A phase I trial of beta-all-trans-retinoic acid delivered via a collagen sponge and a cervical cap for mild or moderate intraepithelial cervical neoplasia.

A phase I trial was conducted of the vitamin A derivative beta-all-trans-retinoic acid (vitamin A acid; TRA), delivered via a collagen sponge and cervical cap for mild or moderate intraepithelial cervical neoplasia. On the basis of known skin and mucosal membrane toxicity, a concentration of 0.05% TRA in a cream-based vehicle was selected as the starting dose and was escalated later with the use of a modified Fibonacchi scale. The delivery device and the TRA were changed daily for 4 days, and side effects were assessed on days 1, 2, 3, 4, 8, and 30 by clinical and colposcopic examination. Vaginal, cervical, and systemic toxicity were evaluated in 35 patients. No dose-related systemic effects were found; mild cervical inflammation increased in many patients at higher doses. Unacceptably high vaginal toxicity was reached at a TRA concentration of 0.484%. A concentration of 0.372% TRA is recommended for use in phase II trials in mild and moderate cervical intraepithelial neoplasia.

Phase I clinical and pharmacokinetic study of mitoxantrone given to patients by intraperitoneal administration.

On the basis of its high degree of cytotoxicity against fresh human ovarian cancers and its relative lack of vesicant activity, mitoxantrone administered by the i.p. route was studied in a Phase I and pharmacokinetic trial. Thirty-three patients with good performance status and diagnoses of metastatic or recurrent ovarian (31 patients) and colon (two patients) cancers were treated with 12- to 38-mg/m2 doses, administered by the i.p. route every 4 wk for up to ten treatment courses. Mitoxantrone doses were escalated at 2- to 3-mg/m2 increments in groups of three to 11 patients. Thirty-eight mg/m2 (by i.p. dwell without removal) were considered the maximally tolerated dose in that, of eight treated patients, four experienced severe leukopenia and six experienced severe abdominal pain. Response to i.p. mitoxantrone was evaluable in 17 patients. None of seven patients with clinically measurable intraabdominal or pelvic tumor masses responded; however, in three (50%) of six patients with nonmeasurable disease, there was normalization of previously elevated serum CA-125 concentrations for 3, 17, and 24 mo. Additionally, two (50%) of four patients who underwent third-look laparotomies were found to have greater than 75% reductions in i.p. tumor masses with response lasting 24 and 25 mo. At 38 mg/m2, mitoxantrone was associated with a mean concentration.time product of 100 micrograms.h/ml in the i.p. space and of 0.071 micrograms.h/ml in plasma, yielding an i.p./plasma area under the curve ratio of 1408. We conclude that chemical peritonitis is the dose-limiting toxicity of i.p. administered mitoxantrone and that a dose of 23 mg/m2 every 3 to 4 wk should be used in future Phase II trials in ovarian cancer patients with minimal residual intraabdominal and pelvic disease following second-look laparotomy.

Phase II randomized trial of cisplatin chemotherapy regimens in the treatment of recurrent or metastatic squamous cell cancer of the cervix: a Southwest Oncology Group Study.

Cisplatin has proven to be the most active single agent in the treatment of metastatic and recurrent squamous cell cancer of the cervix. In a previous southwest Oncology Group (SWOG) pilot study, the addition of cisplatin to a mitomycin-C, vincristine, and bleomycin (MVB) regimen resulted in a relatively high percentage of durable complete responses. To gain more experience with cisplatin-based chemotherapy regimens, the SWOG initiated a phase II randomized trial of cisplatin, mitomycin-C plus cisplatin (MC), and MVB plus cisplatin (MVBC) in 119 patients with advanced squamous cell cancer of the cervix and no prior chemotherapy exposure. Because of slow patient accrual early in the trial, the cisplatin arm was discontinued. Five patients were declared ineligible according to protocol criteria. The three treatment groups were relatively well matched for age, prior radiation exposure, and sites of measurable disease. The overall objective response rates for cisplatin, MC, and MVBC treated patients were 33%, 25%, and 22%, respectively. Median response durations were greater than 6 months. Median survival durations associated with cisplatin, MC, and MVBC treatment were 17.0, 7.0, and 6.9 months, respectively. There were no drug-related deaths. Severe or life-threatening leukopenia and thrombocytopenia were observed in 18% to 24% of patients treated with MVBC and MC, but in none of those receiving cisplatin alone. We conclude that the low response rates and short durations of both response and survival observed in patients randomized to the two chemotherapy combinations suggest that only enhanced toxicity was gained through the addition of mitomycin-C or MVB to cisplatin in patients with advanced cervix cancer.

Double-blind crossover study of the antiemetic efficacy of high-dose dexamethasone versus high-dose metoclopramide.

Nausea and vomiting remain common and debilitating side effects of therapy with many anticancer drugs. Recent reports have shown that both metoclopramide and dexamethasone are effective drugs for the treatment of severe nausea and vomiting caused by cis-platinum. A double-blind crossover study comparing the antiemetic properties of high-dose oral and intravenous regimens of metoclopramide and dexamethasone in outpatients was carried out. Standardized patient questionnaires and interviews were used to evaluate response. Dexamethasone and metoclopramide protected against more than five episodes of emesis in 48% and 40% of patients, respectively. Nausea persisted for less than six hours in 45% of patients on dexamethasone and in 37% on metoclopramide. The antiemetic efficacy of both regimens was retained through repeated courses of chemotherapy. Side effects were minimal with dexamethasone; however, 33% of patients experienced unacceptable extrapyramidal side effects to metoclopramide. Patient preference was significantly in favor of dexamethasone: 70% of patients chose to continue dexamethasone compared to 22% who preferred metoclopramide and 8% who chose other antiemetics. Dexamethasone was the preferred antiemetic in this patient population due to minimal side effects.

Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide: final report by the Southwest Oncology Group of a phase III randomized trial in stages III and IV ovarian cancer.

PURPOSE: To compare cisplatin-cyclophosphamide versus carboplatin-cyclophosphamide as primary chemotherapy for stage III (suboptimal) and stage IV ovarian cancer. PATIENTS AND METHODS: Three hundred forty-two patients were randomly assigned to treatment with six courses of intravenous (i.v.) cisplatin 100 mg/m2 plus i.v. cyclophosphamide 600 mg/m2, or i.v. carboplatin 300 mg/m2 plus i.v. cyclophosphamide 600 mg/m2. RESULTS: The estimated median survivals were 17.4 and 20.0 months for the cisplatin and carboplatin study arms, respectively. The null hypothesis of a 30% survival superiority with the cisplatin arm was rejected at the P = .02 level. Clinical response rates were 52% for the cisplatin arm and 61% for the carboplatin arm. Pathologic complete response rates were similar for both study arms. There was less thrombocytopenia on the cisplatin arm (P less than .001); however, there was less nausea and emesis (P less than or equal to .001 for courses 1 to 5), renal toxicity (P less than .001), anemia (P = .01), hearing loss (P less than .001), tinnitus (P = .01), neuromuscular toxicities (P = .001), and alopecia (P less than .001) on the carboplatin arm. CONCLUSION: Carboplatin-cyclophosphamide proved to have a significantly better therapeutic index than cisplatin-cyclophosphamide in patients with stage III (suboptimal) and stage IV ovarian cancer.

Investigation of binding sites for follicle-stimulating hormone and chorionic gonadotropin in human ovarian cancers.

The binding of FSH and hCG to ovarian tumor biopsies from 31 women was analyzed to determine whether ovarian cancers contain receptors for gonadotropic hormones. For comparative purposes, gonadotropin binding to receptor-positive control tissues was also assessed. Specific binding was defined as [125I]hFSH and [125I]hCG binding prevented by coincubation of tissue samples with an excess of unlabeled gonadotropin. Various types of epithelium-derived tumors (serous, mucinous, endometrioid, and undifferentiated; n = 29) had low levels of specific FSH and hCG binding (less than 15% of receptor-positive control tissues) which were not dependent on tissue concentration and not saturable. A germ cell tumor had similar binding characteristics. In contrast, specific FSH binding to a granulosa cell-theca cell (GC-TC) tumor was directly proportional to tissue concentration, and binding was maximal in the presence of 100 ng/ml [125I]FSH. Scatchard analyses of FSH binding yielded a linear plot. Although the FSH-binding capacity of the GC-TC tumor (6.3 fmol/mg) exceeded that of control tissues, their binding affinities (Kd = 1.4 X 10(-9)M) were similar. Specific hCG binding to the GC-TC tumor was low and not dependent on tissue concentration. We conclude that the specific binding of FSH to the GC-TC tumor was characteristic of the interaction of gonadotropin with receptors in target tissues. However, the low level of FSH and hCG binding to tumors of epithelial origin did not represent gonadotropin-receptor binding. Thus, the common ovarian tumors of epithelial origin may not respond directly to gonadotropin, but malignancies of sex cord-stromal origin, such as GC-TC tumors, could be modulated by FSH.

Phase II trial of mitomycin C plus 5-FU in the treatment of drug-refractory ovarian cancer.

Following cisplatin combination chemotherapy for advanced epithelial type ovarian cancer, response to subsequent treatments has proved relatively poor. Mitomycin C and 5-fluorouracil (5-FU) have both been reported to have useful activity as single agents in patients with drug-refractory ovarian cancer. We have carried out a phase II trial of a combination of these two agents in 25 patients who had previously received a median of two chemotherapy regimens (range, one to five regimens). Patients received mitomycin C, 10 mg/m2 intravenously (IV) on day 1 every 6 weeks, and 5-FU, 500 mg/m2 IV daily on days 1 to 3 every 3 weeks. Four patients experienced a complete response and six patients a partial response, for an overall objective response rate of 40%. The median duration of complete and partial responses was 8 and 4 months, respectively. The median duration of survival for all 25 patients was 10.5 months (range, 2.5 to 49+ months). The most prevalent toxicity was bone marrow suppression. Leukopenia occurred in 68% of the patients, and 36% experienced thrombocytopenia. Severe or life-threatening bone marrow suppression was observed in 36% of the patients and required dose reduction or drug discontinuance in 28% and 24%, respectively. We conclude that mitomycin C plus 5-FU combination therapy appears to be extremely active in patients with drug-refractory disease. Confirmatory trials are indicated.

Intraperitoneal mitomycin C in the treatment of peritoneal carcinomatosis following second-look surgery.

Persistent or recurrent peritoneal carcinomatosis (PC) documented at second-look surgery has proved relatively refractory to second-line therapy. The majority of these tumors do not respond to cisplatin based chemotherapy. Because of the relatively high response rate we observed with systemically administered mitomycin C plus 5-fluorouracil, we initiated a trial of intraperitoneal (IP) mitomycin C (10 mg/m2 in 2 L dialysate fluid every 4 weeks) in 14 patients with refractory PC secondary to gynecologic malignancies. All but one patient had PC secondary to ovarian cancer documented at second-look cytoreductive surgery following intense cisplatin based drug therapy. One patient had endometrial cancer and had been treated previously with radiation. In all, 49 courses of intraperitoneal mitomycin C were administered to 14 patients. Systemic toxicity was minimal, except for mild thrombocytopenia that occurred in four patients. However, abdominal pain due to chemical peritonitis was cumulative and dose limiting after three to five courses of therapy. Of the seven patients with measurable disease (positive serum CA-125 or intraperitoneal cytology), six had normalization of at least one of these two parameters. Eight of the 14 patients remain alive without clinical evidence of disease with a median follow-up duration of 10 months. We conclude that IP mitomycin C is a well-tolerated and potentially effective treatment modality in patients with limited PC following second-look surgical debulking for gynecologic malignancy.

Interstitial parametrial implants in carcinoma of the cervix stage II-B.

This retrospective analysis has been undertaken to ascertain whether an improvement in results can be obtained in Stage II-B cervical carcinoma with the use of interstitial parametrial irradiation. Between September 1972 and March 1982, 43 patients were treated by conventional intracavitary irradiation. Nine patients at high risk for local recurrence underwent post-radiation hysterectomy. Since 1980, 45 patients were entered into a study using parametrial interstitial implants and no hysterectomy. Patients were not allocated randomly and the interstitial group contained a disproportionate number of patients with poor prognostic features. Mean follow-up for the conventional radiotherapy group was 80 months, and for the interstitial group was 42 months. Overall pelvic control and actuarial survival in the conventional radiotherapy group (84 and 75%, respectively) were similar (log rank p-value = .61) to that observed in the interstitial implant group (80 and 77%). Analysis of pelvic control rates showed no significant advantage for either treatment group when compared by the various prognostic factors. The frequency of complications, however, was significantly higher in the interstitially irradiated patients (21% vs. 7%, p = .044).

Treatment of advanced cancer of the cervix with transperineal interstitial irradiation.

A pilot study using transperineal interstitial implantation to the parametrium in patients with locally advanced carcinoma of the cervix or with distorted anatomy is presented. Twenty-one consecutive patients (2 cervical stump Stage IB, 3 Stage IIB, 15 Stage IIIB, 1 Stage IVA) received one (12) or two (9) implants following 40-45 Gy whole pelvis external irradiation. In addition 8 patients underwent staging laparotomies concurrently with the first implant procedure. Control of the pelvic tumor was accomplished in 18 of 21 patients (85%) with a mean follow-up of 26 months (range 15 to 48 months). Seven patients (33%) developed long term complications (fistula 3, superficial necrosis of the vagina 1, severe proctitis or cystitis 3). Six of the complications occurred in 8 patients (75%) who had radioactive sources placed on the surface of the vaginal obturator as a substitute for the lack of tandem. In contrast, only 1 in the remaining 13 patients (8%) who did not have obturator sources placed, developed long term complications.

Treatment of metastatic trophoblastic disease with poor prognosis.

Fifty-one patients are presented who were treated for poor-prognosis gestational trophoblastic disease by physicians at Duke University Medical Center (Southeastern Regional Trophoblastic Disease Center) between 1968 and 1978. Disease in 72% (37 of 51 patients) is currently in remission (8 months to 10 years). Treatment was primarily by multiagent chemotherapy, with adjunctive surgery and radiation therapy in selected patients. Unsuccessful chemotherapy prior to treatment at this center, a prolonged interval from the antecedent pregnancy to treatment, and liver metastases portended a worse prognosis in these patients.

Meigs syndrome and elevated CA 125.

A patient presented with a pelvic mass, ascites, and pleural effusion. The serum CA 125 level was noted to be 226 U/mL (normal 5-35 U/mL). On surgical exploration, she had a benign fibroma-thecoma without malignant cytology in the ascitic fluid. Postoperatively, the pleural effusion resolved and the CA 125 decreased to 32 U/mL. This is the first reported case of Meigs syndrome and an elevated CA 125 level. As previously documented, elevated serum CA 125 does not always indicate malignancy.

Laparoscopic trocar-assisted colpotomy.

Trocar-assisted transvaginal colpotomy was performed in 17 patients to remove large pathologic specimens during laparoscopic operations when the specimen could not be extirpated through the laparoscopic ports. Under direct laparoscopic visualization, colpotomy was performed using a 10- or 11-mm disposable trocar without the sleeve. The trocar was removed, a ring forceps was placed through the incision, the incision was enlarged, and the mass was grasped with the ring forceps and removed. This technique is safe, fast, and easy to perform. In addition, smoke is not created and potential electrocautery damage to pelvic structures is avoided.

Adjunctive radiation therapy in the management of stage I cancer of the endometrium.

One hundred fifty-two patients with stage I, grades 2 and 3 adenocarcinoma of the endometrium, treated in 1972 and 1973 at the Radiumhemmet, are presented. Two uterine packings followed at 4 to 6 weeks by total abdominal hysterectomy and bilateral salpingo-oophorectomy resulted in a 5-year survival of 89%, whereas patients treated primarily with surgery followed by vaginal cylinder irradiation demonstrated 90% survival. Patients in both groups received whole pelvis irradiation postoperatively for deep myometrial invasion (more than 50% invasion by viable tumor). Patients treated with radiation therapy alone had 57% survival. Optimal results in poorly differentiated (grade 3) carcinoma of the endometrium were achieved with preoperative packings (90% survival); only 12% of the patients required external radiation therapy postoperatively.

Laparoscopic staging of the patient with incompletely staged early adenocarcinoma of the endometrium.

OBJECTIVE: To determine the feasibility of laparoscopic staging in patients with presumed early stage but incompletely surgically staged adenocarcinoma of the endometrium. METHODS: Thirteen patients with incompletely staged adenocarcinoma of the endometrium underwent laparoscopic staging. The women ranged in age from 36-74 years (mean age 64) and weighed 132-201 lb (mean 147.5). The interval between hysterectomy and laparoscopic staging ranged from 14-63 days, for an average of 47. All patients underwent inspection of the entire intraperitoneal cavity, procurement of pelvic washings, and/or pelvic or para-aortic lymphadenectomy, and two patients had remaining ovaries removed. RESULTS: Extrauterine disease was found in three patients: One had intraperitoneal washings positive for adenocarcinoma, and two had pelvic lymph nodes positive for microscopic carcinoma. The average number of lymph nodes removed was 17.5. There were no intraoperative complications. Estimated blood loss averaged less than 50 mL, and the mean hospital stay was 1.5 days. CONCLUSION: Our initial experience indicates that this is a safe, effective procedure that offers a short hospital stay. We consider laparoscopic staging an attractive option for some patients with incompletely staged early adenocarcinoma of the endometrium.

Stage II carcinoma of the endometrium. An analysis of treatment.

An analysis of 41 patients with histologically documented Stage II adenocarcinoma of the endometrium treated between 1969 and 1974 is presented. The 3-year survival for all patients was 46%. Patients treated with radiation therapy alone (tandem, ovoids, and external radiation therapy) had 29% survival while patients treated with radiation therapy and surgery had a 71% survival. For all patients, survival by grade was 80% (Grade I), 36% (Grade II), and 20% (Grade III). Among those patients with recurrent disease, 40% of cases were in the pelvis while 20% were isolated distal recurrences. Patients with stromal invasion of the cervix had a 30% survival while patients without stromal invasion had a 67% survival. An analysis of these data, along with a review of the literature, reveals that 1) hysterectomy plays a critical role in survival, 2) invasion of the cervical stroma would appear to be a requisite criteria for the establishment of Stage II disease, and 3) aggressive radiation therapy with uterine packings (Heyman capsules) should be attempted in those patients who are not surgical candidates.

Choriocarcinoma following term pregnancy.

Two hundred and sixty-five patients with malignant trophoblastic disease were admitted to the Southeastern Trophoblastic Disease Center at Duke University Medical Center between July 1966 and June 1976. Of these 165 patients, 20 had choriocarcinoma following a term gestation with a survival rate of 60% as compared to 95% survival rate for the remaining 245 patients. Previously described risk factors of initial human chorionic gonadotropin (hCG) titer of greater than 100,000 IU/24 hr urine, duration of symptoms for more than 4 months, significant prior unsuccessful chemotherapy or cerebral or hepatic metastases identified the "poor prognosis" group. Post-term gestation "poor prognosis" patients had a significantly lower cure rate (47%), than other patients with "poor prognosis" for gestational trophoblastic disease (75%; P less than 0.05). Post-term gestation choriocarcinoma has a propensity for more extensive metastatic spread and would appear to be less responsive to conventional chemotherapy, which may be due to an altered immune response in these patients. This suggests that an antecedent term pregnancy should be added to the previously described high-risk factors for patients with malignant trophoblastic disease.

Transabdominal cerclage: a laparoscopic approach.

BACKGROUND: The placement of a transabdominal cervical cerclage has been regarded as considerably more morbid than a transvaginal cerclage, in part due to the need for two laparotomies. We describe a technique for the laparoscopic placement and removal of a transabdominal cerclage. CASES: Two cases of women with insufficient cervical tissue to place a transvaginal cerclage were managed with a transabdominal cerclage. In one case, the cerclage was placed laparoscopically; in the other, the band was removed, facilitating uterine evacuation following the diagnosis of a missed abortion. In both cases a laparotomy was avoided. CONCLUSION: Laparoscopic placement and removal of a transabdominal cerclage are promising options in the treatment of an incompetent cervix.

Laparoscopic para-aortic lymphadenectomy in gynecologic malignancies.

OBJECTIVE: To determine the feasibility, safety, limiting factors, and advantages of laparoscopic para-aortic lymphadenectomy in a series of patients with gynecologic malignancies. METHODS: During a 2-year period, 61 women underwent laparoscopic para-aortic lymph node dissection as part of their management for invasive gynecologic malignancies. A transperitoneal incision directly over the aorta was used. Initially, only the right-side infra-inferior mesenteric artery nodes were removed. The technique of removal of left-side low para-aortic nodes was then developed, followed by the technique for removal of right- and left-side nodes above the transverse duodenum. A total of 52 right para-aortic lymphadenectomies were performed, 12 of which were combined with left-side lymphadenectomies. A total of 17 left-side lymphadenectomies were performed, 12 of which were bilateral. Four patients had nodes removed above the inferior mesenteric artery. RESULTS: The procedure could not be performed in four instances because of obesity or adhesions. Twenty-four patients had their laparoscopic surgery combined with another procedure, which increased their hospital stays: radical hysterectomy (five), laparoscopy-assisted vaginal hysterectomy (17), transperineal interstitial irradiation (one), and anterior-posterior colporrhaphy (one). The remaining 33 patients had laparoscopic surgical staging only. One patient required laparotomy to control bleeding from the vena cava; however, the others had no short- or long-term complications, and the average hospital stay was 1.3 days. CONCLUSION: Laparoscopic para-aortic lymphadenectomy is a safe, effective procedure that allows a shorter hospitalization than traditional laparotomy.

Abdominal-wall tumor implantation after laparoscopy for malignant conditions.

OBJECTIVE: To determine the incidence of abdominal-wall tumor implantation after laparoscopic procedures in patients with known malignancies. METHODS: We reviewed 557 laparoscopic procedures performed by the Gynecologic Oncology Service between November 1990 and February 1994. In 105 procedures, malignancy was documented cytologically or histologically, 88 with intraperitoneal disease and 17 with retroperitoneal disease. Ovarian cancer represented 80% (70 of 88) of the procedures with intraperitoneal malignancy, and the remaining cases consisted of carcinoma of the fallopian tube (two), endometrium (11), cervix (one), breast (three), and stomach (one). Histologically, ovarian carcinomas ranged from low malignant potential to poorly differentiated. Among 88 patients with intraperitoneal disease, 77 had gross disease and 11 had microscopic disease. Four hundred thirty-seven different abdominal-wall puncture sites were used (38 Veress needle sites and 399 laparoscopic ports). RESULTS: One of the 437 (0.2%) abdominal-wall puncture sites developed implantation, a frequency of 1.0% (one in 105) per procedure; this developed after a second-look laparoscopic procedure for ovarian carcinoma in which only microscopic disease was present. If only intraperitoneal disease is considered, the incidence of implantation was 0.3% (one in 363) per abdominal puncture and 1.1% (one in 88) per procedure. CONCLUSION: Tumor implantation at the abdominal-wall puncture site is an infrequent occurrence after laparoscopy in patients with intraperitoneal and retroperitoneal carcinoma.