C.A. Stringer

Prospective treatment of advanced or recurrent endometrial carcinoma with cisplatin, doxorubicin, and cyclophosphamide

Abstract Both single-agent cisplatin and the combination of doxorubicin and cyclophosphamide demonstrated moderate activity against endometrial carcinoma in earlier salvage trials. Since January 1979, 102 patients with advanced primary ( n = 42) or recurrent ( n = 60) endometrial carcinoma were prospectively treated with cisplatin (50 mg/m 2 ), doxorubicin (50 mg/m 2 ), and cyclophos-phamide (500 mg/m 2 ) (PAC). PAC was administered monthly until disease progression or toxicity precluded additional therapy. Patients received a median of five treatment cycles (range 1–13). Of the 87 patients with measurable disease, 12 had a complete clinical response, while 27 had a partial clinical response, for an overall objective response rate of 45%. No differences in response rates between primary and recurrent disease patients were noted. Median time to response was 2.5 months with a median response duration of 4.8 months. Nonresponders included 33 patients with stable disease and 15 with progression. Median progression-free survival for all patients was 6 months. Dose escalation was possible in 25% of patients; however, 52% of patients required dose reductions during treatment. Clinically significant toxicities included neutropenia (65%), anemia (47%), emesis (21%), nephrotoxicity (17%), and neurotoxicity (4%). Our study indicates that endometrial cancer is significantly responsive to PAC. Enthusiasm for this regimen should be tempered by the limited duration of response and substantial treatment toxicity.

Cisplatin therapy for disseminated mixed mesodermal sarcoma of the uterus.

Eighteen patients with metastatic mixed mesodermal sarcoma of the uterus received cisplatin therapy at the University of Texas (UT) M.D. Anderson Hospital and Tumor Institute at Houston. The dose of cisplatin varied from 75 mg/m2 to 100 mg/m2. Previous therapy included surgery in 11 patients, radiotherapy in two patients, and surgery plus radiotherapy in four patients. One patient had no prior therapy. Seven patients had also received prior chemotherapy with doxorubicin. Of 12 patients with measurable disease, one (8%) had a complete response and four (33%) had a partial response for an overall response rate of 42%. The median progression-free survival of patients treated with cisplatin as first- and second-line therapy was 4.5 and 5.5 months, respectively. Cisplatin demonstrated moderate activity with mild toxicity in this group of patients with metastatic mixed mesodermal uterine sarcomas. Further studies including cisplatin-containing combination regimens seem to be warranted.

Phase I dose escalation of paclitaxel in patients with advanced ovarian cancer receiving cisplatin: rapid development of neurotoxicity is dose-limiting.

PURPOSE To determine the maximum-tolerable dose (MTD) of paclitaxel in a phase I dose-escalation study when combined with cisplatin in patients with advanced ovarian cancer receiving filgrastim for prophylaxis of myelosuppression. PATIENTS AND METHODS A total of 23 patients with stage II (bulky residual), III, or IV epithelial ovarian cancer were treated (following debulking surgery) with paclitaxel as a 3-hour infusion followed by cisplatin (75 mg/m2) administered over 4 hours on day 1, repeated every 21 days for six cycles. Filgrastim (5 micrograms/kg/d) was administered subcutaneously (SC) beginning on day 2 of each cycle through neutrophil recovery (absolute neutrophil count [ANC] > 10,000/microL). Patients were assigned to one of six escalating dose levels of paclitaxel: 150 (n = 3), 175 (n = 3), 200 (n = 3), 225 (n = 4), 250 (n = 4), and 275 mg/m2 (n = 6). RESULTS At each paclitaxel dose level (150, 175, 200, 225, 250, and 275 mg/m2), the numbers of patients who completed six cycles without dose reduction were three (100%), three (100%), two (66%), two (50%), three (75%), and zero (0%), respectively. The numbers of patients who experienced a grade III/IV adverse event (hematologic or nonhematologic) were zero (0%), two (66%), two (66%), one (25%), four (100%), and five (80%), respectively. Reasons for dose reduction included neurotoxicity (225 mg/m2, n = 1; 275 mg/m2, n = 2), neutropenia (225 mg/m2, n = 2), diarrhea (275 mg/m2, n = 2), and nephrotoxicity (225 mg/m2, n = 1). Reasons for not completing six cycles at full or reduced dose included neuropathy (200, 225, and 275 mg/m2, n = 1 each) physician request (275 mg/m2, n = 1), and death (275 mg/m2, n = 1). Hematopoietic toxicity was minimal. Six patients developed grade III/IV neutropenia. No patient developed thrombocytopenia below a level of 50,000/microL. CONCLUSION The MTD of paclitaxel was determined to be 225 mg/m2 when administered as a 3-hour infusion and combined with cisplatin (75 mg/m2). Nonhematologic dose-limiting toxicities were neuropathy and diarrhea. The neuropathy often had a rapid onset, especially at the higher dose levels.

Adjuvant chemotherapy with cisplatin, doxorubicin, and cyclophosphamide (PAC) for early-stage high-risk endometrial cancer: A preliminary analysis☆

Abstract Between October 1985 and January 1989, 33 patients with stage I (31) or clinically occult stage II (2) endometrial cancer at a high risk for recurrence were entered in a prospective study evaluating adjuvant cisplatin, doxorubicin, and cyclophosphamide (PAC) chemotherapy. Eligibility criteria included grade 2 tumors with middle- or outer-third myometrial invasion (16), grade 3 tumors with any degree of myometrial invasion (17), presence of extrauterine disease with no gross residual (17), or a high-risk histologic subtype including papillary serous (4), adenosquamous (5), or clear cell (1) tumors. Patients received PAC (50/50/500 mg/m 2 ) at 4-week intervals for six cycles. Thirty patients (90%) completed therapy. Toxicity included severe neutropenia in 14 patients, neutropenic sepsis in 2 patients, and doxorubicin-related cardiomyopathy in 1 patient. There were no treatment deaths. Current median follow-up is 25 months. Nine patients (27%) have developed a recurrence, 7 of whom died, after a median interval of 14 months. Eight of the 9 with recurrence initially had extrauterine disease ( P = 0.02). The resulting 2-year actuarial progression-free and overall survival rates were 79 and 83%, respectively. The median progression-free interval was 29 months for patients with extrauterine disease and 45 + months for those with no extrauterine disease ( P = 0.02). These results suggest that a phase 3 randomized trial comparing adjuvant PAC with radiation therapy is warranted.

A phase I/II dose escalation study of carboplatin in the treatment of newly diagnosed patients with advanced ovarian cancer receiving paclitaxel.

The objective of this study was to determine the maximum tolerated dose of carboplatin when administered with paclitaxel in previously untreated patients with ovarian cancer. Patients were treated with paclitaxel at 225 mg/m2 for 3 hours followed by carboplatin at an area under the curve (AUC) of 6, 7, 8, or 9 every 3 weeks. Granulocyte colony-stimulating factor was added if needed to maintain dose intensity before dose reductions were used for grade 4 hematologic toxicity or febrile neutropenia. Twenty-two patients were enrolled in the study. At the AUC 6 level, five of six patients finished all six cycles. At the AUC 7 level, four of five patients completed six cycles, although three required dose reductions for toxicity. At the AUC 8 level, all four patients completed six cycles and two required dose reductions. The AUC 9 level was not well tolerated. Only four of seven patients completed six cycles. Neutropenia was common, and transient thrombocytopenia was more severe and required dose reduction, especially in later cycles. An AUC of 8 is the maximum tolerated dose of carboplatin in combination with paclitaxel at 225 mg/m2 for 3 hours.

Radical wide excision and selective inguinal node dissection for squamous cell carcinoma of the vulva

Limited resection of some vulvar cancers may provide cure rates equivalent to those obtained with radical vulvectomy and bilateral inguinal node dissection. Rapid recovery, fewer complications, and better functional result have been described as advantages to less extensive procedures. Since 1978, 32 patients with invasive squamous cell cancer of the vulva (depth greater than 1 mm) and clinically negative inguinal lymph nodes underwent radical wide excisions as primary therapy. Mean age at diagnosis was 61 years. Seventeen patients had T1 and 15 had T2 tumors. Resection of the primary lesion was tailored to lesion location and size, and dissection was carried to the deep perineal fascia. Twenty-two patients had unilateral superficial inguinal lymph node dissections, five with midline lesions had bilateral superficial dissections, and five had node samplings which included deep inguinal nodes. Depth of invasion ranged from 1.5 to 13.0 mm. Mean largest lesion dimension was 23 mm. Five-year lifetable survival for the entire group was 84%. Univariate analysis of potential prognostic variables showed no significant recurrence or survival differences for patient age (P = 0.56), symptom duration (P = 0.57), FIGO stage (P = 0.67), tumor grade (P = 0.20), tumor location (P = 0.26), depth of invasion (P = 0.56), or resection margin status (P = 0.63). Thirty-one percent of patients had perioperative complications, and 16% developed delayed complications. Mean hospital stay was 10 days. Three patients (10%) developed new or recurrent vulvar disease and underwent additional therapy. None have died of disease, although one is alive with persistent tumor. Radical wide excision and selective inguinal lymphadenectomy constitute a reasonable alternative to radical vulvectomy with bilateral inguinal node dissections for squamous tumors clinically limited to the vulva. Outcome may not be strongly influenced by lesion size or depth of invasion.

Adjuvant chemotherapy with cisplatin, doxorubicin, and cyclophosphamide (PAC) for early-stage high-risk endometrial cancer: A preliminary analysis

Between October 1985 and January 1989, 33 patients with stage I (31) or clinically occult stage II (2) endometrial cancer at a high risk for recurrence were entered in a prospective study evaluating adjuvant cisplatin, doxorubicin, and cyclophosphamide (PAC) chemotherapy. Eligibility criteria included grade 2 tumors with middle- or outer-third myometrial invasion (16), grade 3 tumors with any degree of myometrial invasion (17), presence of extrauterine disease with no gross residual (17), or a high-risk histologic subtype including papillary serous (4), adenosquamous (5), or clear cell (1) tumors. Patients received PAC (50/50/500 mg/m2) at 4-week intervals for six cycles. Thirty patients (90%) completed therapy. Toxicity included severe neutropenia in 14 patients, neutropenic sepsis in 2 patients, and doxorubicin-related cardiomyopathy in 1 patient. There were no treatment deaths. Current median follow-up is 25 months. Nine patients (27%) have developed a recurrence, 7 of whom died, after a median interval of 14 months. Eight of the 9 with recurrence initially had extrauterine disease (P = 0.02). The resulting 2-year actuarial progression-free and overall survival rates were 79 and 83%, respectively. The median progression-free interval was 29 months for patients with extrauterine disease and 45+ months for those with no extrauterine disease (P = 0.02). These results suggest that a phase 3 randomized trial comparing adjuvant PAC with radiation therapy is warranted.

Gracilis myocutaneous vaginal reconstruction concurrent with total pelvic exenteration

The gracilis myocutaneous vaginal reconstruction is commonly performed in patients undergoing a total pelvic exenteration. This retrospective review compares the operative and perioperative morbidity in 107 patients who underwent reconstruction with that in 44 patients who did not have reconstruction. With incorporation of the reconstructive procedure, there were no increases in operating time, blood loss, or length of hospitalization. Before 1980, 65% of patients experienced prolapse of the neovagina; in 25% it was severe. The frequency of prolapse has since been decreased to 16% (6% severe) because of several modifications to the initial technique. Modifications have included using smaller flaps, anchoring the neovagina to the levator and retropubic fascia, and, when necessary for mobilization, ligating the neurovascular pedicle. With these modifications, 66% of patients also remained free of wound breakdown or necrosis. The frequency of severe necrosis has decreased from 24% to 13%. The anatomic result of the vaginal reconstructions appears to have been enhanced by these changes in technique.

Endodermal sinus tumor of vagina and cervix

This report describes six patients with endodermal sinus tumor of the vagina and cervix, a polypoid friable tumor whose clinical presentation in girls younger than age 3 years simulates the presentation of sarcoma botryoides. In four of the six patients, the referring diagnosis was sarcoma botryoides. Five patients were treated with excisional surgery, and all six with chemotherapy. One patient with pulmonary metastases maintained a complete clinical response to vincristine, actinomycin-D, and cyclophosphamide (VAC) for 11 months. This is the first report of such a response. One patient with a vaginal lesion remains clinically free of disease 2 years after local excision and 18 months of VAC chemotherapy. This is the first report of apparently successful therapy that allowed retention of childbearing potential. Four of the six patients have been disease-free from 2 to 23 years. After examining the world literature, it is concluded that a combination of chemotherapy and surgery offers a reasonable prospect of cure with a minimum of serious side effects.