Postoperative radiation for cervical cancer with pathologic risk factors.

PURPOSE: To examine the efficacy of postoperative radiation therapy for early-stage cervical cancer with pathologic risk factors. METHODS AND MATERIALS: We reviewed the charts of 83 patients who received postoperative radiation therapy at our facility from March 1980 to November 1993 for early stage cervix cancer with positive surgical margins, positive pelvic or periaortic lymph nodes, lymphovascular space invasion, deep invasion, or for disease discovered incidently at simple hysterectomy. Twenty-eight patients received low dose rate (LDR) intracavitary radiation with or without external beam pelvic irradiation and 55 patients received external beam pelvic irradiation with high dose rate (HDR) intracavitary implants. Of these 83 patients, 66 were evaluable--20 LDR and 46 HDR patients. All patients received 45-50 Gy external beam irradiation and 20 Gy LDR equivalent intracavitary irradiation prescribed to 0.5 cm below the mucosa. Ninety percent of the LDR group and 92% of the HDR group completed treatment within < 56 days. Treatment-related toxicities were scored according to the GOG toxicity scale. Mean and median follow-up times were 101 months and 111 months (3-172 months) for the LDR group and 42 and 40 months (3-98 months) for the HDR group. RESULTS: The 5-year disease-free survival was 89% for the LDR group and 72% for the HDR group. Local control was observed in 90% (18 out of 20) of the LDR patients and 89% (41 out of 46) of the HDR patients for an overall local control rate of 89.5%. Two of 20 LDR patients (10%) experienced recurrence (two pelvic with distant metastasis). Nine of 46 HDR patients (22%) had recurrence of disease (three pelvic, four distant metastasis, and two pelvic with distant metastasis). In the HDR group, 6 out of 16 (38%) with positive lymph nodes died of disease whereas, 27 out of 30 (90%) of the patients with negative lymph nodes remain free of disease. Three of 20 (15%) LDR patients and 4 out of 46 (9%) HDR patients experienced Grade 2 or 3 late treatment- related complications. No patient in either group had Grade 4 or 5 complications. Pathologic risk factors were analyzed. Lymph node positivity and lymphovascular space invasion were found to be significant (p = 0.01 and p = 0.02). Positive margins, deep invasion, and age were not significant. CONCLUSION: Our results demonstrate the efficacy of postoperative irradiation for cervical cancer with pathologic risk factors. Overall, the local control rate was 89.5% The HDR results demonstrate that this method can be delivered safely and effectively.

Tumors of the uterine isthmus: clinicopathologic features and immunohistochemical characterization of p53 expression and hormone receptors.

Five (3%) of 161 endometrial cancers treated surgically between 1988 and 1992 were classified as primary isthmic tumors, and their clinicopathologic features, p53 expression, and hormone receptor status were evaluated. Three were endometrioid adenocarcinomas with squamous differentiation, one was a mixed serous and clear cell carcinoma, and one was a malignant müllerian mixed tumor; all five were high grade, invaded the entire thickness of the myometrium, and exhibited lymphatic space invasion. Four of the five patients had extrauterine metastases identified at the time of hysterectomy. All five patients died due to progressive disease with the survival time ranging from 1 to 23 months. Abnormal p53 gene expression was identified immunohistochemically in three of the five isthmic tumors. Weak positivity for estrogen and progesterone receptors was demonstrated in one case, with the remaining four being negative. Tumors arising in and confined to the uterine isthmus are unusual and, in our series, were uniformly aggressive with an unfavorable prognosis. The histopathologic features and biologic behavior of the isthmic tumors appeared similar to those of other high-grade endometrial cancers arising in the uterine corpus.

Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer.

BACKGROUND: Intravenous platinum-based chemotherapy is the standard primary therapy for advanced ovarian cancer. We conducted a phase 3 trial to compare the effects of intraperitoneal and intravenous cisplatin on the survival of women with previously untreated, stage III, epithelial ovarian cancer. METHODS: The patients underwent an initial exploratory laparotomy and resection of all tumor masses larger than 2 cm. Within four weeks after surgery, six courses of intravenous cyclophosphamide (600 mg per square meter of body-surface area per course) plus either intraperitoneal cisplatin (100 mg per square meter) or intravenous cisplatin (100 mg per square meter) were administered at three-week intervals. RESULTS: Of 654 randomized patients, 546 were eligible for the study. The estimated median survival was significantly longer in the group receiving intraperitoneal cisplatin (49 months; 95 percent confidence interval, 42 to 56) than in the group receiving intravenous cisplatin (41 months; 95 percent confidence interval, 34 to 47). The risk of death was lower in the intraperitoneal group than in the intravenous group (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P = 0.02). Moderate-to-severe tinnitus, clinical hearing loss, and neuromuscular toxic effects were significantly more frequent in the intravenous group. CONCLUSIONS: As compared with intravenous cisplatin, intraperitoneal cisplatin significantly improves survival and has significantly fewer toxic effects in patients with stage III ovarian cancer and residual tumor masses of 2 cm or less.

Multifractionated high-dose-rate brachytherapy with concomitant daily teletherapy for cervical cancer.

BACKGROUND: High-dose-rate (HDR) brachytherapy has been the preferred treatment for cervical cancer at Wayne State University since 1987. The outcome of the first 105 patients treated is analyzed. PURPOSE: To determine clinical efficacy of the HDR modality. METHODS: We reviewed 105 patients and evaluated the 88 patients treated for cervical carcinoma with HDR and external beam radiotherapy (EBRT) from August 1987 to December 1992. Patients received initial external radiation to the pelvis (total dose of 19.8 to 39.6 Gy in 11 to 22 fractions), followed by outpatient HDR brachytherapy (3 fractions/week, 386 cGy/fraction to Point A, total of 8 to 12 fractions) and concurrent daily EBRT (1.8 to 2.0 Gy) to lateral parametria. During the HDR period of treatment, step wedge transmission blocks were used to shield central pelvic tissue while treating peripheral pelvic tissues with EBRT. Patient distributions were as follows: 25, IB/IIA; 35, IIB/IIIA; and 28, IIIB/IVA. There were 56 African American and 32 Caucasian patients with mean age of 55 (range 19-89). The median follow-up was 33 months (range 20 to 76 months). Kaplan-Meier analysis was performed. RESULTS: Three-year survival rates were 88%, IB/IIA; 69%, IIB/IIIA; 56%, IIIB/IVA; and 72% overall. Local control was achieved in 71/88 (80%) of patients. Failure site was cervix or within the pelvis in 12 patients, distant metastasis only 17 patients, and combined local and distant in 5 patients. Of the failures, 82% (28/34) died within 2 years. There were 3 grade III/complications (3.4%). CONCLUSION: Results compare favorably with previous LDR experience.

Experience with the P.A.S.-PORT venous access device in patients with gynecologic malignancies.

Experience with the P.A.S.-PORT, a peripherally implanted central venous access device, is evaluated in a retrospective review of 154 patients from July 1991 to June 1994. Blood could not be aspirated from six patients. Complications included temporary minor thrombophlebitis in seven patients (4.5%), symptomatic axillary or subclavian vein thrombosis in five patients (3.2%), clotted port in two patients (1.2%), port pocket cellulitis in two patients (1.2%), and fungal sepsis in two patients (1.2%). In six patients (3.8%) the P.A.S.-PORT had to be removed because of complications. The P.A.S.-PORT facilitated delivery of chemotherapy, parenteral nutrition, blood products, antibiotics, hydration, and blood sampling. It was demonstrated that the P.A.S.-PORT may be inserted and used with a low incidence of complications in gynecologic cancer patients.

A phase II trial of piroxantrone in endometrial cancer: Southwest Oncology Group study 8918.

A phase II trial of the new anthrapyrazole piroxantrone was carried out by the Southwest Oncology Group in patients with advanced metastatic or recurrent endometrial cancer. A two-stage statistical design targeted accrual of 20 eligible patients. The starting dose of piroxantrone was 150 mg/m2 in patients without prior radiation therapy (RT) and 120 mg/m2 in patients with prior RT. There were 15 eligible patients, six of whom had received prior hormonal therapy while nine patients had not received prior hormonal therapy. Eight patients had received prior RT while seven patients had not received any prior RT. One to seven cycles of piroxantrone were administered. Dose escalation was feasible in four patients. No grade 5 toxicity was experienced by any patients. Most of the grade 4 (granulocytopenia in one) and grade 3 (leukopenia in three, granulocytopenia in three, anemia in two and thrombocytopenia in one) toxicity was related to myelosuppression. Grade 3 non-hematologic toxicities were nausea, fatigue and SGOT elevation. There was one partial response for a response rate of 7% (95% CI 0.2-32%) and median survival was 11 months (95% CI 3-13 months). The study was prematurely terminated due to lack of patient accrual.

Inhibition of breast and ovarian carcinoma cell growth by 1,25-dihydroxyvitamin D3 combined with retinoic acid or dexamethasone.

This study examined the growth inhibitory effects of combining 1,25-dihydroxyvitamin D3 (calcitriol) with retinoic acid or dexamethasone against cultured breast and ovarian carcinoma cells. Retinoic acid (12.5-50 nM) increased the effectiveness of calcitriol (12.5-50 nM) against MCF-7 and NIH:OVCAR3 cells, with synergistic interactions at two of the three ratios tested. Dexamethasone augmented calcitriol effects, with synergism at 0.05 and 0.1 nM dexamethasone in MCF-7 cells and 5 nM in Caov-4 ovarian cells. This study showed favorable interactions for calcitriol-retinoic acid and calcitriol-dexamethasone combinations in breast and ovarian cancer cell lines.

Phase II trial of amonafide in patients with advanced metastatic or recurrent endometrial adenocarcinoma. A Southwest Oncology Group study.

Amonafide, a benzisoquinoline-1,3-dione was administered to 38 patients with recurrent or metastatic, bidimensionally measurable endometrial cancer. There were 34 patients with no prior cytotoxic chemotherapy, performance status of 0-2, and normal bone marrow, renal, and hepatic function were eligible for response and toxicity evaluation. Amonafide, 300 mg/m2, was administered intravenously over 1 hour daily for 5 consecutive days. Courses were repeated every 21 days. The major grade 3 or 4 toxicities were hematologic with granulocytopenia in 18 patients (53%), thrombocytopenia in 6 patients (18%), and anemia in 8 patients (24%). Infectious complications occurred in 3 patients (9%). Other side effects included cardiac dysrhythmias, hypotension, pain and phlebitis at the site of injection, nausea, vomiting, and flu-like symptoms. The overall objective response rate was 6% (95% confidence interval of 1-20%); 2 patients had a complete response (6%), 9 patients had stable disease (26%) and 21 patients had progressive disease (62%). Two patients had insufficient follow-up for response determination and are assumed to be nonresponders. The median survival of the eligible patients was 8 months. With the toxicity observed and the low response rate, amonafide at this dose and schedule has no efficacy in the treatment of endometrial cancer.

[Emergency postpartum hysterectomy. A study over 5 years]. / Notfallmässige postpartale Hysterektomie: Eine Beobachtung über 5 Jahre.

A retrospective review was conducted of 34 women who underwent emergency peripartum hysterectomy at Hutzel Hospital--Wayne State University, Detroit from January 1986 to December 1991. Indications for hysterectomy were placenta accreta, uterine rupture, uterine atony and unspecified uterine bleeding. The median age of the patients was 33 years (20-40 years). The median hospital stay was 6 days (4-26 days) and median blood loss was 2000 ml (1000-6000 ml), with a median blood replacement of 4 units of packed cells (0-16 RPC). Postoperative complications included urinary tract infection (2), vaginal cuff cellulitis (3), wound infections (2), septic thrombophlebitis (2), acute tubular necrosis (1) and wound hematoma (1). No patient died.

Treatment of recurrent and metastatic endometrial carcinoma with cisplatin and doxorubicin.

Between April 1985 and February 1989, 19 patients with advanced or recurrent endometrial carcinoma were treated with the combination of cisplatin (50 mg/m2) and doxorubicin (50 mg/m2) administered intravenously every 21 days. Eight patients had Stage III disease, two had Stage IV and nine had recurrent cancer. Eleven patients had measurable disease at the start of therapy. There were 7 partial responses among the 19 patients, for an overall response rate of 36%. The median survival for the whole group was 17 months with a median progression free interval of 5 months. Patients without measurable disease at the onset of therapy had median survivals and progression free intervals which were significantly better than those patients with measurable disease, p < 0.011 and p < 0.025 respectively. Granulocytopenia (< 1000 microliters) occurred in 7 patients. No important thrombocytopenia, cardiotoxicity nephrotoxicity or neurotoxicity was observed. Emesis and alopecia occurred in all patients. No treatment related deaths were encountered.

Additive inhibition of RL95-2 endometrial carcinoma cell growth by carboplatin and 1,25 dihydroxyvitamin D3.

Responses of stage III/IV endometrial adenocarcinomas to cytotoxic agents have been partial and of short duration, results which indicate a need for new agents and therapeutic strategies. This study was undertaken to determine the effects of carboplatin and the active metabolite of vitamin D, 1,25 dihydroxyvitamin D3 (calcitriol), on the growth of RL95-2 endometrial carcinoma cells. Carboplatin is a second-generation platinum-based cytotoxic agent. Calcitriol is a biologic agent that has activity against multiple solid tumors, including ovarian carcinomas. Carboplatin inhibited the growth of RL95-2 cells in a concentration-dependent manner with maximal inhibition (78%) at 200 micrograms/ml. Calcitriol also inhibited RL95-2 growth in a concentration-dependent manner. Maximal inhibition (29%) was elicited by 80 nM calcitriol. Addition of 10-50 nM calcitriol to 5-20 micrograms/ml carboplatin resulted in improved growth inhibition. The degree of interaction between carboplatin and calcitriol was assessed using isobolographic analysis and was found to be additive at all drug concentrations and ratios examined. These results suggest that carboplatin and calcitriol each inhibit the growth of RL95-2 endometrial carcinoma cells and that the combination of these two agents acts additively to inhibit the growth of RL95-2 cells. These agents merit further investigation for their utility against endometrial carcinomas.

Inhibition of c-myc in breast and ovarian carcinoma cells by 1,25-dihydroxyvitamin D3, retinoic acid and dexamethasone.

The role and regulation of the c-myc protooncogene in breast and ovarian neoplasms is receiving increased attention. The downregulation of the c-myc protooncogene by 1,25-dihydroxyvitamin D3 (calcitriol), retinoic acid (RA) and dexamethasone (Dex) is closely associated with growth inhibition in leukemic cells. Calcitriol, RA and Dex have anti-proliferative activity in breast and gynecologic carcinoma cells; however, the regulation of c-myc by these agents in breast and ovarian cancers is mostly unknown. We have addressed the regulation of c-myc in these cancers using an adaptation of a novel method which employs an immunohistochemical procedure to detect c-myc protein followed by quantification of c-myc staining with computerized image analysis. This system represents an alternative to protein product assay by Western blotting and is straightforward, rapid (1 day), can be carried out on a small scale and provides a sample size that readily facilitates statistical analysis of assay data. In MCF-7 human breast cancer cells, c-myc was suppressed 29% by 0.5 nM Dex, 45% by 0.01 nM RA and 54% by 100 nM calcitriol after 24 h of drug treatment. At the same hormone concentrations, growth was inhibited 18% by Dex, 18% by RA and 39% by calcitriol after 3 days of treatment (p < 0.05 for all hormones). Similar patterns of growth and c-myc inhibition were seen in T47D human breast cancer cells and NIH:OVCAR3 human ovarian cancer cells, with the exception of Dex in T47D cells, which caused no inhibition of c-myc or growth.(ABSTRACT TRUNCATED AT 250 WORDS)

Uterine mixed embryonal rhabdomyosarcoma and fetal rhabdomyoma.

A polypoid uterine tumor, occurring in a 31-year-old woman, with histopathologic features of both embryonal rhabdomyosarcoma and fetal rhabdomyoma is reported. The clinical and pathologic differences between pure fetal rhabdomyoma and embryonal rhabdomyosarcoma are detailed and theories concerning the histogenesis of such a mixed, or intermediate, tumor are discussed. Most likely, this neoplasm represents one example in a spectrum of tumors with varying proportions of immature and mature skeletal muscle elements. Its good prognosis is in keeping with that of uterine (cervical) embryonal rhabdomyosarcomas in general, although the presence of mature skeletal muscle elements may signify an even better prognostic group of tumors.

[Electrosurgical loop excision as diagnostic and simultaneously therapeutic intervention in cervical intraepithelial neoplasia]. / Elektrochirurgische Schlingenexzision als diagnostischer und gleichzeitig therapeutischer Eingriff bei der zervikalen intraepithelialen Neoplasie.

109 women referred to our center for colposcopy because of suspicious cervical cytology and in whom an abnormal epithelial pattern was diagnosed on colposcopy, or in whom a discrepancy between cytology and colposcopy was encountered, concomitantly underwent loop electrosurgical excision procedure as an outpatient procedure. All removed specimens were examined and no invasive cancer was found in any of them. No serious complications occurred. Ambulatory loop electrosurgical excision procedure appears to be a cost-effective and well tolerated treatment modality for the management of women with cervical intraepithelial neoplasia, with the advantage that this conservative procedure allows histologic examination of the removed tissue.

Analysis of patient age as an independent prognostic factor for survival in a phase III study of cisplatin-cyclophosphamide versus carboplatin-cyclophosphamide in stages III (suboptimal) and IV ovarian cancer. A Southwest Oncology Group study.

BACKGROUND: The purpose of this study was to evaluate the effect of age (i.e., less than 65 years or 65 years of age and older) on survival in a recently completed phase III Southwest Oncology Group study in ovarian cancer patients. METHODS: Multivariate and univariate regression analyses were used to identify independent prognostic factors of survival in 342 patients with previously untreated Stage III (suboptimal) or Stage IV ovarian cancer who participated in a randomized, phase III study of intravenous (I.V.) carboplatin 300 mg/m2 plus I.V. cyclophosphamide 600 mg/m2 versus I.V. cisplatin 100 mg/m2 plus I.V. cyclophosphamide 600 mg/m2 every 4 weeks for six courses. RESULTS: Multivariate regression analysis showed the following variables to be independent prognostic factors of survival: age (P = 0.04); performance status (P = 0.004); disease stage (P = 0.03); and race (P = 0.05). Patients under 65 years of age survived significantly longer than those 65 years or older, especially patients with a performance status of 2. Patients with a baseline performance status of 0-1 survived longer than patients with a performance status of 2, and Stage III patients longer than those with Stage IV disease. An unexpected finding was that white patients survived significantly longer than black patients, regardless of age, performance status, or stage of disease. Carboplatin-cyclophosphamide-treated patients experienced similar survival and significantly less nausea and emesis, renal toxicity, hearing loss, tinnitus, neuromuscular toxicities, and alopecia. CONCLUSIONS: Ovarian cancer patients with advanced disease who are 65 years of age or older and/or with a performance status of 2 have significantly decreased survival compared to their younger and/or less debilitated counterparts. Carboplatin-cyclophosphamide is the recommended treatment (rather than cisplatin-cyclophosphamide), especially for older or debilitated patients because it is associated with less toxicity and similar survival.

Receptors for 1,25-dihydroxyvitamin D3 in gynecologic neoplasms.

To determine if gynecologic malignancies are candidates for 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) therapy we measured vitamin D receptor (VDR) levels in 11 tumor specimens using a radiolabeled ligand-binding assay. VDR was demonstrated in 3 of 6 ovarian tumors and 1 of 1 uterine sarcomas, but not in endometrial tumors (2), cervical tumors (1), or Krukenberg tumors (1). Scatchard plots revealed that [3H]1,25(OH)2D3 was bound to a single class of high-affinity (Kd = 0.3 to 0.6 nM), saturable sites characteristic of authentic 1,25(OH)2D3 receptors. Specificity of binding activity for 1,25(OH)2D3, the active vitamin D3 metabolite, was demonstrated by failure of 25-hydroxy- and 24,25-dihydroxyvitamin D3 to compete effectively against 1,25(OH)2D3 binding in total cellular tumor extracts. The ovarian carcinoma cell line NIH:OVCAR3 was shown to possess VDR (binding capacity = 137 fmol/mg protein, Kd = 0.48 nM). A 3-day incubation of NIH:OVCAR3 cells with 100 nM 1,25(OH)2D3 resulted in 49% inhibition of cell growth. The growth inhibition of an ovarian carcinoma line and the observation that 36% of gynecologic tumors assayed were shown to be VDR-positive suggest that further study is warranted to delineate the mechanism and possible therapeutic aspects of 1,25(OH)2D3 action in gynecologic tumors.

Evaluation of amonafide in cervical cancer, phase II. A SWOG study.

The Southwest Oncology Group conducted a Phase II study of amonafide in patients with metastatic or recurrent squamous cell cervical cancer. Twelve of the 15 patients were fully evaluable for response and toxicity. There were no clinical responses seen; 2 patients had stable disease while 13 had progressive disease. The major complication of this therapy was myelosuppression. Four patients had life-threatening granulocytopenia (less than 500/microliters), 3 patients had life-threatening leukopenia (less than 1000/microliters), while 2 patients had life-threatening thrombocytopenia (less than 25,000/microliters). Amonafide has significant toxicity but appears to be an inactive drug in metastatic or recurrent squamous cell cancer of the cervix.

Ovarian cancer. Advances in management.

Substantial progress has been made in understanding the biologic behavior of ovarian cancer and in assessing disease states and response to therapy with transvaginal sonography, CT scan, and tumor markers such as CA-125. There is no longer controversy regarding the importance and feasibility of adequate surgical staging, the need for cytoreduction, and the utility of cisplatin- or carboplatin-based combination chemotherapy in the management of patients with ovarian cancer. Increasing chemotherapy dose through escalated systemic doses or intraperitoneal administration, revising multidrug resistance, the use of biologic response modifiers, and the development of new methods of chemosensitivity testing may help improve the current 5-year survival rate of less than 30% for patients with stage III ovarian cancer. Significant improvement in screening tests and diagnostic capabilities will be necessary for a dramatic increase in survival.

High-dose-rate afterloading brachytherapy, external radiation therapy, and combination chemotherapy in poor-prognosis cancer of the cervix.

Fourteen patients with poor-prognosis cervical cancer were treated with concurrent chemotherapy (cisplatin and mitomycin-C), external radiation therapy (RT), and high-dose-rate (HDR) brachytherapy. Pelvic RT was delivered as (a) external-beam radiation (four-field box technique, 40.0 Gy), (b) brachytherapy using HDR 60Co or 192Ir (3.80 Gy/fraction, thrice weekly; total dose, 46.83 Gy) with intrauterine stent, and (c) parametrial boost using an AP field with custom-fabricated step wedges. Post-radical-hysterectomy patients received 50.40 Gy external RT and 3.23 Gy/day vaginal cylinder HDR at 1/2-cm depth (total dose, 16.15 Gy). Complete clinical and radiographic response was noted in all evaluable patients who are alive with no evidence of disease, 3 to 27 months after completion of therapy (median, 9 months). Toxicity consisted of grade 2 to 3 hematologic toxicity (4 patients) and nausea and vomiting in all, but grade 3 in only 2 patients. One patient had grade 2 diarrhea. The only major complication (small bowel obstruction) occurred in a patient with lupus vasculitis. This pilot study demonstrates the feasibility of this regimen in an outpatient setting with acceptable toxicity. More prolonged follow-up of our patients is required to determine its impact on long-term survival.

A preliminary report of combination chemotherapy with cisplatin and mitomycin-C followed by radical hysterectomy or radiation therapy in patients with locally advanced cervical cancer.

Neoadjuvant chemotherapy with cisplatin and mitomycin-C was used in the primary treatment of 17 patients with locally advanced cervical cancer (stages Ib-IIIb; tumor diameter greater than 5 cm) prior to definitive local treatment with radical hysterectomy or radiotherapy. Thirteen of the seventeen patients (76.5%) responded to initial chemotherapy, permitting a radical hysterectomy in ten patients. At histologic examination of the surgically resected primary tumor and lymph nodes, complete pathologic responses were found in 2 patients and partial pathologic responses in 8 patients. The median follow-up time is 14.5 months with a median survival for all patients of 52 weeks. All responders are alive. No therapy-related deaths, major complications, or delay in treatment occurred. Neoadjuvant chemotherapy with mitomycin-C and cisplatin is feasible and may be of benefit for patients with locally advanced cervical cancer.