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Objectives: Preclinical data suggest histone deacetylase inhibitors improve the therapeutic index of sorafenib. A phase I study was initiated to establish the recommended phase 2 dose of sorafenib combined with vorinostat in patients with unresectable hepatocellular carcinoma., Materials and Methods: Patients received vorinostat (200 to 400 mg by mouth once daily, 5 of 7 d) and sorafenib at standard or reduced doses (400 mg [cohort A] or 200 mg [cohort B] by mouth twice daily). Patients who received 14 days of vorinostat in cycle 1 were evaluable for dose-limiting toxicity (DLT)., Results: Sixteen patients were treated. Thirteen patients were evaluable for response. Three patients experienced DLTs, 2 in cohort A (grade [gr] 3 hypokalemia; gr 3 maculopapular rash) and 1 in cohort B (gr 3 hepatic failure; gr 3 hypophosphatemia; gr 4 thrombocytopenia). Eleven patients required dose reductions or omissions for non-DLTtoxicity. Ten patients (77%) had stable disease (SD). The median treatment duration was 4.7 months for response-evaluable patients. One patient with SD was on treatment for 29.9 months, and another patient, also with SD, was on treatment for 18.7 months. Another patient electively stopped therapy after 15 months and remains without evidence of progression 3 years later., Conclusions: Although some patients had durable disease control, the addition of vorinostat to sorafenib led to toxicities in most patients, requiring dose modifications that prevented determination of the recommended phase 2 dose. The combination is not recommended for further exploration with this vorinostat schedule in this patient population.

Objective: To determine the safety and efficacy of a novel illudin S derivative, irofulven (MGI-114), in patients with recurrent ovarian cancer who had received extensive prior chemotherapy., Methods: The trial was an open label phase II study. Patients initially enrolled in this study were treated every 14 days with a dose of 24 mg/m2. Unexpected retinal toxicity associated with this dose and schedule lead to modification of the dosing to 0.55 mg/kg on the same schedule with a maximum individual dose of 50 mg. Dose reductions were permitted based on both hematologic and non-hematologic toxicities., Results: Seventy-four women were accrued and stratified into two cohorts including 58 women with platinum-resistant disease and 16 with platinum-sensitive disease. Non-hematologic toxicities included nausea, vomiting, and fatigue. Thirty-one women had between one and six visual symptoms, most were Grade 1 and 2 in nature. The majority of visual toxicities resolved either during treatment or post-treatment with irofulven. There was one partial response in each cohort with 19 (33%) and 8 (50%) of women having stable disease in the platinum-resistant and platinum-sensitive cohorts, respectively., Conclusions: Irofulven at 24 mg/m2 on every 14-day schedule is associated with significant retinal toxicity in this patient population. Dosing at 0.55 mg/kg has persistent retinal toxicity, yet demonstrated only limited anti-tumor activity in a population of women who had received extensive prior chemotherapy.

Chemotherapy has been regarded as standard therapy for the majority of women with advanced epithelial ovarian cancer for several decades, with this role filled largely by the alkylating agents - used as monotherapy - until the mid-1980s. The activity of cisplatin in this disorder was established during the 1970s, and combinations of cisplatin and an alkylating agent were widely used during the late 1980s. However, further research prompted by continuing concerns over poor survival and tolerability led to the adoption of paclitaxel in combination with either cisplatin or carboplatin as first-line therapy in ovarian cancer during the 1990s. Most recent research has focused on further optimisation of these regimens to maximise clinical benefit while minimising toxicity, and investigations into alternative taxanes (e.g. docetaxel), other novel agents and new treatment schedules are ongoing.

Before 1993, the standard of care for the chemotherapeutic management of advanced ovarian cancer was cisplatin or carboplatin combined with a classic alkylating agent (typically cyclophosphamide). Studies in the 1990s have changed this standard to one of the platinum-containing agents combined with a taxane, paclitaxel, or docetaxel. This article reviews the pertinent studies regarding paclitaxel combined with cisplatin or carboplatin, discusses the remaining controversies surrounding how best to combine these agents, and provides opinions regarding the discordant outcomes noted in studies of the paclitaxel-platinum doublet. A separate article discusses the docetaxel-platinum doublet and how that might be considered an appropriate option for first-line therapy in patients with advanced, newly diagnosed ovarian cancer.

Purpose: The primary objective of this phase I trial was to determine the feasibility of administering a combination of paclitaxel, cisplatin, and doxorubicin with or without granulocyte colony-stimulating factor (G-CSF) in patients with advanced endometrial and other gynecologic cancers., Patients and Methods: Patients were chemotherapy-naive. Doxorubicin was administered as a brief infusion, paclitaxel for 3 hours, and cisplatin for 60 minutes. Treatments were repeated every 3 weeks. For most dose levels, the cisplatin and doxorubicin were fixed at 60 mg/m(2) and 45 mg/m(2), whereas the paclitaxel was escalated in successive cohorts from 90 to 250 mg/m(2). Patients who had received previous radiotherapy to the whole pelvis were escalated separately from those who had not., Results: Eighty patients received 320 cycles of therapy. When G-CSF was not used, myelosuppression prevented escalation beyond the starting dose for patients with or without previous pelvic radiotherapy. When G-CSF was added, neurotoxicity became dose-limiting for both groups. Ten patients were removed from the study for asymptomatic declines in ejection fraction, but no symptomatic congestive heart failure was observed. Major antitumor responses occurred in 46% of patients (six of 13) with measurable endometrial carcinoma and 50% of patients (eight of 16) with measurable cervical carcinoma., Conclusion: The combination of paclitaxel, doxorubicin, and cisplatin at relevant single-agent doses is active and feasible with the addition of G-CSF. A regimen of cisplatin 60 mg/m(2), doxorubicin 45 mg/m(2), and paclitaxel 160 mg/m(2) with G-CSF support is recommended for further testing.

A phase I study was performed to determine the maximum tolerated doses of intravenous etoposide and paclitaxel for women with previously treated persistent or recurrent ovarian cancer. Starting doses were paclitaxel 135 mg/m2 during 24 hours and etoposide 50 mg/m2/day for 3 consecutive days. The study was designed to escalate first the dose of etoposide, and then the dose of paclitaxel, in successive cohorts of patients. In an attempt to determine whether toxicity was affected by sequence of the drugs, the order of administration of the two drugs was reversed on alternate cycles. The starting doses of paclitaxel (135 mg/m2/24 hours) and etoposide (50 mg/m2/day x 3) caused severe neutropenia even with the addition of granulocyte colony-stimulating factor, and the trial was amended to administer the paclitaxel during 3 hours. However, this also proved too myelosuppressive without growth factor support. Twenty-one women were treated. A complete response was observed in one of nine patients with measurable disease, and a major decrease in CA-125 was noted in two patients who did not have measurable disease. Because of the severe myelosuppression observed in most patients, dose reduction was often required after the first cycle. The power to detect sequence-dependent variation in toxicity was minimal; however, no large differences were observed. A combination of the usual doses of these drugs will be difficult to administer in patients who have received previous chemotherapy for ovarian cancer.

The effect of high-dose chemotherapy on the survival of women with ovarian cancer has been studied in numerous clinical trials. Approaches to dose intensity have included high-dose chemotherapy, combination platinum therapies, intraperitoneal therapy, and stem cell-supported high-dose chemotherapy. Taken together, the data demonstrate increased response rates with high-dose regimens, but any survival advantages observed have been limited. Patients with the most favorable outcome are those with low tumor burden and chemotherapy-sensitive tumors. An attempt to study this group of patients in a randomized trial in the United States (Gynecologic Oncology Group Protocol 164) was unsuccessful because of low accrual. Reasons for low accrual included physician bias, patient bias, and lack of third-party payer support. European randomized trials are under way to evaluate high-dose chemotherapy and stem cell transplantation as part of initial therapy or as consolidation after initial response to therapy and to compare high-dose chemotherapy with standard-dose chemotherapy. Until results from these trials become available, high-dose therapy remains limited to the clinical trial setting.

Objective: To evaluate the impact of the camptothecin analogs on human TCC xenograft, both as monotherapy and in combination with cisplatin (CDDP)., Materials and Methods: Human transitional cell carcinoma (TCC) xenograft tumor line (DU4184) tested by subrenal capsule assay in 112 nude mice(NM-SRCA). CDDP and the camptothecin analogs irinotecan (CPT-11) and 9-aminocamptothecin(9-AC) were evaluated., Results: Both of the camptothecin analogs showed significant short term tumor inhibition which translated into enhanced survival. Maximal tumor inhibition (>95%) was achieved when either of the camptothecin analogs was combined with CDDP with minimal host toxicity. This translated into 400% increase in median survival. While all controls were dead 39 days following tumor implantation, none of the combination treated animals had died., Conclusion: The combination of CDDP with these camptothecin analogs is an effective therapy against this model of advanced TCC. These observations suggest potential clinical value.

Purpose: A phase I and pharmacologic study to evaluate the feasibility of administering paclitaxel (PTX) in combination with topotecan (TPT) without and with granulocyte colony-stimulating factor (G-CSF) in women with recurrent or refractory ovarian cancer., Patients and Methods: TPT was administered as a 30-minute infusion daily for 5 days and PTX was given as a 24-hour infusion (PTX-24) either before TPT on day 1 or after TPT on day 5. Each patient received both schedules on an alternating basis every 3 weeks. Sequential dose escalation of TPT or PTX-24 without and with G-CSF resulted in five dosage permutations of TPT/PTX (mg/ m2): 0.75/135 without G-CSF and 0.75/135, 1.25/135, 1.50/135, and 1.25/170 with G-CSF., Results: Twenty-two patients received 109 courses of therapy. Dose-limiting myelosuppression consistently occurred at the first TPT/PTX-24 dose level (0.75/135 mg/m2) in the absence of G-CSF support. Although the addition of G-CSF resulted in reduced rates of complicated neutropenia, the incidences of dose-limiting neutropenia and thrombocytopenia were unacceptably high after the doses of either TPT or PTX-24 were increased. Paired analysis showed similar hematologic toxicities between the two sequences of drug administration. The pharmacologic behavior of both TPT and PTX-24 was not altered by drug sequencing. Major antitumor responses occurred in 40% of patients with measurable and assessable disease, including 45% and 9% of patients with potentially cisplatin-sensitive and -resistant tumors, respectively., Conclusion: The recommended doses of TPT on a daily times-five schedule combined with PTX-24 in these patients were 0.75 mg/m2/d and 135 mg/m2, respectively, with G-CSF support. Although this dose of PTX has significant single-agent activity in ovarian cancer, the dose of TPT is much lower than the TPT dose at which single-agent activity has been observed. Due to the inability to administer near relevant single-agent doses of both drugs in combination, as well as the requirement for G-CSF support, further evaluations of this regimen in women with refractory or recurrent ovarian cancer are necessary before it can be recommended for previously treated patients in this setting.

Purpose: To develop a tolerable, dose-intense regimen of carboplatin and paclitaxel for the treatment of primary epithelial ovarian carcinoma., Patients and Methods: Patients underwent initial surgical assessment and tumor debulking. Patients with stage III/IV disease received six cycles of chemotherapy on a planned 21-day cycle. Carboplatin dose was calculated based on projected area under the curve (AUC) for concentration over time (mg. mL-1.min) and escalated to determine the maximum-tolerated dose (MTD). Paclitaxel dose was also escalated as a 3-, 24-, or 96-hour infusion. Granulocyte colony-stimulating factors (G-CSFs) were required at selected dose levels or could be added based on hematologic toxicity., Results: Thirty-nine patients were enrolled and assessable for toxicity and response. Dose-limiting toxicity (DLT) was hematologic, primarily neutropenia. Less than 2% of all cycles with paclitaxel as a 3- or 24-hour infusion were associated with either grade 4 thrombocytopenia or febrile neutropenia. The carboplatin MTD was AUC 7.5 (equivalent to a median dose of 471 mg/m2). The MTD for paclitaxel was 135 mg/m2 over 24 hours and 175 mg/m2 over 3 hours without initial G-CSF. A 96-hour infusion of paclitaxel at a dose of 120 mg/m2 was associated with excessive single-cycle and cumulative myelosuppression, and was not further evaluated. Measured carboplatin AUC agreed well with the calculated AUC. The overall complete (n = 16) and partial (n = 2) response rate among 24 patients with measurable disease was 75%, with a median progression-free survival time of 15 months., Conclusion: Carboplatin could be safely combined with paclitaxel using a dose formula based on projected renal clearance. The recommended outpatient regimen is carboplatin AUC 7.5 and paclitaxel 175 mg/m2 over 3 hours without initial G-CSF. This treatment safely achieved a greater dose-intensity of carboplatin than would have been achieved with conventional dosing based on body-surface area.

Ovarian cancer is an important disease due to its occurrence in women in the prime of life (40-70) and its responsiveness to therapy but generally poor outcome due to the emergence of drug-resistant cells. In early-stage disease, adjuvant therapies may improve outcome, but previous studies have concentrated more on the reduction of toxicity of therapy than on improved survival, although modern approaches are evaluating more aggressive intervention in these patients with good survival rates (40%-90% cure with surgery). In advanced disease, the most common presentation, it appears that more aggressive staging and surgical debulking as well as new classes of drugs for treatment have altered, albeit modestly, the outcome in this disease. Future approaches will evaluate taxol, a new active agent, as well as more dose-intense therapy and a continued search will be made for new active drugs and methods to overcome intrinsic and acquired drug resistance.

Table 1 summarizes studies in which clinical or pathologic response rates can be determined. The majority of patients in these studies had macroscopic drug-resistant tumors, and most had received cisplatin-based chemotherapy. It is noteworthy that the response rate in this group of patients is considerably higher than the 30% to 36% seen with the most active salvage therapies, such as taxol (paclitaxel). Like most trials of salvage chemotherapy for refractory ovarian carcinoma, many responses were short-lived. Toxicity in these studies is comparable to that seen in trials of ASCT in other solid tumors. The promising results observed in these small studies of ASCT in ovarian carcinoma warrant further investigation focused on defining which groups of patients are likely to benefit from this approach. Based on evidence from the lymphohematopoietic malignancies, it would seem reasonable to use ASCT in patients early in the course of their disease before extensive pretreatment and preferably at a time of minimal tumor burden. Some groups have been exploring ASCT as consolidation therapy after surgery and limited debulking chemotherapy. Based on kinetic models of tumor growth, other investigators have suggested that multiple courses of high-dose chemotherapy with ASCT after debulking surgery may result in more cures than a single ASCT after conventional chemotherapy. The feasibility of performing sequential ASCT has been well documented. So far the best drug regimens, the number of cycles that should be used, and the patients who should be candidates for high-dose chemotherapy and ASCT remain undefined. Presently, there is no role for this therapeutic modality outside of well-designed clinical trials.

Background: Medullary thyroid carcinoma (MTC) is a neoplasm of the parafollicular C cells of the thyroid gland, which belongs to the diffuse neuroendocrine system. This cancer usually behaves in a relatively indolent manner for most patients. However, approximately 20% of patients have a more aggressive course that requires effective management. There are few reported clinical trials of chemotherapy for MTC. From the literature, the most active agent appears to be doxorubicin, with response rates of 30% reported. On the basis of the activity of cyclophosphamide, vincristine, and dacarbazine (CVD) in other advanced neuroendocrine neoplasms, the authors tested the combination in patients with advanced MTC., Methods: Seven patients with advanced MTC were treated with cyclophosphamide (750 mg/m2), vincristine (1.4 mg/m2), and dacarbazine (600 mg/m2 daily for 2 days in each cycle) every 3 weeks. Assessments of measurable tumor and serum calcitonin and carcinoembryonic antigen were made before treatment and followed up until progressive disease was documented., Results: Two patients had partial tumor and biochemical responses for a duration of 14 and 29 months, respectively. One patient had a partial biochemical response and stable tumor measurements for 9 months, and another patient had stable tumor size and markers for 14 months. Three patients had progressive disease. Diarrhea and flushing improved in two patients who had partial biochemical responses., Conclusion: Our experience suggests that CVD chemotherapy has moderate activity and is well tolerated in patients with advanced MTC. Additional prospective studies of this regimen for MTC are required.

Ovarian carcinoma is the most common cause of death among the gynecologic malignancies. Primary therapy in advanced disease involves debulking surgery followed by platinum-containing chemotherapy. Despite such treatment, most patients die of residual or recurrent disease. Paclitaxel (TAXOL), a new antineoplastic agent, has response rates of 20% to 35% in phase II studies in patients with refractory ovarian cancer. Most women treated in these studies had platinum-resistant disease. Toxicity was primarily hematologic and neurologic. The findings from a large European-Canadian study suggest that hematologic toxicity is schedule dependent whereas neurologic toxicity is dose dependent. Dose escalation of paclitaxel with granulocyte colony-stimulating factor support and combinations of paclitaxel with cisplatin have been tested and shown to be feasible. Intraperitoneal administration of paclitaxel also is possible and advantageous from a pharmacokinetic perspective. In a multi-institutional randomized trial, primary treatment of patients with suboptimal disease with the combination of paclitaxel and cisplatin was compared with cyclophosphamide and cisplatin. Toxicity data from this completed trial show paclitaxel to be safe in this setting. Efficacy awaits maturity of survival data. Future clinical development of paclitaxel will include its use in less bulky disease and further evaluation of its dose escalation in advanced platinum-resistant disease. Paclitaxel currently is considered first-line treatment for platinum-resistant ovarian carcinoma. Further clinical investigation will determine its role in the primary management of ovarian cancer.

Epithelial ovarian cancer is the fifth most common cause of cancer death in women. The management of patients with advanced disease involves surgery followed by platinum-based chemotherapy, but most patients will have either residual or recurrent disease. Salvage therapy in these patients is poor, with response rates less than 20%. Taxol, a new antineoplastic agent, was first noted to have activity in platinum-resistant ovarian cancer in a phase I study. Since then, response rates of 20% to 35% have been noted in several phase II studies involving hundreds of patients. Major toxicities include neutropenia and peripheral neuropathy. Taxol dose escalation with granulocyte-colony stimulating factor support, and Taxol in combination with cisplatin, have been tested and shown to be feasible. Intraperitoneal administration of Taxol is possible and appears advantageous from a pharmacokinetic perspective. A phase III study of Taxol and cisplatin in suboptimal disease was completed, and toxicity data show that Taxol administration is safe in a multi-institutional setting. Planned clinical development of Taxol includes use in less bulky stage III disease and dose escalation in platinum-resistant disease. Taxol has already become a major treatment of platinum-resistant disease. Further investigation will determine its role in the overall management of ovarian cancer.

Immature teratoma is a rare ovarian germ cell tumor with an aggressive clinical behavior. Treatment involves surgical resection, usually followed by chemotherapy. Since the introduction of postoperative chemotherapy several cases of "transformation" of this malignant tumor into mature teratoma (retroconversion) have been described. Usually retroconversion presents during the first year of diagnosis. We report a case of synchronous mature teratomas of the ovary and liver presenting 11 years following chemotherapy for stage III immature ovarian teratoma. The CT scan appearance, incidence, and biological significance of this phenomena are discussed.

Forty-four patients with advanced, measurable, epithelial carcinoma of the ovary were treated with 97 courses of N-methylformamide (N-MF) at doses ranging from 600-800 mg/m2, intravenously, daily for 5 days every 28 days. Forty-one patients had prior surgery and had received one prior chemotherapy regimen. Only seven patients had received any prior radiation therapy. All patients were Gynecologic Oncology Group (GOG) performance status 0, 1, or 2. Three partial responses were seen. Hematologic adverse effects were extremely rare as predicted by early clinical trials. One major toxicity was a syndrome consisting of some combination of myalgias, arthralgias, pleuritic pain, abdominal pain, peripheral neuropathy, anorexia, lethargy, and declining performance status (pain-lethargy syndrome) that was reversible with discontinuation of the drug. This adverse effect was as common a reason as hepatic toxicity for discontinuation of N-MF. As reported in previous studies with this drug, hepatic toxicity was also common, usually reversible, and also a cause for discontinuation of the drug. The low level of clinical activity and the unpleasant adverse effects in this population of patients with previously treated ovarian cancer makes it unlikely that this drug will play any significant role in treatment of epithelial ovarian cancer.

Twenty patients with advanced measurable, squamous carcinoma of the cervix were treated with 25 courses of N-MF at doses ranging from 600-800 mg/m2, intravenously, daily for 5 days every 28 days. Nineteen patients are evaluable for toxicity and 17 for response. All patients had prior radiation and had received one prior chemotherapy regimen while only 10 patients had had prior surgery. All patients were Gynecologic Oncology Group (GOG) performance status 0, 1, or 2. No responses were seen. Hematologic adverse effects were extremely rare as predicted by early clinical trials. One unusual toxicity was a syndrome consisting of pain, anorexia, lethargy, and declining performance status (pain/lethargy syndrome) that was reversible with discontinuation of the drug. This adverse effect was a reason for discontinuation of N-MF in two patients. As reported in previous studies with this drug, hepatic toxicity was also common, usually reversible, and also a cause for discontinuation of the drug. The lack of clinical activity and the unpleasant adverse effects in this population of patients with previously treated cervix cancer makes it unlikely that this drug will play any significant role in treatment.

A randomized control trial was performed in good performance status patients with unresectable non-small cell lung cancer to test a strategy of early aggressive combination chemotherapy (CAMP [cyclophosphamide, doxorubicin, methotrexate, and procarbazine]) versus a strategy of delaying such treatment until clinical deterioration. Thirty-seven patients received immediate CAMP and 35 patients received initial low-dose single-agent CCNU (CAMP was postponed). Immediate CAMP therapy produced an objective response rate of 44% in patients with measurable lesions, and CCNU produced none. Median survival was 193 days for the immediate-CAMP group and 175 days for the postponed-CAMP group (P = 0.26). Measures of quality of life were made and no difference emerged between the two treatment strategies. This trial failed to show substantial benefit from immediate combination chemotherapy in minimally symptomatic patients with non-small cell lung cancer.

Most patients with lung cancer subjected to surgical resection are likely to have residual tumor burdens which lead to clinical relapse and death. Unfortunately, none of the systemic therapies for squamous cell, large cell and adenocarcinoma of the lung have demonstrated curative potential either in the advanced disease or in the surgical adjuvant setting. Interest in clinical trials of adjuvant therapy in lung cancer have been rekindled by three factors: 1) reports indicating the value of immunotherapy, 2) preliminary encouraging experience with new chemotherapy programs, and 3) methodologies including stage- and cell type-specific clinical trials leading to better interpretation of results. These concepts have stimulated new treatment protocol studies within the NCI-sponsored Lung Cancer Study Group, and clinical cooperative groups.

A total of 394 patients with advanced, measurable squamous carcinoma of the uterine cervix and no prior chemotherapy were randomized to therapy with either carboplatin or iproplatin. There were 23 patients ineligible for the study and 10 patients who were not evaluable; the remaining 361 patients were evaluable for response and adverse effects. Randomization was well balanced for age, performance status, and prior therapy. Both platinum analogs were given every 28 days with starting doses of 400 mg/m2 for carboplatin (340 mg/m2 if the patient underwent prior radiation) and 270 mg/m2 for iproplatin (230 mg/m2 if the patient underwent prior radiation). These doses are equivalent to cisplatin doses of 75 to 100 mg/m2. Hematologic toxicity was dose-limiting, among which thrombocytopenia was slightly more common than leukopenia. Gastrointestinal toxicity was also prominent with both agents; however, iproplatin was significantly more toxic than carboplatin (P less than .001). Renal, otic, and peripheral nervous system toxicities were absent or infrequent with both analogs. No electrolyte abnormalities were observed. The percentage of planned dosages that were actually administered was 100% of carboplatin doses and 85% of iproplatin doses (P less than .0001). The reduction in iproplatin dose was apparently due to gastrointestinal toxicity. Response rates were similar for both agents (15% for carboplatin, 11% for iproplatin) and appear to be inferior to those noted with the parent compound, cisplatin.