive value. Accounting for specimen preparation and fixation, a 1-cm tumor-free surgical margin on the vulva results in a high rate of local control, whereas a margin less than 8 mm is associated with a 50% chance of recurrence.
Adult↗
Synergy is documented in vitro with low-dose recombinant tumor necrosis factor, cisplatin, and doxorubicin in ovarian cancer cells.
Ovarian carcinomas have been shown to be sensitive or insensitive to the in vitro exposure of several cytotoxic drugs and cytokines. Because of the potential for cytokines to enhance the efficacy of chemotherapeutic agents and to improve their therapeutic index, the optimal dose and schedule of the combination of these agents have been studied. We examined the cytotoxic effect of a combined modality using a variety of concentrations of recombinant tumor necrosis factor (rTNF) (a cytotoxic cytokine) with Adriamycin (ADR) and cisplatin (CDDP) on human ovarian carcinoma cell lines. Cytotoxicity was determined in a 24-hr 51Cr-release assay and confirmed in a 5-day viability culture assay. Five cell lines were used: PA-1, 222, OVCAR-3, SKOV-3, and OVCAR-8. Doses of rTNF that were minimally cytotoxic resulted in significant cytotoxicity and synergy when used with optimal or suboptimal concentrations of ADR or CDDP. This synergy was observed in four cell lines. Interestingly, the rTNF- and drug resistant SKOV-3 cell line was sensitive to the synergistic effect of Adriamycin and rTNF. The synergistic effect that was obtained was specific to rTNF, while the combined use of ADR and CDDP or recombinant interleukin-2 and cytotoxic drugs had no synergistic effect on tumor cell lysis. Further, the addition of anti-TNF antibody abrogated the synergistic effect seen with rTNF and the cytotoxic drugs. These studies demonstrate clearly that significant synergistic antitumor cytotoxic activity against human ovarian carcinoma cell lines can be achieved with combinations of low doses of rTNF and ADR or CDDP, suggesting their possible adaptation in vivo for cancer therapy. Further, the studies suggest that rTNF and the cytotoxic drugs tested may share a common lytic pathway. Since rTNF used alone has been relatively inactive in clinical trials, its potential activity may be apparent only when combined with conventional cytotoxic chemotherapeutic agents and when administered in relatively low concentration.
Antineoplastic Combined Chemotherapy Protocols↗
Pelvic hemangiopericytomas: a report of five cases and literature review.
Five cases of pelvic hemangiopericytomas are reported. One of these tumors arose from the uterus, and four patients had extrauterine, pelvic hemangiopericytomas. The patient with a primary uterine hemangiopericytomas had only simple excision, and, after 6 years, is alive and free of disease. All four patients with extrauterine, pelvic hemangiopericytomas had incomplete resection of their tumors because of hemorrhage. However, pelvic radiation therapy was then employed in these patients and produced a complete regression in one patient and partial regression in two patients with minimal shrinkage in another patient. The latter patients were reexplored after pelvic radiation and underwent complete resection of their disease. Two patients developed pelvic recurrences at 2 and 9 years, respectively, and these were effectively resected. All four patients are all alive and free of disease 5 to 18 years later. If this lesion is unexpectedly discovered at laparotomy, our experience suggests that the resection should be discontinued and that they should be treated with pelvic radiation and delayed resection of persistent and recurrent pelvic tumors.
Adult↗
Risk factors for the development of lymph node metastasis in vulvar squamous cell carcinoma.
One hundred and ten women who underwent vulvectomy and inguinal-femoral lymphadenectomy for stages I-IV vulvar squamous cell carcinoma were studied. The most important factors that affected the inguinal lymph node status in the order of importance were vascular invasion, clinical stage, tumor thickness, depth of stromal invasion, and amount of keratin. Fourteen (88%) of 16 tumors with vascular invasion in the primary tumor metastasized. In the absence of vascular invasion, 18 (19%) of 94 tumors metastasized. Overall, 82% of tumors were correctly classified into lymph node negative and positive groups on the basis of vascular invasion. Tumor thickness and depth of stromal invasion had a similar accuracy in predicting lymph node status. The risk of lymph node metastasis increased from 0% when tumor thickness or depth of stromal invasion was less than 2 mm, to over 20% when depth of stromal invasion was greater than 2 mm, and to over 40% when tumor thickness exceeded 4 mm. A combination of vascular invasion, tumor thickness (or depth of stromal invasion), and the amount of keratin correctly classified 97% (76/78) of the lymph node negative group and 63% (20/32) of the positive group with an overall accuracy of 87%. The probability of having lymph node metastasis was computed for individual patients on the basis of one or more pathologic parameters using a logistic regression model. This feasibility is an important step toward individualized therapy for vulvar carcinoma.
Carcinoma, Squamous Cell↗
Cytoreductive surgery for advanced ovarian cancer: cardiovascular evaluation with pulmonary artery catheters.
Twenty-three patients underwent pulmonary artery (Swan-Ganz) catheterization for hemodynamic monitoring immediately after cytoreductive surgery for advanced ovarian cancer. Seventeen patients were studied continuously for at least 24 hr to determine the postoperative hemodynamic changes; 6 patients were intermittently monitored. The mean age was 63 years, mean operating time was 4.4 hr, mean ascites volume was 2300 ml, and estimated mean blood loss was 1300 ml. The mean nadir arterial pressure was 90 mm Hg at 6 hr, rising to a maximum of 105 mm Hg at 18 hr. The mean right atrial pressure was 2.6 mm Hg at 6 hr and 7.5 mm Hg at 24 hr; and mean pulmonary capillary wedge pressure nadir was 7.3 mm Hg at 6 hr and 10.7 mm Hg at 24 hr. The systemic vascular resistance zenith was 1400 dyne/sec/cm-5 at 6 hr and 860 dyne/sec/cm-5 at 24 hr. The monitoring technique permitted the early identification of myocardial infarction in two patients, both of whom had increased systemic vascular resistance and pulmonary capillary wedge pressure, and required dopamine to maintain arterial pressure. One patient had a pulmonary embolus, reflected by an increased right atrial pressure, decreased cardiac output, and normal pulmonary capillary wedge pressure. In all three instances, pulmonary artery catheterization facilitated prompt, early diagnosis of cardiovascular compromise and permitted early therapeutic intervention. These data document that rapid and extreme changes in the cardiovascular system occur in patients undergoing cytoreductive surgery. These changes include a rapid increase in systemic vascular resistance, a decrease in pulmonary capillary wedge pressure, a reflex tachycardia, and a decrease in cardiac output; all of these changes result from an acute shift of intravascular volume to the extracellular space and a relative hypovolemia requiring active resuscitation. Pulmonary artery catheterization plays an important role in monitoring these hemodynamic changes and a predictable uniform recovery with fluid resuscitation.
Cardiovascular System↗
Surgical staging of cervical cancer.
Noninvasive radiologic methods to detect paraaortic lymph node metastases are reliable when combined with FNA of enlarged lymph nodes. However, the sensitivity is low, and undetected microscopic metastases leads to treatment failure. These patients with paraaortic lymph node metastasis are not treated with extended-field radiation, and they all die within 3 years. The CT scanning is probably the best diagnostic method to evaluate cervical cancer, because it can assess the primary tumor, the urinary tract, gastrointestinal tract, liver parenchyma, and retroperitoneum. It also permits the guidance of FNA and the arrangement of radiation ports. Surgical staging provides the direct assessment of the peritoneal cavity and the retroperitoneal spaces. Metastatic tumor, including enlarged lymph nodes, can be resected, but this is of dubious benefit. The operative morbidity is acceptable, with fewer intestinal complications when the extraperitoneal approach is used, and long-term morbidity is minimal when appropriate paraaortic radiation doses are employed (less than 5,000 cGy). Surgical staging has provided data on the frequency of paraaortic lymph node metastasis by stage of cervical cancer, and thus, treatment strategies can be better developed. Extended-field radiation results in 5-year survival rates of 20-25% in patients with microscopic paraaortic lymph node metastasis, patients who would not survive without the treatment. However, surgical staging has produced only a modest boost in survival rates, because of the high rate of pelvic and systemic failure. When extended-field radiation is used prophylactically or in patients with probable lymph node metastasis seen on radiographic studies, survival rates are similar to patients irradiated after surgical staging finds paraaortic lymph node disease. As our ability to predict, and detect nonsurgically, positive paraaortic node disease improves, extended radiation (or other adjuvant therapy) could be used more frequently without operation in patients who are at high risk for metastatic disease. In a study by Haie et al, prophylactic paraaortic radiation was given to patients at high risk for paraaortic metastasis. In patients with a high probability of local disease control, paraaortic radiation significantly reduced the incidence of paraaortic and distant metastases. Patients with known paraaortic lymph node metastases frequently have occult systemic metastases. In these same patients, pelvic failure is also common. Thus, until effective systemic therapies emerge, a marked improvement in survival is unlikely in patients who have paraaortic lymph node metastasis.(ABSTRACT TRUNCATED AT 400 WORDS)
Female↗
Intraperitoneal adoptive immunotherapy for peritoneal cancer.
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Humans↗
Malignant neoplasms arising in endometriosis.
Ten cases of malignant tumors arising in foci of gonadal and extragonadal endometriosis are reported and added to 195 previously reported cases from the English literature. The ovary was the primary site in 165 (78.7%) of the cases, whereas extragonadal sites represented 44 (21.3%). Endometrioid adenocarcinomas accounted for 69% of the lesions, clear-cell carcinomas 13.5%, sarcomas 11.6%, and rare cell types 6%. Extragonadal lesions were mostly endometrioid tumors (66%) and sarcomas (25%). Tumors arising in endometriosis were predominantly low grade and confined to the site of origin. Radiation therapy was often able to control completely tumors limited to the pelvis, but was not beneficial in metastatic disease. Only one patient had a response to chemotherapy. Fourteen patients received postoperative progestin therapy, with a 77% 5-year survival. Follow-up has been reported in 86 patients. The tumor was either confined to the ovary (57), confined to the extragonadal site of origin (11), or spread throughout the peritoneal cavity (18). With each of these situations, the 5-year survival was 65, 100, and 10%, respectively. Fourteen patients had malignant transformation in endometriosis associated with presumed estrogenic stimulation; most lesions (69%) were well differentiated and the 5-year survival was 82%. After surgical resection, we recommend that progestin therapy be included in the treatment of cancer arising in endometriosis. The actual frequency of malignancy arising in endometriosis may be higher than reported.
Adult↗
Pathophysiology and management of endometrial hyperplasia and carcinoma.
Endometrial cancer is currently the commonest pelvic malignancy affecting American women, most of whom share the same pathophysiologic basis, that is, unopposed estrogenic stimulation. The initial result of hyperestrogenism is the development of endometrial hyperplasia, which is reversible in most cases by appropriate hormonal therapy. Persistent stimulation eventually leads to atypical hyperplasia with nuclear atypia and invasive carcinoma. Because there is no cost-effective screening method for the detection of endometrial hyperplasia and carcinoma, it is essential to survey the high-risk population with appropriate diagnostic techniques. After diagnosis, therapy should be individualized based on pathologic findings (cell type and histologic grade) and extent of disease (International Federation of Gynaecologists and Obstetricians stage, depth of myometrial invasion, and pelvic and para-aortic lymph node status). Recent studies suggest that sex hormone receptors and nuclear DNA ploidy patterns provide useful prognostic information independent of histologic grade.
Adenocarcinoma↗
Sensitivity of ovarian tumor cells to effector cells generated by various biological response modifiers.
The sensitivity of freshly derived human ovarian tumors (FOT) to various allogeneic cytotoxic effector cells stimulated by recombinant interleukin 2 (rIL-2), recombinant interferon alpha 2 (rIFN-alpha 2), OK-432, and concanavalin A was examined using the 51Cr release assay. Peripheral blood lymphocytes (PBL) of normal female donors were used as source of effector cells. Incubation of PBL with these biological response modifiers for 24 h generated effector cells with high natural killer activity, and only 20% (1/5) of the FOT examined were susceptible to lysis. By contrast, 83% (5/6) of the FOT were sensitive to lymphokine-activated killer (LAK) cells generated by rIL-2. OK-432 and concanavalin A activation of PBL also generated cytotoxic cells, though the cytotoxic activity against FOT was much less than that obtained by LAK cells. The addition of OK-432 to LAK culture medium containing rIL-2 generated effector cells with higher cytotoxicity against FOT than cultures with IL-2 alone. However, the addition of rIFN-alpha 2 in LAK culture medium resulted in the generation of effector cells with lower cytotoxicity. The addition of rIL-2, rIFN-alpha 2, or OK-432 to LAK cells during the in vitro cytotoxicity assay had no significant effect. When FOT target cells were pretreated with OK-432 they became more sensitive to LAK than nontreated tumor cells. However, pretreatment with rIL-2 or rIFN-alpha 2 did not influence cytolysis. These results suggest that the generation of LAK cells in vitro using rIL-2 plus OK-432 may be a more effective way to prepare these cells for adoptive immunotherapy in the treatment of ovarian cancer.
Concanavalin A↗
Ovarian metastases are rare in stage I adenocarcinoma of the cervix.
Over a 32-year period at the University of California, Los Angeles Medical Center, all cases of adenocarcinoma and adenosquamous carcinoma of the uterine cervix were reviewed to determine the incidence of ovarian metastases in stage I disease. One of 25 patients (4.0%) who underwent an exploratory laparotomy and radical hysterectomy had a microscopic ovarian metastasis. A literature review identified nine additional patients who had ovarian metastases and stage I adenocarcinoma of the cervix. Including our series, the overall reported rate of ovarian metastases is 1.8%. All ten patients had at least one of the following additional characteristics: They were postmenopausal, they had adnexal pathology, or they had positive pelvic lymph nodes. Thus, ovarian preservation is warranted in premenopausal patients who do not have ovarian pathology or evidence of other metastatic disease at surgery. Bilateral oophorectomy may be performed if frozen-section examination of enlarged or suspicious nodes documents metastases. If the ovaries are left in the pelvis at the completion of the surgical procedure and microscopic spread to other pelvic tissues is documented, pelvic irradiation can be administered.
Adenocarcinoma↗
Resection of diaphragmatic peritoneum and muscle: role in cytoreductive surgery for ovarian cancer.
Fourteen patients undergoing primary cytoreductive surgery for stage III ovarian malignancies had diaphragmatic peritoneum, muscle, or both resected in an attempt to remove all metastatic disease greater than 0.5 cm in diameter. Resection was completed in 13 of 14 patients (93%), all obtaining optimal cytoreduction. Size of resected specimens varied from 12 x 7 to 17 x 11 cm. The mediastinum was entered in two patients. Four patients had resection of diaphragmatic muscle. All defects were closed primarily and a thoracostomy tube was placed. One patient who did not have muscle resection had a 30% pneumothorax that spontaneously resolved. No subdiaphragmatic hematomas or abscesses occurred. Time (mean 65 min, range 40-150 min) and blood loss (mean 175 ml, range 100-1500 ml) for the surgery depended upon extent of disease. One procedure was terminated due to bleeding from a lacerated liver capsule. We conclude that diaphragmatic peritoneum/muscle resection can be completed successfully with acceptable morbidity.
Diaphragm↗
Utilization of a murine model to optimize volume and dwell time of intraperitoneal cisplatin.
The pharmacokinetics of intraperitoneal (ip) cisplatin were investigated in a murine model. Groups of six animals were studied at initial cisplatin concentrations (Ci) of 50, 100, 200, and 400 micrograms/ml, and at injection volumes (V) of 0.5, 1, 2, and 4 ml. For each Ci and V, four dwell times (Dt) between 1.5 and 120 min were studied. At 180 min mice were killed and five tissues (heart, kidney, liver, bowel, and peritoneum) were obtained for platinum measurement. Platinum recovered from the peritoneal cavity at the end of the dwell time and platinum tissue levels were determined by a radioactive tracer assay using Pt 195m-labeled cisplatin. A total of 384 mice were studied. The permeability times the effective surface area product (pS) was found to be independent of Ci, V, and Dt. Platinum tissue levels were proportional to absorbed dose. As the ratio of platinum tissue level to absorbed dose is constant, it is not possible to change Ci, V, nor Dt to minimize toxicity from a given absorbed dose. This study suggests that the therapeutic index of an individual intraperitoneal cisplatin treatment will not be changed by modifying Ci, V, nor Dt.
Absorption↗
Synchronous primary neoplasms of the female reproductive tract.
A histopathologic review of synchronous primary neoplasms of the female reproductive tract is presented. During a 30-year period, 3863 patients with female genital malignancies were accessioned to the UCLA Tumor Registry: 958 had ovarian cancer, 776 endometrial cancer, 1556 cervical cancer, and 573 other gynecologic malignancies. Twenty-six (0.7%) patients with invasive synchronous primary cancers were identified. The most frequent synchronous genital lesions were ovarian and endometrial cancers in 11 patients (0.3%). No association was documented between genital and extragenital cancers. Patients with synchronous ovarian and endometrial cancers each were low stage and low grade, and the prognosis was excellent. Their detection in a relatively early stage suggests diagnosis may be facilitated by early symptoms from the endometrial carcinoma, and that these lesions are biologically of relatively low grade. These data support the conclusion that there is an association between low-stage epithelial carcinoma of the ovary and endometrial carcinoma.
Antineoplastic Combined Chemotherapy Protocols↗
Vulvovaginal melanoma: report of seven cases and literature review.
Five cases of primary vaginal melanoma were treated at UCLA Medical Center between 1976 and 1986. Two additional cases of melanoma arising at the junction of the vulva and vagina are presented. One of seven (13%) patients is alive, with a median time to recurrence of 7 months, and median survival of 31 months. Four of five vaginal melanomas were located in the distal vagina, and all were advanced at diagnosis (greater than 3 mm depth). Mean size was 3 cm. Initial therapy was local excision in four patients and radical surgery in three. All patients had suboptimal surgical margins: two vaginal primaries had positive margins after local excision, both recurred vaginally within 5 months. Two patients had margins less than 1 mm, one died of distant metastases, the other is alive with disease 30 months after radical distal vaginectomy and hemivulvectomy with post-op pelvic radiotherapy. Three patients had melanoma in situ at the surgical margins, and each had pelvic recurrences between 6 and 26 months. Five of seven cases developed local recurrence as the initial site of treatment failure. All five vaginal cases ultimately developed distant disease, but only two patients had distant disease without local-regional recurrence. Chemotherapy and immunotherapy enabled disease stabilization in three patients. The vulvovaginal junction at the introitus is a high risk site for vaginal and vulvar melanoma. Intraoperative management requires assessment of lateral and deep spread of invasive and in situ melanoma.
Adult↗