Creighton L. Edwards

Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma.

PURPOSE To determine the efficacy and toxicity of topotecan administered as a 5-day intravenous infusion in patients with advanced ovarian cancer refractory to cisplatin-based chemotherapy. PATIENTS AND METHODS Thirty patients with advanced epithelial ovarian cancer refractory to cisplatin-based chemotherapy received intravenous infusions of topotecan 1.5 mg/m2 delivered over 30 minutes each day for 5 days. A course was repeated every 21 days. The patient eligibility requirements included age > or = 18 years, Zubrod score < or = 2, measurable disease, adequate hepatic and renal function, neutrophil count > or = 1,500/microL, platelet count > or = 100,000/microL, and anticipated survival > or = 3 months. RESULTS Twenty eight patients were assessable for response and toxicity. All patients were assessable for survival. The major toxicity from administration of topotecan at this dose schedule was myelosuppression; 21 patients required dose reductions. Four patients had neutropenic fever that required hospitalization, and seven patients required platelet transfusions. Maculopapular pruritic exanthema occurred in 20% of patients; gastrointestinal side effects were mild. No deaths were reported on the study. At dose levels of 1.5, 1.25, and 1.0 mg/m2, 61%, 31%, and 25% of patients, respectively, required dose reductions. Of 28 assessable patients, four (14%; 95% confidence interval [CI], 4% to 34%) achieved a partial response (PR) at a median of 1.4 months and lasting 8.9 months, and 17 had stable disease (SD). The overall median survival time was 10.0 months (95% CI, 8.1 to 13.5). CONCLUSION Topotecan shows modest clinical activity against cisplatin-refractory ovarian cancer, although the dose-intensity is compromised by the depth of the granulocyte nadir and the duration of granulocytopenia. Further studies of topotecan may necessitate a reevaluation of optimal dose schedule, with the possible incorporation of multilineage cytokines, and its activity in taxane-resistant tumors.

Treatment of malignant germ cell tumors of the ovary with bleomycin, etoposide, and cisplatin.

Since 1984, we have treated 26 patients with malignant ovarian germ cell tumors with a combination of bleomycin, etoposide (VP-16), and cisplatin (BEP) at The University of Texas MD Anderson Cancer Center (UTMDACC). The median age of the patients was 19 years (range, 8 to 32). All patients underwent initial surgery (unilateral salpingo-oophorectomy in 14, unilateral salpingo-oophorectomy plus abdominal hysterectomy in one, and bilateral salpingo-oophorectomy with or without hysterectomy in 11 patients). Twenty patients had no residual disease, three had less than or equal to 2 cm (one each, dysgerminoma, mixed, and immature teratoma), and three had more than 2 cm lesions (two dysgerminomas, one endodermal sinus tumor). Fourteen patients had pure dysgerminoma (five, stage I; one, stage II; six, stage III; and two, recurrent), and 12 had nondysgerminomatous tumors (five, stage I; two, stage II; three, stage III; and two, recurrent). All four patients with clinically measurable disease had a complete response. All four patients who underwent second-look laparotomy had negative findings. Twenty-five patients (96%) remain in sustained remission 10.4 to 54.4 months from the start of chemotherapy. One patient died of progressive disease 14 months after beginning chemotherapy. We conclude that the BEP regimen has excellent activity and acceptable toxicity in patients with malignant ovarian germ cell tumors.

Extramammary Paget's disease of the perineal skin : role of radiotherapy

We have reviewed our treatment results in 65 patients with extramammary Pagets disease arising in the vulva, perianal area, or scrotum. In 30 patients with primary disease, positive surgical margins were found in 53%, and there was an actuarial local recurrence rate of 40% within 5 years. The median follow-up period for primary extramammary Pagets disease patients treated with surgery alone was 198 months, and none died of this disease. Three patients treated with definitive radiotherapy were without recurrence at 12, 21, and 60 months after 56 Gy of supervoltage x-rays. In 22 patients with extramammary Pagets disease and associated adnexal or rectal adenocarcinoma, nine treated with surgery alone had a 75% local control rate. Three patients treated with surgery and adjuvant radiotherapy all had local control; of two patients treated with radiotherapy alone, one had persistent adenocarcinoma. The median survival for all patients with extramammary Pagets disease and adenocarcinoma was 22 months. We conclude that patients with extramammary Pagets disease have excellent survival but that local recurrence and morbidity from surgery, especially in the elderly, can be high. Radiotherapy greater than 50 Gy as primary treatment for extramammary Pagets disease in those medically unfit for surgery, or as an alternative to further surgery for recurrence after surgery and for anyone wishing to avoid mutilating surgery, is indicated. For those with adenocarcinoma and extramammary Pagets disease, the use of adjuvant postoperative radiotherapy in doses greater than 55 Gy is indicated because of the high risk of local recurrence after surgery alone.

Prognosis of surgically determined complete responders in advanced ovarian cancer

From January 1971 through through December 1981, 246 patients with advanced (Stages III and IV) epithelial ovarian cancer underwent second‐look laparotomy at The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston. Eighty‐five of these patients had a complete response (negative second‐look laparotomy) following treatment with a variety of chemotherapeutic regimens. Three patients had also received irradiation. Patients were analyzed according to pretreatment characteristics (age, FIGO stage, ascites, pleural effusion, histologic grade, tumor type, type of surgery, residual tumor diameter, initial clinical status) and by the number of biopsy specimens taken at second‐look laparotomy. The probability of recurrence and the length of survival following a negative second‐look laparotomy are statistically related to these characteristics. Twenty of the 85 patients (24%) developed recurrent disease 5 to 32 months after laparotomy. The estimated 2‐ and 5‐year survival rates are 99% and 85%, respectively. Patients who achieve a surgically determined complete response have an excellent chance for long‐term survival.

Phase II study of irinotecan in prior chemotherapy-treated squamous cell carcinoma of the cervix.

PURPOSE A phase II study was performed to evaluate the antitumor activity and toxicity of irinotecan (CPT-11), a water-soluble derivative of camptothecin, in patients with prior chemotherapy-treated squamous cell cancer of the cervix. PATIENTS AND METHODS Forty-two patients were included in the study. The median age was 44 years (range, 24 to 59 years). The median Zubrod performance status was 1. All patients were refractory to first-line chemotherapy and 88% had received prior radiotherapy. The initial dose of CPT-11 was 125 mg/m2 given as a weekly 90-minute intravenous infusion for 4 weeks, every 6 weeks. Subsequent doses were unchanged, reduced, or omitted according to toxicity grade. RESULTS Forty-two patients were assessable for response. The overall response rate was 21%. The median time to response was 6 weeks and the median duration of response was 12 weeks. The overall median duration of survival was 6.4 months. A statistically significant survival advantage (median of 12.6 v 5.1 months) was found in patients whose disease responded to the treatment (P < .015). The major dose-limiting toxic effects (grade > or = 3) were nausea and vomiting (45%), diarrhea (24%), and granulocytopenia (36%). Grade > or = 3 anemia was encountered in 62% of patients and the incidence of thrombocytopenia was negligible. Less severe side effects were alopecia (48%), drug fever (43%), anorexia (33%), fatigue (33%), skin rash (21%), stomatitis (14%), and allergic reaction (9%). The gastrointestinal intolerance was dose-related. The incidence of bone marrow depression did not decrease with dose reduction, possibly because of a cumulative effect or hematologic intolerance by a subset of patients. CONCLUSIONS CPT-11 has significant activity in refractory cervical carcinoma. Gastrointestinal intolerance and hematologic toxicity must be monitored carefully. Further studies of alternative schedules may improve the tolerance and response rate.

Carboplatin reinduction after taxane in patients with platinum-refractory epithelial ovarian cancer.

PURPOSE To determine the activity of carboplatin in patients with ovarian cancer who progressed on taxane (paclitaxel or docetaxel) therapy. PATIENTS AND METHODS Thirty-three patients with ovarian cancers refractory to platinum and taxane therapy were treated with single-agent carboplatin reinduction once the disease progressed on a taxane. The starting dose of carboplatin was 300 mg/m2 at 28-day intervals. RESULTS Patients were a median age of 56 years (range, 31 to 80), had a median Zubrod performance status of 1 (range, 0 to 2) and had received a median of three prior chemotherapy regimens (range, two to eight) and one pretaxane platinum regimen (range, one to three). Twenty-six patients had a platinum-free interval of at least 12 months at the time of posttaxane re-treatment with carboplatin. There were seven of 33 (21%) partial responses, with a median duration of 7+ months (range, 2+ to 12+). Responses were noted only in patients with at least a 12-month platinum-free interval and an initial sensitivity to a taxane. The therapy was well tolerated and neurotoxicity was absent. CONCLUSION A subset of patients with platinum-refractory disease that initially responded to a taxane and who eventually have a platinum-free interval of at least 1 year may respond to carboplatin reinduction. This finding may be secondary to paclitaxel or docetaxel therapy that leads to the reversal of platinum resistance, or the prolonged platinum-free interval permits the loss of resistance to platinum by the tumor. Carboplatin reinduction should be considered in the treatment of patients whose ovarian cancer progresses after an initial sensitivity to a taxane and who had a prolonged platinum-free interval.

Secondary cytoreductive surgery for recurrent epithelial ovarian cancer

Thirty patients with recurrent epithelial ovarian carcinoma who underwent secondary tumor-reductive surgery at M. D. Anderson Cancer Center were studied retrospectively. All had been initially treated by primary reductive surgery and postoperative chemotherapy and had a period of clinical remission of at least 6 months thereafter. Ninety percent of patients had grade 2 or 3 tumors. In 17 (57%), residual tumor volume was reduced to less than 2 cm. There were no postoperative deaths, but 40% of patients suffered postoperative morbidity, mostly prolonged ileus. Median survival after second surgery was 16.3-18 months for patients with residual tumor volume less than 2 cm and 13.3 months for those with residual volume greater than 2 cm (nonsignificant). When the second surgery followed the first by less than 18 months, survival was a median of 13.5 months after the second operation as compared with 19 months when the interval was 18 months or longer (nonsignificant). Twenty-two patients received postsurgical chemotherapy; only 11% of those who were evaluable responded. Although secondary tumor-reductive surgery for recurrent ovarian cancer is technically feasible, in the absence of an efficacious second-line medical therapy, its value is limited.

Microscopic disease at second‐look laparotomy in advanced ovarian cancer

During the 11‐year interval from January 1971 to January 1982, 50 of 246 patients with advanced (Stage III and IV) epithelial ovarian carcinoma at second‐look laparotomy had biopsy or cytologic evidence of persistent microscopic carcinoma. The stage and grade profile include 46 Stage III and 4 Stage IV patients: 4 borderline, 9 grade 1, 20 grade 2, and 17 grade 3 patients. Following second‐look laparotomy, 4 patients received no further therapy, 45 received chemotherapy, and 1 received external radiation. No patient was lost to follow‐up, and the median interval off therapy was 24 months. Progressive or recurrent disease has manifest in 12 (24%). No recurrences have developed either in patients younger than age 40 or in patients with grade 1 tumors. Two patients died of leukemia, 1 died of heart disease, and 35 (70%) are alive with no evidence of disease. In patients developing recurrence, the median progression‐free interval was 17.5 months, with a range of 6 to 46 months. The median interval of survival following disease progression was 7 months. There was no evidence of progression at 2 years and 5 years in 81% and 70% of patients, respectively. The uncorrected 2‐ and 5‐year survival rates were 96% and 71%, respectively. The 5‐year survival rates for grades 1, 2, and 3 were 100%, 79%, and 36%, respectively. Other variables analyzed include number of positive foci, residual tumor volume at initial surgery, cytologic findings at second‐look laparotomy, type of chemotherapy, and number of courses of chemotherapy before second‐look laparotomy. In summary, patients with only microscopic evidence of disease at second‐look surgery have a good probability for extended survival.

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

Abstract 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 > 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.

Recurrent cervical carcinoma after radical hysterectomy

The characteristics of recurrent carcinoma following radical hysterectomy and pelvic lymphadenectomy for cervical carcinoma are not well known. Disease recurrence was noted in 27 of 249 patients (11%) with stage IB cervical carcinoma who were treated with a primary surgical approach between January 1962 and December 1984. Fourteen recurrences (52%) occurred within 1 year of surgery, and 24 (89%) within 2 years. Patients with pelvic node metastases or adenocarcinoma had a significantly higher recurrence rate than did patients with negative nodes (33% vs 8%) or with squamous carcinoma (22% vs 8%). Seventeen patients (63%) had disease recurrence in the pelvis or vulva and 12 of these patients had recurrences within 1 year. Eight patients developed asymptomatic pelvic or vulvar recurrences, and all were diagnosed within 1 year. Ten patients (37%) developed recurrences outside the pelvis and 8 of these experienced recurrence after 1 year. Successful treatment after recurrence was independent of clinical or histopathologic parameters except site of recurrence. Eight of 15 patients (53%) who were treated with irradiation for a recurrence in the pelvis or vulva are free of disease 10 to 126 months (median, 48 months) after recurrence. Since irradiation can aid in salvaging patients with recurrent cervical carcinoma confined to the pelvis following radical surgery, clinical vigilance for this site of recurrence is emphasized.