Total hip arthroplasty revision: a decade of change.

We studied the incidence, indications, and changing patterns of total hip arthroplasty (THA) revision by comparing all consecutive THA revisions performed at a single institution between July 1989 and June 1991 with all those performed at the same institution between January 2000 and December 2000. Aseptic loosening was the main reason for THA failure during both periods. Between the periods, the number of revisions for polyethylene wear, instability, and leg-length discrepancy increased, and the number of revisions for conversion of failed hemiarthoplasty to THA and for deep infection decreased significantly. We evaluate the reasons for these trends in an attempt to identify preventable causes of failure and to stimulate further research on prevention.

Results of revision total knee arthroplasty after exposure of the knee with extensor mechanism tenolysis.

The purpose of this research was to investigate the utility of 1 surgical exposure method, extensor mechanism tenolysis (EMT), for total knee revision, and to evaluate complications associated with this technique. Two hundred seven knee revisions were performed on 198 patients (9 bilateral) over a 3-year period (September 1997 to October 2000). The surgical exposures used were EMT in 203 cases, V-Y quadricepsplasty in 2 knees, and patellectomy in 2 additional cases. The complications associated with EMT were peripatellar fibrosis requiring arthroscopy, 7.2%; hematoma, 4.8%; stiffness requiring manipulation, 3.9%; patellar subluxation, 1.4%; extensor lag >5 degrees, 1.0%; quadriceps tendon rupture, 0.5%; and instability, 0.5%. EMT is associated with a low complication rate comparable with or better than other exposure methods.

Feasibility of laparoscopic management of presumed stage I endometrial carcinoma and assessment of accuracy of myoinvasion estimates by frozen section: a gynecologic oncology group study.

INTRODUCTION: To assess laparoscopic management of presumed stage I endometrial cancer, and to compare gross, frozen, and paraffin section methods measuring myoinvasion. PATIENTS AND METHODS: Eligible patients underwent laparoscopic exploration. Patients with preoperative grade 1 histology underwent laparoscopic-assisted vaginal hysterectomy and bilateral salpingo-oophorectomy (LAVHBSO). Pelvic and periaortic lymph node sampling (PPANS) was performed for deep (> or =50%) myoinvasion confirmed by frozen section. Patients with preoperative grade 2 or 3 histology without evidence of extrauterine metastasis underwent PPANS + LAVHBSO. RESULTS: Of 50 eligible patients selected, LAVHBSO was successfully completed in all but five. There was one trocar bowel perforation. Myoinvasion depth was correlated between paraffin section and gross estimate, and between paraffin and frozen section estimate, in 89 and 90% of cases, respectively. Myoinvasion was underestimated by gross versus paraffin in three of five discrepancies, and by frozen versus paraffin section in one of three discrepancies. CONCLUSIONS: Laparoscopic surgical staging for early stage endometrial cancer is feasible. Gross/frozen section methods correlate with paraffin section to measure myoinvasion. Tumor grading and gross/frozen section myoinvasion estimates can guide operative management.

A phase I study of weekly topotecan and Paclitaxel in previously treated epithelial ovarian carcinoma patients.

OBJECTIVE: We have previously reported on the feasibility of weekly topotecan as single-agent therapy in previously treated patients with ovarian cancer. The objective of this study was to assess the maximum tolerated dose (MTD) of weekly bolus intravenous (IV) topotecan combined with weekly paclitaxel in a comparable patient population. METHODS: Previously treated ovarian cancer patients with measurable disease and/or elevated cancer antigen 125 (CA-125) received (as second-line or third-line therapy) weekly 30-min bolus IV topotecan starting at 2 mg/m(2) combined with weekly paclitaxel starting at a dose of 60 mg/m(2). In this intrapatient dose-escalation study, topotecan and paclitaxel were escalated in parallel until the MTD was reached, defined as the first dose level at which >or= 2 of 6 patients experienced dose-limiting toxicity. RESULTS: Twenty-one of 26 patients were evaluable for toxicity and received a total of 306 weeks of therapy (median, 13 weeks; range, 5 to 33 weeks). No significant dose-limiting toxicity was observed up to a weekly bolus IV topotecan dose of 3 mg/m(2) and a concurrent paclitaxel dose of 80 mg/m(2). The MTD was topotecan 3.5 mg/m(2) plus 90 mg/m(2) paclitaxel. The dose-limiting toxicities included anemia and fatigue, with 10 of 21 patients receiving epoetin alfa for grade 3 or 4 anemia; only 1 patient required a blood transfusion. Two patients had a treatment delay of at least 1 week and only 1 patient required a dose reduction to maintain the weekly schedule. CONCLUSIONS: Based on the results of this study, the recommended initial dose for this novel regimen is topotecan 3 mg/m(2) and paclitaxel 80 mg/m(2). Further investigation of the efficacy of weekly topotecan plus paclitaxel in less heavily pretreated patients is warranted.

A dose-escalating study of weekly bolus topotecan in previously treated ovarian cancer patients.

OBJECTIVE: Topotecan is an established topoisomerase I inhibitor for the treatment of relapsed ovarian cancer. Myelotoxicity and suboptimal patient convenience associated with daily topotecan, however, have prompted investigators to explore alternate regimens, including a weekly regimen of topotecan. The objective of this study was to determine the maximum tolerated dose (MTD) of topotecan given as a weekly bolus in previously treated ovarian cancer patients. METHODS: Second- and third-line ovarian cancer patients with measurable disease or elevated cancer antigen 125 received weekly bolus topotecan intravenously starting at 1.5 mg/m(2). Topotecan was escalated in dose increments of 0.5 mg/m(2) every 21 days as tolerability allowed. Dose-limiting toxicity was defined as grade 3/4 neutropenia or thrombocytopenia. RESULTS: Thirty-two of 35 patients were evaluable for safety and tolerability. No notable toxicity was observed with weekly topotecan doses < 4 mg/m(2). Additionally, there was an absence of dose-limiting myelotoxicity and thrombocytopenia with weekly topotecan. The MTD of weekly topotecan without the use of granulocyte colony-stimulating factor support was 4 mg/m(2), with grade 2 anemia, chronic fatigue, and grade 2 gastrointestinal toxicity limiting further dose escalation. Weekly topotecan also demonstrated antitumor activity at doses >2 mg/m(2). CONCLUSIONS: The establishment of a well-tolerated, weekly regimen of topotecan (4 mg/m(2), with a maximum recommended dose of 6 mg/m(2)) provides the basis for further investigation in phase II studies of single-agent and combination regimens in previously treated ovarian cancer patients.

Tamoxifen in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study.

PURPOSE: In two large Gynecologic Oncology Group studies of patients with advanced or recurrent endometrial carcinoma and no previous systemic therapy, progestins have demonstrated activity against advanced or recurrent endometrial carcinoma with response rates between 15% and 25%. Tamoxifen has been reported as variously active or inactive with or without previous systemic therapy. The purpose of this study was to determine whether tamoxifen exhibits enough activity in patients with advanced or recurrent endometrial carcinoma, who have not received systemic therapy, to warrant a phase III trial. PATIENTS AND METHODS: Sixty-eight eligible patients with advanced or recurrent endometrial carcinoma received oral tamoxifen 20 mg bid until toxicity was unacceptable or disease progressed. RESULTS: Three complete (4%) and four partial (6%) responses were observed for an overall response rate of 10% (90% confidence interval [CI], 5.7% to 17.9%). Patients with tumors that were more anaplastic tended to respond less frequently. The median progression-free survival for all 68 eligible patients was 1.9 months (90% CI, 1.7 to 3.2 months). The median survival was 8.8 months (90% CI, 7.0 to 10.1 months). CONCLUSION: Tamoxifen demonstrated modest activity at best against endometrial carcinoma and does not warrant further investigation as a single agent for this disease. Ongoing trials will assess the sequential use of tamoxifen and progestational agents.

Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the Gynecologic Oncology Group.

PURPOSE: Progestins have definite activity against advanced or recurrent endometrial carcinoma. Both parenteral and oral progestins yield similar serum levels and response rates, which range from 18% to 34%. The one major study that used oral medroxyprogesterone acetate (MPA) noted a response rate at the lower end of the range (18%) and much poorer progression-free and overall survival times (4 and 10.5 months, respectively) than previously reported. The present study sought to confirm this earlier study of oral MPA, to assess the importance of prognostic factors such as histologic grade and receptor levels, and to determine whether a higher dose of MPA would yield a higher response rate. PATIENTS AND METHODS: Two hundred ninety-nine eligible women with advanced or recurrent endometrial carcinoma were randomized to receive oral MPA either 200 mg/d or 1, 000 mg/d until unacceptable toxicity intervened or their disease progressed. RESULTS: Among 145 patients receiving the low-dose regimen, there were 25 complete (17%) and 11 partial (8%) responses for an overall response rate of 25%. The 154 patients receiving the high-dose regimen experienced 14 (9%) complete and 10 (6%) partial responses for an overall response rate of 15%. Median durations of progression-free survival were 3.2 months and 2.5 months for the low-dose and high-dose regimens, respectively. Median survival durations were 11.1 months and 7.0 months, respectively. The adjusted relative odds of responding to the high-dose regimen compared with the low-dose regimen was 0.61 (90% confidence interval, 0.36 to 1.04). Prognostic factors having a significant impact on the probability of response included initial performance status, age, histologic grade, and progesterone receptor concentration. Compliance with oral therapy was documented with serum levels 1 month after starting therapy, when possible. MPA levels were commensurate with the assigned dose and schedule. CONCLUSION: Oral MPA is active against endometrial carcinoma. Response to progestin therapy is more frequent among patients with a well-differentiated histology and positive progesterone receptor status. This study provides no evidence to support the use of MPA 1,000 mg/d orally instead of MPA 200 mg/d orally. In fact, the trends suggest the opposite. The use of oral MPA 200 mg/d is a reasonable initial approach to the treatment of advanced or recurrent endometrial carcinoma, particularly those lesions that are well-differentiated and/or progesterone receptor-positive (> 50 fmol/mg cytosol protein). Patients with poorly differentiated and/or progesterone receptor levels less than 50 fmol/mg cytosol protein had only an 8% to 9% response rate.

Bleomycin, etoposide, and cisplatin combination therapy of ovarian granulosa cell tumors and other stromal malignancies: A Gynecologic Oncology Group study.

OBJECTIVES: The objectives of this study were to assess efficacy and toxicity of the combination of bleomycin, etoposide, and cisplatin (BEP) in this Phase II trial as first-line therapy for ovarian stromal malignancies. METHODS: Patients with incompletely resected Stages II-IV or recurrent cancer underwent surgical debulking. There were two bleomycin-related deaths early in the trial; thus, the initial schedule of bleomycin (20 units/m2 x 9 weeks for a maximum dose of

Phase II trial of vinorelbine in recurrent and progressive epithelial ovarian cancer.

OBJECTIVE: A phase II, multicenter trial was conducted to define the efficacy and safety of vinorelbine (Navelbine (vinorelbine tartrate) injection, NVB) in the treatment of advanced epithelial ovarian cancer (EOC). METHODS: Patients with persistent or recurrent EOC who had received one prior platinum-based chemotherapy regimen were eligible. NVB was administered at 30 mg/m2 as a weekly outpatient intravenous infusion. RESULTS: Using an intent-to-treat analysis of the 38 patients who received at least one dose, 11(29%, 95% confidence limits 15-46%) objective responses (4 complete, 7 partial) were observed. The median duration of response was 19 weeks. For all 38 patients, the median time to treatment failure and median survival were 12 and 60 weeks, respectively. Four of the 12 patients with platinum-resistant disease responded, while 7 of the 24 patients with platinum-sensitive disease responded. Toxicity was evaluable in all 38 patients. During course 1, 15 patients required dose reduction and 21 required dose delays. Grade 3-4 granulocytopenia occurred in 23 (62%) of 37 reporting patients. Grade 3-4 anemia and thrombocytopenia occurred in 16 and 5%, respectively. The most common nonhematologic toxicities were nausea (grade 3 or less, in 34%), constipation (grade 3 or less, in 29%), and asthenia (grade 2 or less, in 24%). No life-threatening adverse effects were reported. CONCLUSIONS: NVB is an effective, palliative agent for women with recurrent EOC. Dose-limiting granulocytopenia is substantial, yet manageable.

Phase 2 trial of moderately high dose single agent mitoxantrone in platinum and paclitaxel-refractory ovarian cancer.

In the human clonogenic assay, mitoxantrone possesses among the steepest dose-response curves of any cytotoxic agent against ovarian cancer. To test the potential clinical relevance of this observation, we conducted a phase 2 trial of moderately high dose single agent mitoxantrone (28 mg/m2 delivered every 3-4 weeks) along with granulocyte-macrophage colony stimulating factor (250 micrograms/m2/day beginning 24 h after mitoxantrone and continuing until neutrophil recovery) in 34 patients with clinically defined platinum and paclitaxel-refractory ovarian cancer. The major toxicity of treatment was severe neutropenia which was almost universal. However, there were no treatment-related infectious deaths. Significant cardiac toxicity was not observed. Five of 33 evaluable patients demonstrated objective evidence of a response to treatment (1 patient achieving a partial response of measurable tumor masses, 4 patients achieving a > or = 50% reduction in CA-125 antigen level), with a median duration of response of 3 months (range 2-5 months). We conclude that moderately high dose mitoxantrone has definite, although very limited, single agent activity in platinum and paclitaxel-refractory ovarian cancer. Unfortunately, as this regimen produces severe hematologic toxicity and response durations are short, it cannot be recommended for routine clinical use. The role of an even higher dose mitoxantrone schedule employed as a component of a high dose chemotherapy program with bone marrow or peripheral progenitor cell protection in the treatment of ovarian cancer remains to be defined.

Tomudex (ZD1694, NSC 639186) in platinum-pretreated recurrent epithelial ovarian cancer: a phase II study by the Gynecologic Oncology Group.

PURPOSE: Tomudex is a second-generation folate analogue that when polyglutamated is a potent inhibitor of thymidylate synthase (TS). METHODS: Based on indications of antitumor activity in phase I trials, the Gynecologic Oncology Group initiated a phase II study of Tomudex 3 mg/m2 intravenously every 3 weeks in patients with epithelial ovarian cancer, who had been pretreated with platinum drugs, and had subsequently recurred more than 6 months following such treatment. RESULTS: Of 30 patients entered into the trial, 2 were pathologically ineligible, leaving 28 fully evaluable. In this patient population, Tomudex was generally well tolerated, but only three objective (partial) responses were documented. CONCLUSIONS: With the level of activity seen, the drug was not considered for further clinical development in ovarian cancer by the Gynecologic Oncology Group. However, it may be worthwhile to explore whether quantitation of TS could lead to selection of patients more likely to respond to this TS inhibitor.

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.

Single-agent therapy for nonmetastatic and low-risk gestational trophoblastic disease.

OBJECTIVE: To assess the effectiveness of single-agent chemotherapy in the treatment of nonmetastatic and low-risk metastatic gestational trophoblastic tumors. STUDY DESIGN: The medical literature was reviewed concerning single-agent chemotherapy in the treatment of nonmetastatic and low-risk metastatic gestational trophoblastic tumors. RESULTS: Methotrexate and actinomycin-D have achieved excellent and comparable remission rates with acceptable levels of toxicity. CONCLUSION: The optimal single-agent chemotherapy for nonmetastatic and low-risk metastatic gestational trophoblastic tumors has not yet been identified and can be best determined through a prospective, randomized trial.

Early invasive carcinoma of the cervix (3 to 5 mm invasion): risk factors and prognosis. A Gynecologic Oncology Group study.

OBJECTIVE: Our purpose was to evaluate the risk factors and prognosis in patients with stage IA squamous cell carcinoma of the cervix and 3 to 5 mm of invasion. STUDY DESIGN: From 1981 to 1984 the Gynecologic Oncology Group conducted a prospective clinicopathologic study of patients with stage I carcinoma of the cervix. A selective study group that was previously defined and reported included patients with squamous cell carcinoma of the cervix who were treated with radical hysterectomy and pelvic lymphadenectomy and who had disease confined to the uterus, with or without microscopically positive lymph nodes. RESULTS: One hundred eighty-eight patients had invasion of 3, 4, or 5 mm as determined by central pathology review. Patients who satisfied the 3 to 5 mm invasion definition of the current stage IA2 classification of the International Federation of Gynecology and Obstetrics (1995) are the subject of this report. CONCLUSIONS: Patients with stage IA2 carcinoma of the cervix who have 3 to 5 mm of invasion present on conization with no invasion in the hysterectomy specimen are at very low risk for lymph node metastases, recurrences, or death caused by cancer.

Prolonged oral etoposide as second-line therapy for platinum-resistant and platinum-sensitive ovarian carcinoma: a Gynecologic Oncology Group study.

PURPOSE: A phase II trial was conducted to determine the activity of prolonged oral etoposide in platinum-resistant and platinum-sensitive ovarian carcinoma. PATIENTS AND METHODS: Platinum-resistant disease was defined as progression on platinum-based chemotherapy or recurrence within 6 months of completing therapy. The starting dose was 50 mg/m2/d (30 mg/m2/d for prior radiotherapy) for 21 days, every 28 days. A dose escalation to a maximum dose of 60 mg/m2/d was prescribed. RESULTS: Of 99 patients entered, 97 were assessable for toxicity and 82 were assessable for response. Among 41 platinum-resistant patients a 26.8% response rate (7.3% complete response [CR] and 19.5% partial response [PR] rate) occurred. The median response duration was 4.3 months (range, 1.3 to 8.7), median progression-free interval (PFI) was 5.7 months (range, 0.8 to 30.8+), and median survival time was 10.8 months (range, 1.9 to 45.8). Twenty-five of 41 platinum-resistant patients had also previously received paclitaxel; of which eight (32%) responded. Among 41 platinum-sensitive patients, a 34.1% response rate (14.6% CR and 19.5% PR rate) occurred. The median response duration was 7.5 months (range, 1.9 to 15.2+), median PFI was 6.3+ months (range, 0.9 to 20.4), and median survival time was 16.5+ months (range, 0.9 to 34.8). Of 97 patients assessable for toxicity, grade 3 or 4 hematologic toxicity was common, with leukopenia occurring in 41.2% (grade 3, 29%; grade 4, 12%), neutropenia in 45.4% (grade 3, 20%; grade 4, 25%), thrombocytopenia in 9% (grade 3, 5%; grade 4, 4%), and anemia in 13.4%. Three treatment-related deaths occurred: two from neutropenic sepsis and one from thrombocytopenic bleeding after an overdose. One patient developed leukemia. CONCLUSION: This regimen is active in platinum-resistant and platinum-sensitive ovarian carcinoma. Additionally, the regimen is active in paclitaxel-resistant ovarian carcinoma.

A phase I study of weekly cisplatin and whole abdominal radiation for the treatment of stage III and IV endometrial carcinoma: a Gynecologic Oncology Group pilot study.

A Gynecologic Oncology Group Phase I study was designed to evaluate the toxicity of whole abdominal radiation therapy with concurrent weekly cisplatin in patients with surgical International Federation of Gynaecology and Obstetrics (FIGO) Stage III and IV endometrial carcinoma. Cisplatin 15 mg/m2 was given once weekly during radiation therapy to the whole abdomen with a pelvic boost and optional para-aortic radiation. All eight patients received the prescribed dose of radiation therapy. Cisplatin chemotherapy was halted in one patient due to increased serum creatinine after three cycles. Acute adverse effects were within acceptable limits, with one patient admitted to the hospital after completion of treatment for diarrhea. Hematopoietic toxicity was clinically unimportant. Serious late toxicities included one radiation enteritis requiring a bowel resection and chylous ascites in one patient. There was no late renal damage reported. This regimen appears to be tolerated acutely and the late toxicities were similar to those seen with whole abdominal radiation therapy alone.

An analysis of cell type in patients with surgically staged stage IB carcinoma of the cervix: a Gynecologic Oncology Group study.

The influence of cell type on recurrence-free interval (RFI) and survival after radical hysterectomy for patients with Stage IB carcinoma of the cervix was investigated. Patients with Stage IB carcinoma of the cervix (>3-mm invasion) underwent a radical hysterectomy and pelvic lymphadenectomy. Patients with involved paraaortic nodes or gross extracervical disease were excluded. Of 813 evaluable patients, 645 had squamous, 104 with adenocarcinoma, and 64 had adenosquamous cell type. The time to failure and the following clinical/pathologic characteristics were compared among the three cell types: age, Gynecologic Oncology Group performance status (PS), gross versus occult tumor, histologic grade, depth of invasion, node status, uterine extension, parametrial extension, surgical margins, and capillary-lymphatic space (CLS) involvement. A Cox proportional hazards model was used to compare the patients with adenosquamous and adenocarcinoma to those with squamous while adjusting for prognostic factors. The median age was 40 years (range, 21-87). Pelvic nodes were involved in 119 (15%) of patients. There were no significant differences between cell types in distributions of the following factors: age, PS, positive nodes, depth of invasion, uterine extension, surgical margins, or parametrial extension. There were statistically significant differences between cell types with regards to grade (P < 0.001), gross versus occult primary status (P = 0.016), and CLS involvement (P = 0.005). There was no statistically significant difference detected between cell types in crude comparisons of RFI (P = 0.29); however, there was a difference in survival (P = 0.02) with shorter survival seen in the adenosquamous cell type. After adjusting for CLS involvement, PS, depth of invasion, and clinical tumor size, survival remained worse for patients with adenosquamous primaries when compared to squamous carcinoma (P = 0.02) and adenocarcinoma (P = 0.007). In conclusion, no statistically significant differences were seen in RFI among cell types; however, in patients with Stage I carcinoma of the cervix overall survival after radical hysterectomy may be slightly worse for those with adenosquamous cell type.

Are more antiemetic trials with a placebo necessary? Report of patient data from randomized trials of placebo antiemetics with cisplatin.

BACKGROUND: Because of the predictability of significant emesis after its use, cisplatin serves as the standard emetic stimulus for trials of antiemetic drugs. To define better the incidence, severity, and pattern of emesis that follows cisplatin, facilitate the testing of new agents, and obviate the need for further placebo-controlled trials for this indication, individual patient data were compiled from completed studies with placebo antiemetics and cisplatin. METHODS: The time and number of emetic episodes during the 24 hours after cisplatin were obtained for 48 patients given a placebo antiemetic. Each was treated as part of a randomized, double-blind trial reported between 1981 and 1990. Emesis after antiemetic "rescue" therapy was also assessed. RESULTS: Emesis occurred in 47 of 48 patients (98% observed rate, 95% confidence interval, 89-99%). The median number of emetic episodes during the 24 hours after cisplatin was 6. Emesis continued after rescue in 77% of patients. CONCLUSIONS: Cisplatin caused severe emesis that persisted despite rescue in placebo-treated patients. Using the data presented, any therapy preventing acute emesis in 8 or more of the 48 individuals receiving cisplatin > 50 mg/m2 was an active antiemetic (P = 0.05). The four trials discussed here documented the antiemetic effectiveness of granisetron, metoclopramide, and ondansetron. The placebo-treated patients studied can serve as a control group for testing new therapies. Because of the certainty of severe emesis after cisplatin, and the availability both of these data and several proven drugs for this condition, prospective comparisons of antiemetics should employ active control medications.

Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer.

PURPOSE: Serious cumulative toxicity is a well-recognized consequence of chemotherapy. Amifostine, an organic thiophosphate, has demonstrated the ability to protect selectively a broad range of normal, but not neoplastic, tissues from the cytotoxic effects of chemotherapy and radiotherapy. This study was designed to determine if amifostine could reduce the serious toxicities associated with cyclophosphamide and cisplatin (CP), without reducing antitumor efficacy in patients with ovarian cancer. PATIENTS AND METHODS: Two hundred forty-two patients with advanced ovarian cancer were randomized to receive six cycles of cyclophosphamide (1,000 mg/m2) and cisplatin (100 mg/m2) with or without amifostine (910 mg/m2) every 3 weeks for six cycles. The occurrence of hematologic, renal, neurologic, and ototoxicity was evaluated. Antitumor efficacy was assessed by pathologic tumor response and survival. RESULTS: Pretreatment with amifostine before each cycle of chemotherapy resulted in a reduction of cumulative toxicities. Hematologic toxicity consisted of grade 4 neutropenia associated with fever and/or infection that required antibiotic therapy (P = .005), days in hospital (P = .019), and days on antibiotics (P = .031). Platinum-specific toxicities consisted of protracted serum creatinine elevations (P = 0.004), > or = 40% reduction from baseline in creatinine clearance (P = .001), and severity of neurologic toxicity (P = .029). Twenty-four percent of CP patients compared with 9% of amifostine plus CP patients discontinued therapy because of protocol-specified toxicity (P = .002). Pathologic tumor response rates were 37% with amifostine and 28% in controls, with comparable median survival times of 31 months. Amifostine was generally well tolerated; the principal side effects were emesis and a transient decrease in blood pressure. CONCLUSION: Pretreatment with amifostine reduces the cumulative hematologic, renal, and neurologic toxicities associated with the CP regimen, with no reduction in antitumor efficacy.

Phase I study of N-(phosphonacetyl)-L-aspartate with fluorouracil and with or without dipyridamole in patients with advanced cancer.

We conducted a combined biochemical modulation trial of N-(phosphonacetyl)-L-aspartate (PALA), dipyridamole (DP), and fluorouracil (5-FU) in patients with cancer. Eighty-eight patients with advanced cancer were entered into this Phase I trial. During the first part of the study, four doses of PALA (125, 250, 500, and 1000 mg/m2, administered on day 1) were evaluated to determine the PALA dose with maximal suppression of aspartate transcarbamylase (ATCase) activity that was clinically tolerable. Patients were randomized to receive DP (or no DP), 50 mg/m2, p.o. every 6 h on days 1-6, and all patients received 5-FU, 400 mg/m2, by bolus administration on days 2-5. Prior to and during therapy, WBCs were collected and assayed for ATCase activity. After the maximally tolerated PALA dose with 400 mg/m2 5-FU +/- 50 mg/m2 DP was defined, the 5-FU dose was escalated using the same administration schedule of 5-FU, PALA, and DP. The dose of 5-FU was escalated by 25% in each of the DP cohorts until dose-limiting toxicity was reached. ATCase activity was inhibited in a dose-dependent manner with PALA doses of 125, 250, 500, and 1000 mg/m2, resulting in 0, 13, 17, and 49% inhibition of ATCase activity. Only at the higher PALA doses (i.e., 500 and 1000 mg/m2) was ATCase activity suppressed during days 2-5, but the activity returned to pretreatment levels by day 15. Based on the clinical tolerance and significant suppression of ATCase activity, a PALA dose of 500 mg/m2 was selected for the 5-FU dose escalation phase. At a 5-FU dose of 625 mg/m2, dose-limiting toxicity (leukopenia, stomatitis, and diarrhea) occurred in both DP cohorts. We recommend that for this monthly treatment schedule, 500 mg/m2 PALA and 500 mg/m2 5-FU, with or without 50 mg/m2 DP, be used in subsequent Phase II trials.