Gisele Sarosy

Anthracycline analogs The past, present, and future

Doxorubicin (Adriamycin, Adria Laboratories) has the widest spectrum of antitumor activity of all chemotherapeutic agents and is used with a high degree of efficacy in many human cancers. It is probably the most utilized antitumor drug worldwide, and a majority of patients needing systemic treatment for cancer receive doxorubicin (DOX) at some time during their clinical course. The major obstacle to its use is its cumulative dose-limiting cardiotoxicity. Great effort has been expended to discover means of ameliorating, preventing, or at least delaying the onset of this cardiotoxicity. One method has been to create DOX analogs that cause less cardiotoxicity. Concomitant with this search for less cardiotoxic analogs is a search for analogs that may be administered orally or that have greater antitumor efficacy, especially for human cancers such as melanoma and colon carcinoma that are insensitive to DOX. In the last decade a number of anthracycline analogs have been synthesized or isolated. One of these agents (epirubicin) has been developed to the point where it is commercially available in Europe and Canada. Others are undergoing clinical trials. Developments in this field of anthracycline analogs are rapid and sometimes confusing. Many new analogs have been placed in clinical trial and others have been dropped because of inferiority in various respects. We review in depth four of these analogs (epirubicin, esorubicin, idarubicin, and menogaril) that are of current high interest and then review in a briefer fashion analogs in disuse and those with promise for the future.

Autologous bone marrow transplantation. Current status and future directions.

PURPOSE To assess the current status of high-dose chemotherapy with autologous marrow transplantation in hematologic malignancies and solid tumors. DATA IDENTIFICATION Studies reported between 1978 and May 1988 were identified through computer searches using Medline and Cancerline and through extensive manual searching of bibliographies of identified books and articles. STUDY SELECTION More than 160 studies that contained adequate response, toxicity, or survival data were selected for analysis, including peer-reviewed articles, book chapters, and proceedings of meetings. The most current or complete references were used for series reported more than once. DATA ANALYSIS Information abstracted included regimen used, number of patients, response rates, disease-free and overall survival, and toxicities. A meta-analysis of the pooled data was done. RESULTS OF DATA ANALYSIS For many tumor types, autologous marrow transplantation offers higher response rates than standard approaches. For leukemias and lymphomas, response rates of 60% to 80% may be achieved with the potential for cure. With solid tumors, response rates range from 30% in gliomas, 50% in melanomas and colon cancer, more than 60% in lung cancer, and 80% in breast cancer. Although responses tend to be short-lived, long-term survival can occasionally be seen. CONCLUSIONS Results with autologous marrow transplantation can be improved through systematically developed, carefully designed clinical trials that may be facilitated by collaborative research. Studies should focus on disease-directed drug combinations, several courses of high-dose therapy, treatment at a time of lower tumor burden, and reducing toxicity with hematopoietic growth factors.

The systemic administration of intravenous melphalan.

Melphalan (L-phenylalanine mustard) is a bifunctional alkylating agent that is commonly administered orally to treat a wide variety of malignancies, including cancers of the breast and ovary, as well as multiple myeloma. Although commercially available in Europe and Canada, intravenous (IV) melphalan remains investigational in the United States. The role of IV melphalan in cancer chemotherapy is not well defined, despite its manageable toxicity and higher and more predictable blood levels following IV administration compared with oral administration. In addition, unlike oral melphalan, an extensive phase I evaluation of IV melphalan has not been undertaken. At lower doses (eg, 30 to 70 mg/m2), both as a single agent and in combination, the activity of IV melphalan has been evaluated in only a limited number of diseases. However, striking activity has been observed in previously untreated patients with rhabdomyosarcoma, a disease not generally considered responsive to alkylating agents. When administered at high doses (greater than 140 mg/m2) requiring bone marrow reinfusion, melphalan effects a high response rate (but no improvement in survival) in a variety of nonhematologic tumor types, including resistant tumors such as melanoma and colon carcinoma. In contrast, in poor-prognosis patients with non-Hodgkins lymphoma, Hodgkins disease, multiple myeloma, or neuroblastoma, high-dose melphalan-containing regimens have yielded both high response rates and improved survival, despite considerable toxicity. Additional clinical trials will be necessary to define the spectrum of activity of lower doses of IV melphalan and to define subgroups of patients most likely to benefit from high-dose melphalan.

Phase II trial of carboxyamidotriazole in patients with relapsed epithelial ovarian cancer.

PURPOSE Carboxyamidotriazole (CAI) is a cytostatic inhibitor of nonvoltage-operated calcium channels and calcium channel-mediated signaling pathways. It inhibits angiogenesis, tumor growth, invasion, and metastasis. We hypothesized that CAI would promote disease stabilization lasting >/= 6 months in patients with relapsed ovarian cancer. PATIENTS AND METHODS Patients with epithelial ovarian cancer, good end-organ function, measurable disease, and three or fewer prior regimens were eligible. Oral CAI was given daily using a pharmacokinetic-dosing approach to maintain plasma concentrations between 2 and 4 microg/mL. Radiographic imaging to assess response was performed every 8 weeks. Positive outcome included stabilization or improvement of disease lasting >/= 6 months. Plasma vascular endothelial growth factor (VEGF), interleukin (IL)-8, and matrix metalloproteinase (MMP)-2 were measured. RESULTS Thirty-six patients were assessable for primary end point analysis, and 38 were assessable for toxicity. Forty-four percent of patients had three prior regimens, more than 50% had four or more disease sites, and 48% had liver metastases. Thirty-three patients reached the targeted concentration range during the first cycle. Eleven patients (31%) attained the >/= 6-month outcome end point, with one partial response (8 months) and three minor responses (8, 12+, and 13 months). Median time to progression was 3.6 months (range, 1.6 to 13.3 months). CAI was well tolerated, with mostly grade 1 to 2 toxicity. Grade 3 events included fatigue (5%), vomiting (2%), neutropenic fever (2%), and neutropenia (2%). There were no grade 4 adverse events. No associations between VEGF, IL-8, and MMP-2 with CAI concentration or clinical outcome were observed. CONCLUSION CAI is a potential agent for additional study in the stabilization of relapsed ovarian cancer. Given a limited toxicity profile, it may have utility as a maintenance therapeutic agent for this disease.

Steady-state plasma concentrations and effects of taxol for a 250 mg/m2 dose in combination with granulocyte-colony stimulating factor in patients with ovarian cancer

Taxol, a natural product initially isolated from the stem bark of the western yewTaxus brevifolia, is undergoing phase II and III evaluation due to its reported activity against a variety of tumors. Previous studies have described correlations between plasma concentrations and toxicity when taxol is given (a) at lower doses, (b) for shorter infusion times, and (c) without granulocyte-colonystimulating factor. Because the 24-h infusion schedule is most commonly used in current clinical trials, we attempted to correlate steady-state plasma concentrations of taxol achieved with a 24-h continuous i.v. infusion with toxicities and responses. Plasma samples from 48 refractory ovarian cancer patients were obtained 1–2 h prior to the end of the first taxol infusion. Taxol concentrations were measured by high-performance liquid chromatography (HPLC). Interpatient variation of taxol plasma concentrations was small (mean±SD, 0.85±0.21 μM. Total taxol body clearance was 256±72 ml min−1m−2 (mean±SD). Taxol plasma protein binding was 88.4%±1.3% (mean±SD,n=9). Grade 3–4 hematologic toxicity, mainly leukopenia, occurred in 92% of the patients. The leukopenia was transient and did not warrant a reduction in the dose of taxol. Grade 3–4 nonhematologic toxicity occurred in 8% of the patients. No severe hypersensitivity reaction or grade 3–4 neurotoxicity was observed. Correlations of plasma concentrations and toxicities were not feasible due to the high frequency of hematologic effects and the low frequency of nonhematologic toxicity. The low degree of interpatient variation in plasma concentrations hindered the development of correlations with response.

Borderline ovarian tumors

Borderline tumor of the ovary (BOT) is an epithelial tumor with a low rate of growth and a low potential to invade or metastasize. This tumor often is associated with a significantly better prognosis than epithelial ovarian cancer. Most tumors are either serous or mucinous in histology and present as early stage lesions. However, stage III lesions with peritoneal implants are not uncommon. Patients with early stage lesions have an excellent prognosis. Patients with higher stage lesions have a worse prognosis. Long-term follow-up of patients with BOT is required since the tumor can recur up to 20 years after the initial diagnosis. Recently, investigators have begun to identify subsets of patients with a worse prognosis, such as patients with aneuploid tumors. Treatment for early stage lesions is surgical and conservative surgery can be accomplished successfully in younger patients who desire to maintain fertility. Treatment for later stage lesions has been approached in a variety of ways. All approaches initially begin with maximal cytoreductive surgery. Studies suggest that early stage disease should be managed with surgery alone. Conflicting results on the usefulness of adjuvant therapy for patients with later stage disease have been obtained. At this time, the usefulness of adjuvant therapy for advanced disease remains undetermined. Further understanding of the basis of the disease and analysis of specific higher risk subsets might identify patients in whom adjuvant therapy could be tested in the setting of controlled clinical trials.

Dose Intensive Combination Platinum and Cyclophosphamide in the Treatment of Patients with Advanced Untreated Epithelial Ovarian Cancer

The authors combined cisplatin and carboplatin together with cyclophosphamide to maximize platinum dose intensity in patients with advanced epithelial ovarian cancer (AOC).

N-methylformamide: cytotoxic, radiosensitizer, or chemosensitizer.

N-methylformamide (NMF), a polar solvent, is currently being evaluated by the National Cancer Institute (NCI) as an antineoplastic agent because of its activity against colon, mammary, and lung tumor xenografts. Results from preclinical studies suggest that it has radiosensitizing, chemosensitizing, and differentiating activity. Its mechanism of action remains unknown, but may involve cellular depletion of glutathione, cell membrane changes, or modulation of proto-oncogene expression. Preclinical toxicology studies conducted in mice, rats, and beagle dogs showed reversible hepatotoxicity to be dose-limiting. Clinically, NMF is administered both orally and by intravenous (IV) injection. The bioavailability with oral administration is 90% to 95%. The highest reported plasma concentration of NMF is approximately 4 mmol/L in a patient who received a dose of 2,000 mg/m2 of IV NMF. Biphasic elimination with IV NMF is seen on both the daily for five days and weekly for 3 weeks schedule. Approximately 5% to 7% of the total administered IV dose is excreted in the urine. In phase I studies, dose-limiting toxicities included reversible hepatotoxicity, a generalized malaise syndrome, and nausea and vomiting. One partial response has been reported in the 111 patients treated on phase II trials in colorectal, head and neck, and renal carcinomas. Suggestions for the future development of this drug are presented.

FUTURE DIRECTIONS WITH TAXANE THERAPY

The potential biochemical and genetic mechanisms by which a cell might experience a decreased sensitivity to taxanes and other drugs of this class are discussed in the first part of this article. The use of taxanes in the current gynecologic-oncologic clinical setting is reviewed with special consideration given to the pharmacokinetics of taxane in relation to dose intensity and length of administration.

Autologous Stem-Cell Transplantation in Ovarian Cancer: Is More Better?

Although advanced-stage epithelial ovarian cancer is highly responsive to initial therapy, most patients ultimately succumb to the disease. According to a series of studies conducted by multi-institution cooperative groups, such as the Gynecologic Oncology Group, surgery to accomplish maximal cytoreduction followed by six cycles of carboplatin and paclitaxel, or cisplatin and paclitaxel, is the current standard of care (1-4). Better treatment is urgently needed to improve long-term disease-free survival for patients with ovarian cancer. On the basis of extrapolation of data (1-4), it can be expected that approximately 80% of patients with ovarian cancer will at some point achieve complete clinical remission. However, disease will recur in approximately 40% of patients within 2 years and in another 20% within the next 2 to 5 years. Only approximately 20% of patients with ovarian cancer will have long-term disease-free survival. Several general approaches have been developed in an attempt to increase the percentage of patients in whom disease can be permanently eradicated. Among these approaches are consolidation intraperitoneal chemotherapy (4, 5), consolidation systemic chemotherapy (4, 6), and autologous stem-cell transplantation, which is discussed by Stiff and colleagues (7) in this issue. Other factors that should be considered but are usually not reported are careful analysis of treatment costs, comparative toxicities, toxicity costs, and quality-of-life issues (8). Stiff and colleagues report data from the Autologous Blood and Marrow Transplant Registry (ABMTR) on all patients with ovarian cancer treated in participating ABMTR centers between 1 January 1989 and 31 December 1996. Their study involved 57 North American transplantation centers and 513 eligible registered patients but focused on 421 women for whom comprehensive data were available. Autologous stem-cell transplantation has been shown to be a reasonable treatment approach for several malignant diseases. It is usually most effective when tumor burden is low, and it can have a favorable impact in subsets of patients with acute myelogenous leukemia or myelodysplasia (9-11), Hodgkin disease (12), and non-Hodgkin lymphoma (13). To determine the role of autologous stem-cell transplantation in ovarian cancer, one should compare available data with data from other treatment strategies in similar patients. We compare best-case scenario data on several approaches. Stiff and colleagues report that the best progression-free and overall survival (35% [95% CI, 17% to 53%] and 60% [CI, 39% to 76%]) were seen in the 34 patients (8% of the entire group) who received transplants while in first complete remission. The best-case scenario for intraperitoneal chemotherapy performed in a similar setting was seen in a study by Howell and coworkers (5), which reported a 2-year progression-free survival of 69% in 25 patients with minimal residual disease who received intraperitoneal cisplatin and antimetabolites. The best-case scenario for systemic chemotherapy was seen in a study by Kohn and colleagues (6), in which 36 patients received a three-drug combination of paclitaxel, cisplatin, and cyclophosphamide for six cycles; second-look surgery; and two to four cycles of paclitaxel and cyclophosphamide. Two-year progression-free survival in this study was 71%. Stiff and colleagues found that within the first 100 days of therapy, 14 patients died of infection, 13 died of organ failure, and 4 died of hemorrhage. Therefore, 7.4% of patients (31 of 421) died of potential treatment-related complications. No treatment-related deaths were noted in the 25 patients studied by Howell and coworkers (5) or the 36 patients studied by Kohn and colleagues (6). The number of deaths related to autologous stem-cell transplantation seems to be substantially higher than the number of deaths following other treatment approaches for advanced disease (4). Physicians and patients should decide whether the toxicity of autologous stem-cell transplantation is acceptable. In addition to concerns about toxicity, there are other questions to consider. What subset of patients should be studied with dose-intensity approaches in the future? What is the optimal dose-intensity approach for ovarian cancer? What level of cost is acceptable for a given level of efficacy? What are the tradeoffs in terms of quality of life? Stiff and colleagues suggest that phase III clinical trials of autologous stem-cell transplantation are necessary. Should other treatment arms of such trials be structured along the lines of the work of Howell and coworkers (5), Kohn and colleagues (6), or both? What about newer graft-versus-tumor types of autologous stem-cell transplantation, antiangiogenesis agents, vaccines, other biological agents, or agents directed against specific molecular targets? Although the future may lie with one or more of these newer treatment options, they are not yet sufficiently developed to be seriously considered for phase III testing in human ovarian cancer. Current standard chemotherapy at standard doses holds limited promise for major improvement in advanced epithelial ovarian cancer. We believe that four general approaches to chemotherapy could be considered for phase III studies in this disease: a standard dosing approach of novel combinations, standard dosing followed by consolidation of autologous stem-cell transplantation, standard dosing followed by cisplatin-based combination intraperitoneal therapy, and standard or intermediate dosing followed by paclitaxel-based systemic consolidation. The timing of the first surgical procedure (14) and the concept of interval debulking (15) are matters that also should be considered in the overall development of new treatment strategies. Autologous stem-cell transplantation is a reasonable experimental approach to explore, but other potentially useful strategies have not been fully studied in phase III trials. Because autologous stem-cell transplantation seems to be somewhat toxic and offers limited improvement in efficacy, less toxic approaches should also be considered in patients with ovarian cancer.