Long-term results and pharmacokinetics of high-dose paclitaxel in patients with refractory epithelial ovarian carcinoma.

The purpose of this study was to analyze the efficacy and toxicity of a high dose of paclitaxel in patients with ovarian cancer refractory to platinum chemotherapy. Another phase II study of hydroxyurea was run in the same patient population. Fifty patients with measurable ovarian cancer were entered on this phase II study at The University of Texas M. D. Anderson Cancer Center. Treatment consisted of 250 mg/m2 of paclitaxel given by continuous intravenous infusion over 24 h every 3 weeks. Patients with disease unresponsive to paclitaxel could then be crossed over to hydroxyurea, and vice versa. Twenty-five (53%) out of 47 evaluable patients had a response (two complete responses and 23 partial responses). Twelve (26%) patients had stable disease. The median survival was 11.3 months. The main toxic effect was neutropenia (98% of patients) with 28 (9%) episodes of neutropenic fever. Neutropenia required therapy with granulocyte colony-stimulating factor. Other side effects were alopecia (100%), anemia (98%), gastrointestinal problems (57%), stomatitis (27%), and neurotoxicity (55%). Paclitaxel administered at a high dose as a single agent proved to be very active in patients who had platinum-refractory ovarian cancer and was well tolerated. Further studies of high-dose paclitaxel in patients with ovarian carcinoma are indicated.

A phase II and pharmacokinetic study of enloplatin in patients with platinum refractory advanced ovarian carcinoma.

This was a study of enloplatin in 18 evaluable patients with platinum refractory ovarian cancer. They received an i.v. infusion of enloplatin over 1.5 h without prehydration every 21 days. One patient had a partial response (6%; 95% CI 0-26%) lasting 2.8 months. The median survival was 9.4 months (95%; CI 5.1-19.7%). Neutropenia was the dose-limiting toxicity. Nephrotoxicity was manageable. Enloplatin is the major form of the free drug in plasma. However, 13.5 h after initiation of treatment, 85% of the drug in plasma is protein bound. Elimination of the drug is mainly renal. Enloplatin pharmacokinetics is similar to that of carboplatin. Thus, the plasma pharmacokinetics of enloplatin is dictated by the cyclobutanedicarboxylato (CBDCA) ligand and not the novel amino ligand.

Remission of refractory gestational trophoblastic disease in the brain with ifosfamide, carboplatin, and etoposide (ICE): first report and review of literature.

Gestational trophoblastic disease (GTD) metastatic to the brain has a very poor prognosis with a survival rate of less than 25%, especially for patients in whom brain metastases develop while on or after chemotherapy. Cure can be achieved by chemotherapy alone. The regimen of etoposide, methotrexate, actinomycin-D, vincristine, and cyclophosphamide has shown encouraging results and is considered to be standard first-line treatment for high risk patients. For patients in whom this regimen fails, a salvage chemotherapy regimen is used. The combination of ifosfamide, carboplatin, and etoposide (ICE) has synergistic activity in preclinical studies. This regimen has shown activity in metastatic breast cancer and non-small-cell lung cancer as well as platinum-resistant germ-cell tumors and metastatic GTD. This is the first report of a patient with a highly refractory GTD in whom brain metastasis developed while on chemotherapy, and whose brain metastasis went into remission with a low dose ICE regimen. Accordingly, ICE may be considered for patients with chemotherapy refractory GTD metastatic to the brain.

A phase I study of TNP-470 administered to patients with advanced squamous cell cancer of the cervix.

A Phase I study of the novel angiogenesis inhibitor TNP-470 was performed. Patients with inoperable recurring or metastatic squamous cell cancer of the cervix with evaluable disease, no coagulopathy, and adequate renal, hepatic, and hematological function were eligible. One course of treatment consisted of an i.v. infusion of TNP-470 over 60 min every other day for 28 days, followed by a 14-day rest period. The starting dose was 9.3 mg/m2. Eighteen evaluable patients were treated, with a median age of 48 years (range 27-55) and performance status Zubrod 1 (range 0-2). Grade 3 neurotoxicities consisting of weakness, nystagmus, diplopia, and ataxia were encountered in two patients receiving the 71.2 mg/m2 dose. An intermediate dose level of 60 mg/m2 was evaluated and found to be well tolerated by three patients. Only one patient experienced grade 3 nausea on the 60 mg/m2 dose level. No myelosuppression, retinal hemorrhage, weight loss, or significant alopecia were observed. One patient had a complete response, which continues for 26 months, and three patients with initially progressive disease stage had stable disease for 5, 7.7, and 19+ months. Other Phase I studies, including over 200 patients, were performed concurrently with this study. Based on this experience, the dose of TNP-470 recommended for further studies is 60 mg/m2 as a 60-min i.v. infusion every Monday, Wednesday, and Friday. Neurotoxicity was dose limiting, but appears to be reversible. Otherwise, the treatment was well tolerated. The drug may be active in squamous cell cancer of the cervix. Further studies of TNP-470 in squamous cell cancer of the cervix are warranted.

Remission of refractory gestational trophoblastic disease with high-dose paclitaxel.

High-risk metastatic gestational trophoblastic disease (GTD) in patients who have failed primary chemotherapy has a very poor prognosis. About 25% of women with high-risk metastatic disease become refractory to EMA-CO (etoposide, methotrexate, actinomycin-D, cyclophosphamide and vincristine) and fall to achieve a complete remission. Currently, there is no standard salvage chemotherapeutic regime for EMA-CO failure. Paclitaxel, a taxane analog extracted from the bark of the western yew (Taxus brevlfolla), has shown antitumor activity in a variety of cancer cell lines. High in vivo efficacy was confirmed in phase II trials, especially for breast and epithelial ovarian cancer patients. Recently, two in vitro studies have shown that paclitaxel is a highly effective antineoplastic agent in choriocarcinoma cell lines. We present the first clinical report of a serologic remission with high-dose paclitaxel (250 mg/m2 i.v. infusion over 24 h every 3 weeks) of a highly refractory GTD in a patient who developed brain metastasis after multiple combined chemotherapeutic regimens. The patient tolerated paclitaxel with granulocyte colony stimulating factor support very well. The remission with paclitaxel in this patient confirms its preclinical activity in high-risk, refractory GTD.

Preliminary report of the activity of docetaxel in advanced or recurrent squamous cell cancer of the cervix.

Eighteen patients with squamous cell cancer of the cervix were treated with i.v. docetaxel 100 mg/m2 over 1 h every 21 days. No patient received prior chemotherapy, except as a radiation sensitizer. Median age was 42 years (range 30-58) and Zubrod performance status was 1 (0-2). Ten (59%) patients had prior surgery and 11 (65%) had prior radiation therapy. Sixteen patients were evaluable for response. Two patients had a partial response (13%; 95% CI 0-32%) and eight (50%; 95% CI 23-77%) had stable disease. Dose reduction to 75 mg/m2 was required in 10 patients and to 55 mg/m2 in one patient. Granulocytopenia was the major hematopoietic toxicity (31% grade 3 and 44% grade 4). Docetaxel is active in patients with squamous cell cancer of the cervix and may be tolerable at this dose schedule.

Paclitaxel retreatment in patients with platinum and paclitaxel resistant ovarian cancer.

The optimal role of paclitaxel in the treatment of epithelial ovarian cancer has not been determined. Dose intense paclitaxel therapy is safe and often recommended as second-line treatment for platinum resistant ovarian cancer. Retreatment with a higher dose-intense schedule of paclitaxel is feasible and patients who had a prior dose of 135 mg/m2 or paclitaxel free interval of at least six months may respond. Sensitivity to initial doses and a prolonged paclitaxel-free interval are predictors of a successful reinduction. We report 10 patients who had paclitaxel as second-line treatment and were later retreated with paclitaxel. Three of these patients had a partial response (30%; 95% CI 6-66%). All but one patient had platinum resistant disease. Initial dose and the best response to initial paclitaxel were assessed in relation to reinduction response. Patients with at least a six-month paclitaxel-free interval and previously low dose paclitaxel (135 mg/m2), or a complete response with high dose paclitaxel (250 mg/m2) may respond to high dose paclitaxel retreatment. Prospective trials of paclitaxel retreatment are warranted.

A case report of paclitaxel administered to a patient with platinum-refractory ovarian cancer on long-term hemodialysis.

We present the second case of a patient with platinum-refractory ovarian cancer who was treated safely with paclitaxel while on hemodialysis. Paclitaxel was administered at 175 mg/m2 as a 24-hour intravenous infusion on a nondialysis day. The patient tolerated this therapy well with minimal toxic reactions except for total alopecia and myelosuppression, which was unremarkable. Paclitaxel may be used in patients receiving long-term hemodialysis in the same dose schedule as in patients with normal renal function.

Transcatheter arterial embolization for the control of life-threatening pelvic hemorrhage in a patient with locally advanced cervix carcinoma.

A woman with a refractory locally advanced recurrent cervical cancer was brought to the emergency room because of a life-threatening vaginal hemorrhage from the tumor. She presented with a compromised hemodynamic status that necessitated multiple blood transfusions and large volume of fluid resuscitation. An arteriogram revealed the site of bleeding from the uterine branch of the right internal iliac artery. The branches of anterior and posterior internal iliac artery were embolized with Gelfoam, Ivalon and coils. This emobolization successfully controlled the bleeding and stabilized the hemodynamic status of the patient. The treatment options in patients with massive pelvic hemorrhage are reviewed and discussed.

Primary fallopian tube adenocarcinoma: clinical complete response after salvage treatment with high-dose paclitaxel.

This Case Report describes a patient with primary fallopian tube cancer who had a late recurrence of pelvic disease following adjuvant chemotherapy for early-stage disease. Secondary cytoreductive surgery was suboptimal. The bulky residual disease was refractory to platinum-based therapy. Extension of the disease to the retroperitoneum resulted in obstructed venous return, ureteral obstruction, and renal infection. The latter necessitated a third laparotomy and a nephrectomy. Upon recovery from surgery and failure of platinum reinduction, the patient was treated with high-dose paclitaxel. The large pelvic mass regressed rapidly and completely. Current chemotherapy for fallopian tube cancer is briefly reviewed.

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.

Peritoneal papillary serous carcinoma: response to Taxol in platinum resistant disease.

A case of peritoneal papillary serous carcinoma which developed after total abdominal hysterectomy and bilateral salpingo-oophorectomy for a benign condition is presented. The patient was treated with platinum-based chemotherapy to which she initially responded, but then the tumor progressed. High dose paclitaxel (250 mg/m2) was given. The patient tolerated this treatment well, achieving a rapid partial response with good palliation of symptoms. Paclitaxel should be considered for patients with a platinum resistant peritoneal papillary serous carcinoma.