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Biomedical subjects

M L Rothenberg

Publications and source records attributed to M L Rothenberg.

At least 37 records · Page 2Linked to original sources
PubMed1998

Dose intensive combination platinum and cyclophosphamide in the treatment of patients with advanced untreated epithelial ovarian cancer.

BACKGROUND: The authors combined cisplatin and carboplatin together with cyclophosphamide to maximize platinum dose intensity in patients with advanced epithelial ovarian cancer (AOC). METHODS: The authors treated 26 consecutive, newly diagnosed patients with International Federation of Gynecology and Obstetrics (FIGO) Stage III/IV AOC with carboplatin, 600 mg/m2, on Day 1; cyclophosphamide, 250 mg/m2, on Day 1; and cisplatin, 100 mg/m2, on Day 8 every 4 weeks with or without pretreatment with amifostine (range, 740-1140 mg/m2). Platinum dose intensity was estimated using a 4:1 conversion for equipotent doses of cisplatin and carboplatin for expression as cisplatin dose equivalents (CDE). RESULTS: The mean administered CDE was 49.4 mg/m2/week, which was 79% of the planned dose. Hematologic toxicity was severe, with FIGO Grade 3-4 anemia in 81% of patients, Grade 3-4 neutropenia in 92% of patients, and Grade 4 thrombocytopenia in 96% of patients. Eleven patients (42%) were admitted to the hospital for febrile neutropenia and there was 1 toxic death. Sensory neuropathy > or = Grade 2 occurred in 10 patients (38%), ototoxicity > or = Grade 2 occurred in 18 patients (69%), and 6 patients (23%) required long term hearing aids. Elevations in serum creatinine > or = Grade 2 occurred in 7 patients (27%) and > or = Grade 2 hypomagnesemia was noted in 23 patients (88%). Other Grade 3 toxicities were nausea (42%), emesis (38%), fatigue (15%), mucositis (4%), and respiratory toxicities (4%). Twenty-two of 26 patients (85%) had a clinical response (19 with a complete response [CR] and 3 with a partial response). Pathologic CR was demonstrated in 10 of 26 patients (38%) and residual microscopic disease in 4 of 26 patients (15%) for a total pathologic response rate of 53%. The median progression free survival was 13.5 months and the median overall survival was 37.2 months at a median potential follow-up of 79.3 months. Three of 26 patients remained free of disease at 66, 71, and 103 months, respectively. CONCLUSIONS: Although dose intensive combination platinum treatment combined with cyclophosphamide in patients with AOC is active, it also is associated with substantial toxicity.

Adult↗
PubMed1998

Phase I trial of paclitaxel and gemcitabine administered every two weeks in patients with refractory solid tumors.

PURPOSE: Paclitaxel and gemcitabine possess broad spectra of clinical activity, distinct mechanisms of cytotoxicity, and are differentially affected by mutations in cell-cycle regulatory proteins, such as bcl-2. This phase I trial was designed to identify the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of paclitaxel and gemcitabine when both drugs were given together on a once-every-two-week schedule in patients with solid tumors. PATIENTS AND METHODS: A total of 37 patients were treated at nine different dose levels ranging from paclitaxel 75-175 mg/m2 administered over three hours followed by gemcitabinc 1500-3500 mg/m2 administered over 30-60 minutes. Both drugs were administered on day 1 of a 14-day cycle. Dose escalation was performed in a stepwise manner in which the dose of one drug was escalated while the dose of the other drug was kept constant. RESULTS: Dose limiting toxicity (DLT) was observed at dose level 9: paclitaxel 175 mg/m2 and gemcitabine 3500 mg/m2 in the form of grade 4 neutropenia lasting for > or = 5 days (one patient) and grade 3 elevation of alanine aminotransferase (AST/SGPT) (one patient). An analysis of delivered dose intensity (DI) over the first three cycles revealed that higher dosages of both drugs were delivered at dose level 7, paclitaxel 150 mg/m2 and gemcitabine 3000 mg/m2 dose level, than at the MTD, dose level 8, paclitaxel 150 mg/m2 and gemcitabine 3500 mg/m2. Partial responses were confirmed in two patients with transitional cell carcinoma (one of the bladder, one of the renal pelvis) and in one patient with adenocarcinoma of unknown primary. CONCLUSIONS: Paclitaxel and gemcitabine is a promising drug combination that can be administered safely and repetitively on an every-other-week schedule. Using this drug administration schedule, the recommended phase II dose is paclitaxel 150 mg/m2 and gemcitabine 3000 mg/m2.

Adult↗
PubMed1998

Bcl-2 overexpression is associated with resistance to paclitaxel, but not gemcitabine, in multiple myeloma cells.

Multiple myeloma (MM) is an incurable disease despite an initial response-rate of >60% with conventional or high-dose chemotherapy using glucocorticosteroids (i.e. dexamethasone), or alkylating agents (i.e. melphalan). Although these agents are capable of inducing complete remission (CR) in >50% of MM patients, resistance develops rapidly, in >90% of patients, within 2 years of treatment. Therefore, there is a need for new drugs for the treatment of relapsing and refractory MM patients. Gemcitabine (GEM) is a pyrimidine analog that blocks DNA synthesis, whereas, paclitaxel (TAX) is a mitotic spindle poison that promotes microtubular aggregation. Since it appears that these two drugs have different cellular targets, we examined the effect of each drug individually for several parameters and for possible synergy. We studied the cytotoxic effect of TAX and GEM on MM cells expressing varying levels of the antiapoptotic protein bcl-2, which is overexpressed in the majority of myeloma cell from MM patients. We found that both drugs are cytotoxic by inducing apoptosis, however, the extent of apoptosis with TAX, but not with GEM was dependent on the levels of bcl-2 expression. We further investigated the effect of TAX and GEM on the cell cycle distribution and on the levels of bcl-2. The results indicate that the two drugs have different modes of action with respect to each parameter tested. TAX induced arrest of the cells in the G2/M phase of the cell cycle, regardless of bcl-2 levels, however, apoptosis was induced in mitotic cells expressing relatively low levels of bcl-2. In contrast, GEM caused apoptosis of cells in the S-phase, regardless of level of bcl-2 expression. A major difference between TAX and GEM was in their effects on the levels of bcl-2. Whereas, TAX induced an early downregulation of bcl-2 (only in the cells with relatively low levels of bcl-2), treatment with GEM did not affect bcl-2 levels. The effects of TAX on both the cell cycle and bcl-2 were detected very early (4-8 h) and preceded the onset of apoptosis. GEM and TAX act synergistically, at low doses (IC50 of 0.5 microM for GEM and 0.025 microM for TAX), to effectively kill bcl-2 overexpressing cells that are resistant to higher doses (0.25 microM) of TAX alone. Therefore, we have initiated a phase II clinical trial of TAX and GEM for MM patients refractory to current therapy.

Antimetabolites, Antineoplastic↗
PubMed1998

Phase I and pharmacokinetic study of GI147211, a water-soluble camptothecin analogue, administered for five consecutive days every three weeks.

GI1147211 is a 7-substituted 10,11-ethylenedioxy-20(S)-camptothecin analogue that inhibits the nuclear enzyme topoisomerase I. In this Phase I and pharmacological study, 24 patients with advanced solid malignancies received a total of 72 courses of GI147211 as a 30-min infusion daily for 5 consecutive days, at doses ranging from 0.3 to 1.75 mg/m2/day. Severe neutropenia precluded dose escalation above 1.5 mg/m2/day in minimally pretreated patients, and both severe neutropenia and thrombocytopenia were dose limiting in heavily pretreated patients at doses above 1.0 mg/m2/day. These doses are, therefore, recommended for subsequent Phase II evaluations of GI147211 in patients with comparable prior therapy. Nonhematological toxicities, including nausea, vomiting, fatigue, and anorexia, were mild to moderate. The disposition of GI147211 in blood was described by a linear three-compartment model, with renal elimination accounting for only 11% of drug distribution. No relationship was observed between the pharmacological exposure to GI147211 and effects on neutrophils; however, patients who developed dose-limiting myelosuppression did experience greater exposure to both the lactone and total forms of the drug. The hydrolysis kinetics of GI147211 revealed not only a shift of the drug to the inactive carboxylate form in human serum albumin but also stabilization of the lactone in erythrocytes, perhaps accounting for the observed lactone:total area under the concentration-time curve ratio of 0.27. These results indicate that GI147211 exhibits predictable toxicities and that further studies are warranted to determine the distinct role of this compound among currently available camptothecin analogues.

Adult↗
PubMed1998

[New cancer therapies: balancing risk and benefit].

Irinotecan has been approved in Japan, France and USA, however, its clinical usefulness seems to be differently understood. There is a strong opinion, especially in Japan, that the drug is too toxic since it may harm as many patients than it helps. On the contrary, irinotecan is well accepted to the US cancer chemotherapy practices. With irinotecan as a typical example of new chemotherapeutic agents, benefit and risk of cancer chemotherapy is discussed. Differences in cancer chemotherapy practices between Japan and USA are discussed as well.

Antineoplastic Agents↗
PubMed1998

A phase I and translational study of sequential administration of the topoisomerase I and II inhibitors topotecan and etoposide.

Because topoisomerase (topo) I- and topo II-targeting agents exert their principal effects on the two major classes of enzymes involved in regulating DNA topology in the cell, there has been considerable interest in evaluating combinations of these classes of agents. In preclinical studies of inhibitors of topo I and topo II in combination, drug scheduling and sequencing have been critical determinants of antitumor activity, with a greater magnitude of cytotoxicity generally occurring when treatment with the topo I inhibitor precedes treatment with the topo II-targeting agent. The underlying mechanism that has been proposed to explain this schedule dependency is compensatory up-regulation of topo II and, therefore, enhanced cytotoxicity of topo II inhibitors in cells treated initially with topo I inhibitors. The feasibility of sequentially administering the topo I inhibitor topotecan (TPT) followed by the topo II inhibitor etoposide to patients with advanced solid malignancies was evaluated in this Phase I and translational laboratory study. Fifty patients with solid neoplasms were treated with TPT doses ranging from 0.17 to 1.05 mg/m2/day as a 72-h continuous (i.v.) infusion on days 1-3 followed by etoposide, 75 or 100 mg/m2/day as a 2-h i.v. infusion daily on days 8-10. The combined rate of severe neutropenia and thrombocytopenia was unacceptably high above the TPT (mg/m2/day)/etoposide (mg/m2/day) dose levels of 0.68/100 and 0.68/75 in minimally and heavily pretreated patients, respectively, and these dose levels are recommended for further disease-directed evaluations of TPT/etoposide on this administration schedule. Successive biopsies of accessible tumors were obtained for quantitation of topo I and II levels prior to and immediately after treatment with TPT and prior to and immediately after treatment with etoposide in seven patients. The results of these limited studies in tumors did not fully support the proposed mechanistic rationale favoring the development of this particular sequential TPT/etoposide regimen, because only two of the six patients' tumors in whom topo I was successively measured had either modest or substantial decrements in topo I levels following treatment with TPT, and the principal effect of interest, up-regulation of topo II following treatment with TPT, was clearly documented in the tumors of only one of six subjects in whom successive measurements of topo I were performed. Even in view of the notable objective antitumor activity in three subjects, including a complete response in a patient with colorectal carcinoma and partial responses in one patient each with non-small cell lung and gastric carcinomas, the toxicity and ancillary laboratory results do not provide substantial evidence that sequential treatment with TPT and etoposide might be more advantageous than either TPT or etoposide administered as a single agent.

Adult↗
PubMed1998

Alternative dosing schedules for irinotecan.

Most of the clinical experience with irinotecan (CPT-11 [Camptosar]) has been with either a weekly or an every-3-week schedule. Recent phase I trials have explored new routes and schedules of administration. One approach attempts to maximize dose frequency and intensity by giving irinotecan every 2 weeks. A phase I trial of this approach is now complete and has led to a phase II trial in patients with recurrent colorectal cancer. Data suggest that smaller doses of a topoisomerase I inhibitor administered repeatedly may result in greater antitumor activity than large doses administered intermittently. A phase I trial has been performed in adults in which irinotecan was administered daily for 5 consecutive days, followed by 2 days off, for 2 weeks out of 3. Similar trials are under way in children. Oral administration, another strategy that has undergone phase I testing, has several theoretical advantages:(1) The acidic pH of the stomach favors maintenance of irinotecan in the active lactone ring form. (2) Irinotecan is more rapidly and extensively converted to SN-38 by tissue carboxylesterases found in high concentrations in the gut and liver. (3) Low doses can be delivered over a protracted period. (4) The oral route enhances patient convenience. These alternative dosing schedules may facilitate integration of irinotecan into combination chemotherapy and combined-modality treatment regimens.

Adult↗
PubMed1998

Efficacy and toxicity of irinotecan in patients with colorectal cancer.

In six published phase II trials, irinotecan (CPT-II; Camptosar; Pharmacia & Upjohn Co, Kalamazoo, MI) has demonstrated consistent activity with response rates of approximately 13% to 27% in patients with advanced colorectal cancer (CRC) refractory to 5-fluorouracil (5-FU) therapy. Similar response and median survival rates have been achieved using either the US regimen (once a week for 4 weeks followed by a 2-week rest) or the European regimen (once-every-3-week schedule). The optimal administration schedule for irinotecan is uncertain. Phase II evaluation of a biweekly administration schedule in a similar group of patients produced similar response rates. With all schedules tested, the most common toxicities remain delayed diarrhea, neutropenia, and nausea and vomiting. The most common toxicity, late diarrhea, can be ameliorated using high-dose loperamide. Irinotecan has been explored as a single agent in patients with newly diagnosed CRC and has generated response rates in the range of 19% to 32% and a median survival time of approximately 12 months, suggesting a level of antitumor activity similar to that observed with 5-FU and leucovorin. Two recently completed phase III studies in 5-FU-refractory patients have shown that treatment with irinotecan confers a survival advantage compared with treatment with infusional 5-FU or best supportive care. Current studies focus on the activity of irinotecan as part of combined chemotherapy in patients with newly diagnosed advanced-stage CRC, as part of combined-modality therapy with radiation therapy, and as adjuvant chemotherapy for patients with locally advanced CRC.

Antineoplastic Agents, Phytogenic↗
PubMed1997

Pharmacokinetics of elemental platinum (ultrafiltrate and total) after a thirty minute intravenous infusion of ormaplatin.

Preclinical data suggest that ormaplatin (tetrachloro-(dl-trans)-1, 2-diamminocyclohexaneplatinum) has substantial activity in cisplatin-resistant tumor models and may be less nephrotoxic than cisplatin. Based on these data we initiated a phase I clinical trial in patients with refractory metastatic cancer. This report characterizes the pharmacokinetic profile of both the total plasma concentrations of elemental platinum and the unbound ultrafiltrate concentrations of elemental platinum, following a 30 min intravenous infusion of ormaplatin. Platinum concentrations were determined by AAS, and pharmacokinetic parameters for both the total plasma concentration and the ultrafiltrate concentration of elemental platinum were determined using both compartmental and noncompartmental methods. Twenty-eight patients (14 males and 14 females; median age, 58) received ormaplatin. There was a linear relationship between Cmax and dose (r2 = 0.945) and AUC and dose (r2 = 0.976). Ormaplatin is more accurately described by a two-compartment model than by a one-compartment model. The distribution half-life (t1/2 alpha) was 0.3 h and the terminal half-life (t1/2 beta) was 39.1 h. The volume of the central compartment (V) was 68.6 L and the volume of distribution at steady state (Vdss) was 183 L. Like total plasma platinum, unbound platinum is also best characterized by a two-compartment model. The elimination of free platinum is also biphasic with a distribution half-life (t1/2 alpha) of 0.3 h and a terminal half-life (t1/2 beta) of 19.3 h. The mean volume of the central compartment (V) was 200.5 L, and the mean volume of distribution at steady state (Vdss) was 560.5 L. Clinical development of ormaplatin has been terminated due to increased frequency of neurological complications noted over other platinum agents; however, the pharmacokinetics are, in general, similar to those of other clinically used platinum compounds.

Adult↗
PubMed1997

Phase II study of flutamide as second line chemotherapy in patients with advanced pancreatic cancer.

Androgen receptors are present in both pancreatic cancer tissue and cell lines. Flutamide is a potent antiandrogen widely used in clinical practice for patients with metastatic prostate cancer. This Phase II trial was undertaken to evaluate the impact of flutamide in patients with advanced pancreatic adenocarcinoma who had developed progressive disease following therapy with one 5-FU-based regimen. Fourteen patients were treated with flutamide, 250 mg orally three times per day. Therapy was generally well tolerated. No patients achieved objective tumor response. No patient had improvement in tumor-related symptoms as measured by improvement in pain intensity, analgesic requirement, performance status, or nutritional status. Median survival was 4.7 months. We conclude that flutamide is ineffective second line therapy for patients with advanced pancreatic adenocarcinoma.

Adenocarcinoma↗
PubMed1997

Topoisomerase I inhibitors: review and update.

This review presents a summary of preclinical and clinical data on the topoisomerase I (topo I) inhibitors that are under clinical development. To date, all of the topo I inhibitors that have been clinically evaluated are analogues of camptothecin, an extract of the Chinese tree Camptotheca acuminata. The therapeutic development of camptothecin was initially limited by its poor solubility and unpredictable toxicity. More recently, a number of water-soluble camptothecin analogues have undergone extensive evaluation and have demonstrated significant clinical activity. These include irinotecan (CPT-II), topotecan, and 9-aminocamptothecin (9-AC). Preliminary data are also reviewed on other camptothecin analogues (GG-211 and DX-8951f), on oral formulations, and on non-camptothecin topoisomerase I inhibitors. The topoisomerase I inhibitors have already demonstrated a broad spectrum of antitumour activity, most probably due to their unique mechanism of action and lack of clinical cross-resistance with existing antineoplastic compounds. The challenge for the next five years is to identify ways to integrate the topo I inhibitors into multidrug and multimodality therapies to achieve optimal antitumour effect, while keeping the side effects of these therapies manageable.

Animals↗
PubMed1997

Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial.

PURPOSE: Most patients with advanced pancreas cancer experience pain and must limit their daily activities because of tumor-related symptoms. To date, no treatment has had a significant impact on the disease. In early studies with gemcitabine, patients with pancreas cancer experienced an improvement in disease-related symptoms. Based on those findings, a definitive trial was performed to assess the effectiveness of gemcitabine in patients with newly diagnosed advanced pancreas cancer. PATIENTS AND METHODS: One hundred twenty-six patients with advanced symptomatic pancreas cancer completed a lead-in period to characterize and stabilize pain and were randomized to receive either gemcitabine 1,000 mg/m2 weekly x 7 followed by 1 week of rest, then weekly x 3 every 4 weeks thereafter (63 patients), or to fluorouracil (5-FU) 600 mg/m2 once weekly (63 patients). The primary efficacy measure was clinical benefit response, which was a composite of measurements of pain (analgesic consumption and pain intensity), Karnofsky performance status, and weight. Clinical benefit required a sustained (> or = 4 weeks) improvement in at least one parameter without worsening in any others. Other measures of efficacy included response rate, time to progressive disease, and survival. RESULTS: Clinical benefit response was experienced by 23.8% of gemcitabine-treated patients compared with 4.8% of 5-FU-treated patients (P = .0022). The median survival durations were 5.65 and 4.41 months for gemcitabine-treated and 5-FU-treated patients, respectively (P = .0025). The survival rate at 12 months was 18% for gemcitabine patients and 2% for 5-FU patients. Treatment was well tolerated. CONCLUSION: This study demonstrates that gemcitabine is more effective than 5-FU in alleviation of some disease-related symptoms in patients with advanced, symptomatic pancreas cancer. Gemcitabine also confers a modest survival advantage over treatment with 5-FU.

Adult↗
PubMed1996

A rationale for expanding the endpoints for clinical trials in advanced pancreatic carcinoma.

BACKGROUND: Using classical endpoints, such as response rate and survival, as the sole measures of benefit, little progress has been made in the treatment of advanced pancreatic carcinoma in the past 30 years. We challenge the assumption that response rate and survival are the only appropriate endpoints for clinical trials in this disease setting. METHOD: A review of the literature and roundtable discussion were undertaken. RESULTS: Using current imaging techniques, it is inherently difficult to distinguish pancreatic tumor from normal pancreas, inflammatory tissue, local fibrosis, and unopacified bowel. As a result, objective tumor measurements are often imprecise, unreliable, and irreproducible. This difficulty may explain the wide variation in response rates reported in clinical trials even when the same therapies are used. Tumor-related symptoms, such as anorexia, weight loss, severe pain (requiring opioid analgesia), and impaired functional status, are prevalent and debilitating characteristics of this disease. Tools that can assess these symptoms in a consistent fashion over time have been developed and have been integrated into clinical trials to evaluate new drugs in this setting. CONCLUSIONS: Systematic assessment of the impact of a new therapy on tumor-related symptoms may provide a sensitive and accurate way to identify useful new treatments for patients with advanced pancreatic carcinoma. Such analyses can be a useful complement to the classical endpoints of response rate and survival.

Clinical Trials as Topic↗
PubMed1996

A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer.

PURPOSE: To assess the effect of gemcitabine in patients with metastatic pancreas cancer that had progressed despite prior treatment with 5-FU. PATIENTS AND METHODS: Seventy-four patients were enrolled in this multicenter trial. Alleviation of cancer-related symptoms was the primary endpoint. Sixty-three patients completed a pain stabilization period and were treated with gemcitabine. Clinical Benefit Response was defined as a > or = 50% reduction in pain intensity, > or = 50% reduction in daily analgesic consumption, or > or = 20 point improvement in KPS that was sustained for > or = 4 consecutive weeks. RESULTS: Seventeen of 63 pts (27.0%) attained a Clinical Benefit Response (95% CI: 16.0%-38.0%). The median duration of Clinical Benefit Response was 14 weeks (range: 4-69 weeks). Median survival for patients treated with gemcitabine was 3.85 months (range: 0.3-18.0+ months). Therapy was generally well-tolerated with a low incidence of grade 3 or 4 toxicities. CONCLUSION: Systematic assessment of subjective outcomes can be used to evaluate the clinical impact of new therapies for pancreas cancer, a highly symptomatic disease. Our findings suggest that gemcitabine is a useful palliative agent in patients with 5-FU-refractory pancreas cancer.

Adenocarcinoma↗
PubMed1996

Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer.

PURPOSE: To evaluate irinotecan (CPT-11; Yakult Honsha, Tokyo, Japan) in patients with metastatic colorectal carcinoma that had recurred or progressed following fluorouracil (5-FU)-based therapy. PATIENTS AND METHODS: Patients were treated with irinotecan 125 to 150 mg/m2 intravenously (IV) every week for 4 weeks, followed by a 2-week rest. Forty-eight patients were entered onto the study and all were assessable for toxicity. Forty-three patients completed one full course of therapy and were assessable for response. RESULTS: One complete and nine partial responses were observed (response rate, 23%; 95% confidence interval [CI], 10% to 36%). The median response duration was 6 months (range, 2 to 13). The median survival time was 10.4 months and the 1-year survival rate was 46% (95% CI, 39% to 53%). Grade 4 diarrhea occurred in four of the first nine patients (44%) treated on this study at the 150-mg/m2 dose level. The study was amended to reduce the starting dose of irinotecan to 125 mg/m2. At this dose, nine of 39 patients (23%) developed grade 4 diarrhea. Aggressive administration of loperamide also reduced the incidence of grade 4 diarrhea. Grade 4 neutropenia occurred in eight of 48 patients (17%), but was associated with bacteremia and sepsis in only case. CONCLUSION: Irinotecan has significant single-agent activity against colorectal cancer that has progressed during or shortly after treatment with 5-FU-based chemotherapy. The incidence of severe diarrhea is reduced by using a starting dose of irinotecan 125 mg/m2 and by initiating loperamide at the earliest signs of diarrhea. These results warrant further clinical evaluation to define the role of irinotecan in the treatment of individuals with colorectal cancer.

Adenocarcinoma↗
PubMed1996

CPT-11: an original spectrum of clinical activity.

Due to its novel mechanism of action, CPT-11 (irinotecan) has significant in vitro activity against a variety of solid tumors, including those particularly resistant to other cytotoxic agents. This activity has been confirmed in clinical trials of single-agent CPT-11 conducted in Japan, Europe, and the United States. In chemotherapy-naive patients with advanced non-small cell lung cancer, a response rate of 32% to 34% has been shown in Japan with CPT-11 monotherapy, although this has been improved to within the range of 43% to 54% using CPT-11 in combination with cisplatin. Prior chemotherapy appears to reduce the response rate substantially in this setting, although the mechanisms of cross-resistance are unknown. CPT-11 is also active in small cell lung cancer, with a single agent response rate of 47% in patients previously treated with cisplatin. As might be expected, CPT-11 is more active when combined with cisplatin as first-line chemotherapy for small cell lung cancer, with Japanese investigators reporting an average response rate of 85%. Consistent results from studies of colorectal cancer in Japan, the United States, and Europe, indicate that CPT-11 is active as a single agent in patients who have developed progressive disease following 5-fluorouracil (5-FU)-based treatment. In patients with metastatic colorectal cancer, approximately 18% to 27% of patients with 5-FU refractory disease and 15% to 32% of patients who are chemotherapy-naive respond to single agent therapy. Efforts to combine CPT-11 with 5-FU with or without folinic acid are ongoing. There is less clinical experience with CPT-11 in the treatment of other solid tumors, but activity has been reported in phase II trials of patients with squamous cell carcinoma of the uterine cervix or skin, and in those with cancer of the ovary, stomach, or pancreas and in patients with lymphoma. While notable objective response rates have been reported for single agent CPT-11, the precise role of this drug in the treatment of patients with solid tumors has yet to be defined, especially as part of first-line therapy. CPT-11 appears to be one of the most exciting new drugs to reach clinical development in the past decade, and its seemingly wide spectrum of clinical activity suggests that it may have a substantial impact on the treatment of many of the most common epithelial malignancies.

Antineoplastic Agents, Phytogenic↗