Phase I trial of ifosfamide and 24-h infusional paclitaxel in pelvic malignancies: a Gynecologic Oncology Group study.

OBJECTIVE: The goal of this work was to develop a combination chemotherapy regimen consisting of ifosfamide and paclitaxel to be evaluated in the management of gynecologic malignancies. METHODS: The Gynecologic Oncology Group conducted a Phase I trial of the regimen, initially with paclitaxel (24-h infusion) delivered on Day 1 and ifosfamide (1 h) administered (with Mesna) over the subsequent 4 days. All patients received granulocyte colony-stimulating factor (G-CSF) starting 24 h after the Day 5 chemotherapy. Treatment was repeated on a 28-day schedule. A cohort of patients also received the alternate sequence of ifosfamide (4 days) followed by paclitaxel. RESULTS: Twenty-two patients were evaluated. Even at the lowest dose level tested (paclitaxel 135 mg/m(2) followed by ifosfamide 1 g/m(2)/day x 4 days) grade 4 neutropenia was almost universal, despite the routine use of G-CSF. The alternate drug administration sequence resulted in marrow suppression of similar severity. CONCLUSION: The combination of 24-h infusional paclitaxel with ifosfamide delivered over 4 days results in severe neutropenia, despite the administration of G-CSF, and is not recommended for further evaluation. In view of the known activity of the two agents in several malignancies, including cervix cancer, it would be reasonable to investigate the delivery of the agents employing alternative treatment schedules predicted to result in less severe marrow suppression (e.g., 3-h infusional paclitaxel).

Preoperative chemo-radiation for carcinoma of the vulva with N2/N3 nodes: a gynecologic oncology group study.

PURPOSE: To determine if patients with carcinoma of the vulva, with N2/N3 lymph nodes, could undergo resection of the lymph nodes and primary tumor following preoperative chemo-radiation. METHODS AND MATERILAS: Fifty-two patients were entered in the study, but six patients did not meet the criteria of the protocol and were excluded. The remaining 46 patients are the subject of this report. Patients underwent a split course of radiation, 4760 cGy to the primary and lymph nodes, with concurrent chemotherapy, cisplatin/5-FU, followed by surgery. RESULTS: Four patients did not complete the chemo-radiation, because three expired and one refused to complete the treatment. Four patients who completed chemo-radiation did not undergo surgery, because two of them died of non-cancer-related causes, and in the other two patients, the nodes remained unresectable. Following chemo-radiation, the disease in the lymph nodes became resectable in 38/40 patients. Two patients who completed the course of chemo-radiation did not undergo surgery as per protocol because of pulmonary metastasis. One underwent radical vulvectomy and unilateral node dissection and the other radical vulvectomy only. The specimen of the lymph nodes was histologically negative in 15/37 patients. Nineteen patients developed recurrent and/or metastatic disease. The sites of failure were as follows: primary area only, 9; lymph node area only, 1; primary area and distant metastasis, 1; distant metastasis only, 8. Local control of the disease in the lymph nodes was achieved in 36/37 and in the primary area in 29/38 of the patients. Twenty patients are alive and disease-free, and five have expired without evidence of recurrence or metastasis. Two patients died of treatment-related complications. CONCLUSION: High resectability and local control rates of the lymph nodes were obtained in patients with carcinoma of the vulva with N2/N3 nodes treated preoperatively with chemo-radiation.

A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma of the uterus: A Gynecologic Oncology Group Study.

OBJECTIVE: The aims of this study were to substantiate the previously reported activity of ifosfamide in patients with advanced, persistent, or recurrent carcinosarcoma (mixed mesodermal sarcoma) of the uterus, and to determine whether the addition of cisplatin results in an improved response or survival. Secondarily, we sought to determine the toxicity of ifosfamide-cisplatin in this patient population. METHODS: Patients were randomized to receive ifosfamide (1.5 g/m(2)/day) times 5 days every 3 weeks for eight courses with mesna uroprotection, with or without cisplatin (20 mg/m(2)/day) times 5 days. No patient had received previous chemotherapy. RESULTS: Of 224 patients entered on this study, 30 were ineligible for a variety of reasons, leaving 194 evaluable patients. Early in the study, the dose of the combination regimen was reduced by 20% (1 day) because of toxicity. The investigational arms were balanced for age, grade, and Gynecologic Oncology Group performance status. Percentages of adverse effects reported in 191 patients receiving chemotherapy included (ifosfamide/cisplatin-ifosfamide) grade 3 or 4 granulocytopenia (36/60), grade 3 or 4 anemia (8/17), grade 3 or 4 central nervous system toxicity (19/14), and grade 3 or 4 peripheral neuropathy (1/12). Treatment may have contributed to the deaths of 6 patients treated with full doses of ifosfamide and cisplatin for 5 days. The proportion of patients responding to ifosfamide alone versus ifosfamide-cisplatin therapy was (0.36 versus 0.54) overall, 0.47 versus 0.61 for pelvic, 0.21 versus 0.54 for lung, and 0.33 versus 0.40 for "other" metastatic sites of measurable disease. The relative odds ratio of response adjusted for measurable sites of disease was 1.82 (P = 0.03, one-tailed test; 95% lower confidence limit, 1.06). Progression-free survival (PFS) and survival data suggest that the combination offers a slight prolongation of PFS (relative risk, 0.73; 95% upper confidence limit, 0.94; P = 0.02, one-tailed test), but no significant survival benefit (relative risk, 0.80, 95% upper confidence limit, 1.03; P = 0.071, one-tailed test). CONCLUSION: The addition of cisplatin to ifosfamide appears to offer a small improvement in progression-free survival over ifosfamide alone in the management of advanced carcinosarcoma of the uterus; the added toxicity may not justify the use of this combination.

Topotecan has substantial antitumor activity as first-line salvage therapy in platinum-sensitive epithelial ovarian carcinoma: A Gynecologic Oncology Group Study.

PURPOSE: Topotecan is known to be active in recurrent ovarian cancer, but most prior studies have focused on platinum-resistant or refractory populations. This study was undertaken to define the response rate and progression-free interval in platinum-sensitive patients. PATIENTS AND METHODS: Patients with recurrent ovarian cancer after one or two prior chemotherapy regimens and in whom the interval between prior platinum therapy and the initiation of protocol therapy was greater than 6 months were treated with topotecan 1.5 mg/m(2) intravenously over 30 minutes daily for 5 days, with this cycle repeated every 21 days. RESULTS: Forty-eight patients were entered onto the study; 47 were assessable for toxicity and 46 for response. The response rate was 33% (two complete responses and 13 partial responses), with a median response duration of 11.2 months. Hematologic toxicity predominated but was manageable in most patients with frequent incorporation of cytokines and RBC and platelet transfusions. Fatigue was reported in 15 patients and resulted in the discontinuation of therapy in five responding patients. CONCLUSION: Topotecan is an active drug in platinum-sensitive ovarian cancer, with significant but manageable hematologic toxicity. Fatigue is also a common problem that may be dose-limiting in some patients.

Intraperitoneal interferon-alpha in residual ovarian carcinoma: a phase II gynecologic oncology group study.

OBJECTIVE: The purpose of this study was to confirm the activity of interferon-alpha intraperitoneally in minimal residual epithelial ovarian cancer in a Phase II multi-institutional trial and to investigate the activity of the agent based on prior response to first-line platinum compounds. METHODS: Ninety-two patients with minimal residual (<0.5 cm) epithelial ovarian cancer at reassessment laparotomy were entered into a multicenter trial of intraperitoneal interferon-alpha given for 12 cycles unless disease progression or unacceptable toxicity occurred first. Patients were considered favorable if they were platinum sensitive and/or relapsed 6 months or longer after completing treatment and unfavorable if they were platinum insensitive and/or relapsed shorter than 6 months after completing treatment and/or had stable or progressive disease during initial therapy. A third-look laparotomy was performed within 12 weeks of completion of treatment in those patients who were in clinical remission. RESULTS: Eighty patients were clinically evaluable for toxicity only (48 favorable, 32 unfavorable) and 46 of them were evaluable for response, of whom 25 were favorable (platinum sensitive) and 21 unfavorable (platinum resistant). In the favorable group, there was a 28% surgically documented response rate (7/25 patients): 16% (4/25) had complete responses (negative reassessment operation), 12% (3/25) had partial responses, 32% (8/25) were nonresponders, and 40% (10 patients) developed progressive disease before planned reassessment operation. In the unfavorable group, there were no responding patients: 6 were nonresponders at reassessment operation and 15 developed progressive disease before planned reassessment operation. Of the 80 patients evaluable for toxicity, the most common adverse effects that were more than grade 2 were gastrointestinal (12; 15%), fever (8; 10%), neutropenia (7;9%), and leukopenia (6; 8%). Grade 4 toxicity was seen in 5 patients; each had fever and gastrointestinal toxicity, and 1 each had neutropenia and thrombocytopenia. CONCLUSIONS: Interferon-alpha is an active and generally well-tolerated agent in favorable patients with minimal residual epithelial ovarian cancer at second-look surgery. These results are comparable to those achieved with cytotoxic chemotherapy. If Phase III trials are considered in the patients with minimal residual ovarian cancer, they should be limited to the platinum-sensitive patient population.

A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: A Gynecologic Oncology Group Study.

OBJECTIVE: The objective of this study was to evaluate the benefits and risk of adjuvant pelvic radiotherapy aimed at reducing recurrence in women with Stage IB cervical cancer treated by radical hysterectomy and pelvic lymphadenectomy. METHODS: Two hundred seventy-seven eligible patients were entered with at least two of the following risk factors: >1/3 stromal invasion, capillary lymphatic space involvement, and large clinical tumor diameter. Of 277 patients, 137 were randomized to pelvic radiotherapy (RT) and 140 to no further treatment (NFT). RESULTS: Twenty-one (15%) in the RT group and 39 (28%) in the NFT group had a cancer recurrence, 18 of whom were vaginal/pelvic in the RT and 27 in the NFT group. In the RT group, of 18 (13%) who died, 15 died of cancer. In the NFT group, of the 30 (21%) who died, 25 died from cancer. Life table analysis indicated a statistically significant (47%) reduction in risk of recurrence (relative risk = 0.53, P = 0.008, one-tail) among the RT group, with recurrence-free rates at 2 years of 88% versus 79% for the RT and NFT groups, respectively. Severe or life-threatening (Gynecologic Oncology Group grade 3 or 4) urologic adverse effects occurred in 4 (3.1%) in the RT group and 2 (1.4%) in the NFT group; 3 (2.3%) and 1 (0.7%) hematologic; 4 (3.1%) and 0 gastrointestinal (GI); and 1 (0.8%) and 0 neurologic, respectively. One patient's death was attributable to grade 4 GI adverse effects. CONCLUSIONS: Adjuvant pelvic radiotherapy following radical surgery reduces the number of recurrences in women with Stage IB cervical cancer at the cost of 6% grade 3/4 adverse events versus 2.1% in the NFT group.

Postmenopausal diagnosis of testicular feminization.

A case of testicular feminization diagnosed in a postmenopausal 67-year-old woman who had a pelvic mass, absent uterus, and a markedly elevated serum testosterone level is described. After the surgical extirpation of the patient's gonads, including a 15-cm Sertoli cell adenoma, the serum testosterone level normalized.

Altretamine (hexamethylmelamine) in platinum-resistant and platinum-refractory ovarian cancer: a Gynecologic Oncology Group phase II trial.

OBJECTIVES: In an effort to critically examine the antitumor activity of altretamine (hexamethylmelamine) as salvage therapy of platinum-refractory ovarian cancer, the Gynecologic Oncology Group initiated a Phase II trial of the agent administered in this clinical setting. METHODS: Altretamine was administered at a dose of 260 mg/m2 orally for 14 days in a 28-day course. Treatment was continued until disease progression or unacceptable side effects prevented further therapy. A total of 36 patients (median age: 56.5) were treated on this trial, of whom 33 were evaluable for toxicity and 30 for response. All patients had previously received either cisplatin or carboplatin and paclitaxel. RESULTS: The major side effect was emesis (grade 3-4, 7/33, 21%). The objective response rate was 10% (one complete response, two partial responses). CONCLUSION: We conclude that altretamine has limited activity in platinum-refractory ovarian cancer.

Effects of perioperative blood transfusion on prognosis in early-stage cervical cancer.

BACKGROUND: This study was designed to evaluate the prognostic effects of transfusion on patients undergoing radical hysterectomy for early cervical cancer. METHODS: This retrospective chart review analyzed 412 patients with stage IA-IIA disease, of whom 374 were evaluable. RESULTS: Three hundred (80%) patients received transfusions and 74 (20%) did not. The clinical characteristics of the two groups were similar, with the exception that the transfused group was older. Pathologic comparisons found that microscopic parametrial disease and larger cervical lesions were more common in the transfused group. Follow-up analysis revealed no difference between the two groups in recurrence or survival. Multivariate analysis found only grade, depth of invasion, and nodal status as independent predictors of recurrence and survival. Kaplan-Meier survival analysis showed no difference in overall survival or disease-free interval between the transfused and nontransfused groups. CONCLUSIONS: After correction for other prognostic factors, blood transfusion had no prognostic significance in patients with early cervical cancer undergoing radical hysterectomy.

Gynecologic problems in older women.

Regular gynecologic evaluation in older women is an integral part of medical care, just as it is for women of reproductive age. This should be emphasized since older women often neglect early symptoms of gynecologic diseases, some of which are potentially lethal. With this in mind, the health care provider must be cognizant of not only gynecologic problems that affect all women, but also those disease processes which are either specific to or more prevalent in an older population. This article emphasizes these aspects in caring for the older gynecologic patient.

Phase II trial of piroxantrone in advanced squamous cell carcinoma of the cervix: a Gynecological Oncology Group study.

Piroxantrone was administered at a starting dose of 160 mg m2 given as a 1-h infusion every 3 weeks to 19 patients with histologically confirmed advanced, persistent, or recurrent squamous cell carcinoma of the cervix. All patients were required to have measurable disease and no prior chemotherapy. Eighteen women were evaluable for toxicity and response. Toxicity was modest and consisted primarily of myelosuppression with six (33%) patients experiencing grade 3 or 4 leukopenia. There were no complete (CR) or partial responses (PR) among the 18 evaluable patients. Six (33%) patients had stable disease while on treatment and 12 (67%) patients experienced progressive disease. Piroxantrone appears to have no beneficial effect in advanced or recurrent squamous cell cancer of the cervix at this dose and schedule.

A phase II trial of 5-fluorouracil and high-dose leucovorin in patients with recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study.

The addition of leucovorin to 5-fluorouracil (5-FU) has been shown to improve the response rate in recurrent colon cancer. The combination of low-dose leucovorin and 5-FU was previously tested by the Gynecologic Oncology Group (GOG) and did not produce response rates greater than rates using 5-FU alone. From June 1990 to April 1992, 55 patients with unresectable recurrent squamous cervical cancer received high-dose leucovorin at 200 mg/m2 i.v. bolus, followed by 5-FU at 370 mg/m2 i.v. bolus daily for 5 days every 4 weeks for the first two courses. Subsequent courses were given every 5 weeks. The median number of courses delivered was two (range 1-15). Fifty patients were evaluable for toxicity and 45 for response. Prior radiotherapy had been given to 43 patients and prior chemotherapy to 38. The overall response rate was 8.8% (95% confidence interval, 2.5-21.2%). There were two complete responses (4.4%) and two partial responses (4.4%). One response was in the pelvis and three were outside the pelvis. None of the extrapelvic responses had received irradiation at the site of measurable disease. The major adverse effect was granulocytopenia, with 15/50 (30%) experiencing GOG grade 3 or 4 granulocytopenia. The median white blood count for patients experiencing leukopenia was 2,000 (range 400-3,800). Grade 3 or 4 gastrointestinal toxicity was seen in 12 patients (24%). In this pretreated population, patients receiving high-dose leucovorin with 5-FU had moderate toxicity but only minimal activity.

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

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

Paclitaxel has moderate activity in squamous cervix cancer. A Gynecologic Oncology Group study.

PURPOSE: Taxol (paclitaxel; Bristol-Myers Squibb, Princeton, NJ) is a new antineoplastic drug with broad-spectrum activity in solid tumors, including epithelial ovarian cancer, head and neck cancer, esophageal cancer, breast cancer, bladder cancer, and lung cancer. Its unique mechanism of action, polymerization of tubulin monomers, has stimulated both clinical and preclinical research on this agent. As limited drug supplies became more plentiful, a phase II trial of Taxol was initiated in patients with advanced squamous cervix cancer who had received no prior chemotherapy. PATIENTS AND METHODS: In this trial, 30 assessable patients were initially entered onto the study and four partial responses were seen. Further accrual of 22 assessable patients was then accomplished to define better the response rate with smaller confidence intervals. The starting dose of Taxol was 170 mg/m2 (135 mg/m2 for patients with prior pelvic radiation) given as a 24-hour continuous intravenous infusion with courses repeated every 3 weeks. Dose escalations to 200 mg/m2 and deescalations to 110 mg/m2 were allowed based on adverse effects. RESULTS: The final response rate was 17% (two complete responses and seven partial responses). The primary and dose-limiting toxicity was neutropenia. CONCLUSION: The response rate makes Taxol a drug with sufficient activity to explore it in combination with other agents with similar activity.

High-dose megestrol acetate in advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group Study.

PURPOSE: Progestins represent the most widely used form of endocrine therapy in advanced or recurrent endometrial carcinoma. Based on encouraging response rates in breast cancer with high-dose megestrol acetate (MA) 800 mg/d, this phase II trial assessed response rates in patients with endometrial carcinoma treated with high-dose MA. PATIENTS AND METHODS: Sixty-three patients with recurrent or advanced endometrial carcinoma were entered into this Gynecologic Oncology Group (GOG) study. Patients had either failed to respond to or were considered incurable with local therapy and had not received prior cytotoxic or hormonal therapy. MA 800 mg/d was administered orally in divided doses. Standard GOG toxicity criteria were used. RESULTS: Of 63 patients entered, 58 were assessable for toxicity and 54 for response. Of 13 responders (24%), six (11%) had a complete and seven (13%) a partial response. Four of the responses lasted greater than 18 months. Twelve patients (22%) had stable disease. The response rate of patients with grade 1 or 2 lesions (11 of 30, 37%) was significantly higher (P = .02) than that of patients with more poorly differentiated tumors (two of 24, 8%). There was no difference in response rates comparing advanced versus recurrent disease, cell type, including papillary serous lesions, site of disease, prior radiation, age, or weight. The median progression-free survival (PFS) and overall survival intervals were 2.5 and 7.6 months, respectively. Grade 3 weight gain (> 20%) was seen in three patients and grade 3/4 hyperglycemia in three. Three deaths secondary to cardiovascular events were possibly related to therapy; diabetes was also a contributing factor in all three cases. CONCLUSION: High-dose MA is active in endometrial carcinoma, but appears to have no advantage over lower-dose progestins.

Radiation-induced vesicosacral fistula: treatment with continent urinary diversion.

This is the first Case Report of a vesicosacral fistula related to prior radiation therapy. This patient developed recurrent adenosquamous carcinoma of the cervix 1 year after radical hysterectomy. She received 5000 cGy to the whole pelvis and a 1500-cGy boost to the area of recurrence in the right pelvic sidewall. The patient had significant toxicity with recurrent pelvic fistula formation ultimately requiring an end sigmoid colostomy. In addition, the patient required urethral catheterization due to urinary incontinence secondary to a hypertonic bladder. Approximately 14 years after radiation therapy the patient developed a vesicosacral fistula. With a nonfunctional bladder, the decision was made to proceed with a continent urinary diversion procedure. Despite a prior ileocecal resection due to radiation injury, a Miami pouch reservoir was created. Postoperatively, the patient remained continent using intermittent catheterization of the pouch.

Osteitis pubis: a review.

Osteitis pubis is a painful, noninfectious inflammatory condition that involves the pubic bone, symphysis, and surrounding structures. Initially associated with urologic procedures, osteitis pubis has been described as a complication of various obstetrical and gynecological procedures including vaginal deliveries. An incidence of approximately 2 to 3 percent has been observed after the Marshall-Marchetti-Krantz urethropexy. Although the pathogenesis of osteitis pubis is not clear, periosteal trauma seems to be an important initiating event. Pain is the primary symptom associated typically with difficulty in ambulation and the characteristic "waddling gait." A low grade fever, elevated sedimentation rate, and mild leukocytosis may be observed. Radiographic findings which include reactive sclerosis, rarefaction, and osteolytic changes lag behind the symptoms by about 4 weeks. The major differential diagnosis is osteomyelitis; however, the self-limiting nature and its response to nonantibiotic therapy indicates that osteitis pubis is a separate clinical entity. Treatment is directed at the associated inflammation with most minor cases responding to antiinflammatory agents and bedrest. Other more recalcitrant cases require more involved therapy including systemic steroids and rarely surgical resection. The diagnosis of osteitis pubis should be considered when pelvic pain is present in association with potential trauma to the symphysis pubis. Also, with more women participating in sporting activities patients may present to the physician with osteitis pubis related to athletic injury.

Topical sucralfate in the treatment of vaginal ulceration.

BACKGROUND: Non-neoplastic vaginal ulceration is at times recalcitrant to traditional methods of treatment. Sucralfate, a basic aluminum salt of sucrose octasulfate, binds preferentially to ulcerated areas and promotes healing, an effect that does not appear to be acid-dependent. CASE: Three cases of vaginal ulceration were treated with vaginal douches of sucralfate 10% suspension twice daily. One of the cases was due to laser ablation for intraepithelial neoplasia, one was of uncertain etiology, and one was caused by pessary use. CONCLUSION: After failure of the initial therapeutic regimens, sucralfate treatment was successful in all three cases and was well tolerated without side effects. Sucralfate vaginal douches should be considered for the treatment of non-neoplastic vaginal ulcerations, particularly when other therapy has failed.