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.

Multicenter phase II trial of adjuvant therapy for resected pancreatic cancer using cisplatin, 5-fluorouracil, and interferon-alfa-2b-based chemoradiation: ACOSOG Trial Z05031.

BACKGROUND: The American College of Surgeons Oncology Group sought to confirm the efficacy of a novel interferon-based chemoradiation regimen in a multicenter phase II trial. PATIENTS AND METHODS: Patients with resected (R0/R1) adenocarcinoma of the pancreatic head were treated with adjuvant interferon-alfa-2b (3 million units s.c. on days 1, 3, and 5 of each week for 5.5 weeks), cisplatin (30 mg/m(2) i.v. weekly for 6 weeks), and continuous infusion 5-fluorouracil (5-FU; 175 mg·m(2)/day for 38 days) concurrently with external-beam radiation (50.4 Gy). Chemoradiation was followed by two 6-week courses of continuous infusion 5-FU (200 mg·m(2)/day). The primary study end point was 18-month overall survival from protocol enrollment (OS18); an OS18 ≥65% was considered a positive study outcome. RESULTS: Eighty-nine patients were enrolled. Eighty-four patients were assessable for toxicity. The all-cause grade ≥3 toxicity rate was 95% (80 patients) during therapy. No long-term toxicity or toxicity-related deaths were noted. At 36-month median follow-up, the OS18 was 69% [95% confidence interval (CI) 60% to 80%]; the median disease-free survival and overall survival were 14.1 months (95% CI 11.0-20.1 months) and 25.4 months (95% CI 23.4-34.1 months), respectively. CONCLUSIONS: Notwithstanding promising multi-institutional efficacy results, further development of this regimen will require additional modifications to mitigate toxic effects.

Incidence and evolution of oxaliplatin-induced peripheral sensory neuropathy in diabetic patients with colorectal cancer: a pooled analysis of three phase III studies.

BACKGROUND: The purpose of this study was to determine whether the presence of diabetes mellitus (DM) influences the incidence, severity, and/or course of peripheral sensory neuropathy (PSN) after oxaliplatin (FOLFOX) therapy in patients with colorectal cancer (CRC). METHODS: A retrospective pooled analysis incorporating three phase III studies was conducted: Multicenter International Study of Oxaliplatin, 5-Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) (adjuvant treatment; stage II/III colon cancer), EFC4584 (second-line treatment; metastatic CRC), and EFC2962 (first-line treatment; metastatic CRC). Patients were ineligible for the studies if they had known PSN (EFC4584) or PSN grade > or =1 (MOSAIC and EFC2962) at baseline. The incidence of PSN was evaluated retrospectively in patient subgroups with or without DM at baseline that received FOLFOX. Kaplan-Meier curves were used to assess the probability of PSN with increasing cumulative oxaliplatin dose. RESULTS: Of 1587 patients enrolled across the three studies, 135 (8.5%) had DM at baseline. The incidence of PSN (non-DM/DM) was 45.0%/46.7% (grade 1), 28.6%/26.7% (grade 2), and 13.0%/12.6% (grade 3). The probability of PSN by cumulative dose of oxaliplatin was similar in DM and non-DM patients. CONCLUSIONS: This retrospective analysis indicates that oxaliplatin-based therapy does not influence the incidence, severity, or time to onset of PSN in asymptomatic DM patients with CRC who meet eligibility criteria for clinical trials.

Capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX-4) as second-line therapy in metastatic colorectal cancer: a randomized phase III noninferiority study.

BACKGROUND: To demonstrate the noninferiority of capecitabine plus oxaliplatin (XELOX) versus 5-fluorouracil/folinic acid and oxaliplatin (FOLFOX-4) as second-line therapy in patients with metastatic colorectal cancer after prior irinotecan-based chemotherapy. PATIENTS AND METHODS: A total of 627 patients were randomly assigned to receive XELOX (n = 313) or FOLFOX-4 (n = 314) following disease progression/recurrence or intolerance to irinotecan-based chemotherapy. The primary end point was progression-free survival (PFS). RESULTS: PFS for XELOX was noninferior to FOLFOX-4 [hazard ratio (HR) = 0.97; 95% confidence interval (CI) 0.83-1.14] in the intention-to-treat (ITT) population. Median PFS was 4.7 months with XELOX versus 4.8 months with FOLFOX-4. The robustness of the primary analysis was supported by multivariate and subgroup analyses. Median overall survival in the ITT population was 11.9 months with XELOX versus 12.5 months with FOLFOX-4 (HR = 1.02; 95% CI 0.86-1.21). Treatment-related grade 3/4 adverse events occurred in 50% of XELOX- and 65% of FOLFOX-4-treated patients. Whereas grade 3/4 neutropenia (35% versus 5% with XELOX) and febrile neutropenia (4% versus < 1%) were more common with FOLFOX-4, grade 3/4 diarrhea (19% versus 5% with FOLFOX-4) and grade 3 hand-foot syndrome (4% versus < 1%) were more common with XELOX. CONCLUSION: XELOX is noninferior to FOLFOX-4 when administered as second-line treatment in patients with metastatic colorectal cancer.

Phase I trial of oral MAC-321 in subjects with advanced malignant solid tumors.

PURPOSE: MAC-321 is a novel taxane that has demonstrated exceptional activity in human xenograft models when administered intravenously and orally. Preclinical studies of MAC-321 have shown antitumor activity in MDR-expressing and paclitaxel-resistant tumors. This phase I dose escalation study was performed to determine the safety, tolerability, and pharmacokinetic profile of orally administered MAC-321 given once every 21 days. Preliminary antitumor activity of MAC-321 was also examined. METHODS: Key eligibility criteria included adult subjects with refractory solid tumors or solid tumors for which conventional therapy was unsuitable or did not exist, good performance status (ECOG ( 2), and adequate hematologic, hepatic, and renal functions. Plasma pharmacokinetic (PK) sampling was performed during the first cycle of therapy. RESULTS: Five dose levels of MAC-321 ranging from 25 to 75 mg/m(2) were evaluated in 18 subjects (four women and 14 men). MAC-321 was well tolerated at the first three dose levels (25, 37, 50 mg/m(2)). Two subjects developed dose-limiting toxicities (DLTs) at 75 mg/m(2); one subject with grade 3 and one subject with grade 4 neutropenia with fever. Three subjects treated at an intermediate dose level of 60 mg/m(2) had no DLTs. However, the study was terminated prior to completion of the maximal tolerated dose cohort after subjects treated with intravenous MAC-321 in a concurrent study experienced life-threatening toxicities. Other common toxicities included grades 1-2 fatigue and grades 1-2 diarrhea. There was substantial interpatient variability in the PK parameters. MAC-321 was rapidly absorbed with a mean C (max) value of less than 1 h. Mean C (max) and AUC values generally increased in a dose-related manner. The median terminal phase elimination half-life was 45 h (range 20-228 h). Disease stabilization was seen in four subjects with the following tumors: mesothelioma (14 cycles), chondrosarcoma (12 cycles), small cell carcinoma (10 cycles), and prostate carcinoma (6 cycles). CONCLUSIONS: MAC-321 can be safely administered orally once every 21 days up to a dose of 60 mg/m(2). The major DLT was neutropenic fever. Four subjects had disease stabilization.

High-dose carboplatin with diethyldithiocarbamate chemoprotection in treatment of women with relapsed ovarian cancer.

Diethyldithiocarbamate (DDTC) has been found to protect the bone marrow, kidneys, and gastrointestinal tract from the toxic effects of cisplatin and carboplatin (CBDCA) in animal models. In an attempt to minimize the toxic effects of high-dose CBDCA (800 mg/m2), a pilot study was undertaken in which women with relapsed or refractory epithelial ovarian cancer were treated with high-dose CBDCA, which was followed 3 hours later with DDTC (4 g/m2). There were four partial responses and no complete response in 21 patients who could be evaluated (overall response rate, 19%). Significant toxic effects, including three treatment-related deaths, were associated with the regimen. This study suggests that while high-dose CBDCA plus DDTC may be active in relapsed or refractory ovarian cancer, it is associated with clinically significant hematologic and autonomic toxic effects.

Matrix metalloproteinases: biologic activity and clinical implications.

Tumor progression is a complex, multistage process by which a normal cell undergoes genetic changes that result in phenotypic alterations and the acquisition of the ability to spread and colonize distant sites in the body. Although many factors regulate malignant tumor growth and spread, interactions between a tumor and its surrounding microenvironment result in the production of important protein products that are crucial to each step of tumor progression. The matrix metalloproteinases (MMPs) are a family of degradative enzymes with clear links to malignancy. These enzymes are associated with tumor cell invasion of the basement membrane and stroma, blood vessel penetration, and metastasis. They have more recently been implicated in primary and metastatic tumor growth and angiogenesis, and they may even have a role in tumor promotion. This review outlines our current understanding of the MMP family, including the association of particular MMPs with malignant phenotypes and the role of MMPs in specific steps of the metastatic cascade. As scientific understanding of the MMPs has advanced, therapeutic strategies that capitalize on blocking the enzymes have rapidly developed. The preclinical and clinical evolution of the synthetic MMP inhibitors (MMPIs) is also examined, with the discussion encompassing important methodologic issues associated with determining clinical efficacy of MMPIs and other novel therapeutic agents.

Dose-intensive induction therapy with cyclophosphamide, cisplatin, and consolidative abdominal radiation in advanced-stage epithelial ovarian cancer.

PURPOSE: The primary goal of this trial was to evaluate the clinical activity of a high-dose cisplatin-based induction regimen for women with advanced-stage ovarian cancer. A secondary goal was to assess the use of whole-abdominal radiation as consolidative therapy in the subset of women left with less than 5 mm residual disease after completion of chemotherapy. PATIENTS AND METHODS: Fifty consecutive patients with newly diagnosed, advanced-stage ovarian cancer received cisplatin 40 mg/m2/d and cyclophosphamide 200 mg/m2/d intravenously (IV) for 5 days, every 4 to 6 weeks. After three to four cycles of chemotherapy, patients who still had residual disease less than 5 mm in greatest diameter at second-look surgery were given whole-abdominal radiotherapy. RESULTS: The overall response rate in 49 patients assessable for response was 61.3% (24.5% pathologic complete responses [pCRs], 32.7% pathologic partial responses [pPRs], and 4.1% clinical partial responses [cPRs]). Median survival for all patients was 23.4 months, and actuarial 4-year survival was 33.7% (95% confidence interval [CI], 21.8% to 48.1%). Multivariate analysis showed stage III and serous histology as independent favorable prognostic factors for survival. Median survival for stage III patients was 36.5 months, with an actuarial 4-year survival of 41.6% (95% CI, 25.5% to 59.6%). Median survival for stage IV patients was 12.0 months, with actuarial 4-year survival of 22.9% (95% CI, 9.5% to 45.5%). The major acute toxicities encountered were myelosuppression and peripheral neuropathy. Patients who received consolidative radiotherapy were at increased risk of developing late-onset enteropathy. CONCLUSIONS: This regimen is active against advanced-stage ovarian cancer, but the associated toxicity is severe. Consolidative whole-abdominal radiation did not appear to prolong survival in the subset of women left with less than 5 mm residual disease after chemotherapy.

Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel.

PURPOSE: To review and assign attribution for the causes of early deaths on two National Cancer Institute-sponsored cooperative group studies involving irinotecan and bolus fluorouracil (5-FU) and leucovorin (IFL). PATIENTS AND METHODS: The inpatient, outpatient, and research records of patients treated on Cancer and Leukemia Group B protocol C89803 and on North Center Cancer Treatment Group protocol N9741 were reviewed by a panel of five medical oncologists not directly involved with either study. Each death was categorized as treatment-induced, treatment-exacerbated, or treatment-unrelated. RESULTS: The records of 44 patients who experienced early deaths on C89803 (21 patients) or N9741 (23 patients) were reviewed. Patients treated with irinotecan plus bolus 5-FU/leucovorin had a three-fold higher rate of treatment-induced or treatment-exacerbated death than patients treated on the other arm(s) of the respective studies. For C89803, these rates were 2.5% (16 of 635) for IFL versus 0.8% (five of 628) for bolus weekly 5-FU and leucovorin. For N9741, these rates were 3.5% (10 of 289) for IFL, 1.1% (three of 277) for oxaliplatin plus bolus and infusional 5-FU and leucovorin, and 1.1% (three of 275) for oxaliplatin plus irinotecan. Multiple gastrointestinal toxicities that often occurred together were characterized into a gastrointestinal syndrome. Sudden, unexpected thromboembolic events were characterized as a vascular syndrome. The majority of deaths in both studies were attributable to one or both of these syndromes. CONCLUSION: Close clinical monitoring, early recognition of toxicities and toxicity syndromes, aggressive therapeutic intervention, and withholding therapy in the presence of unresolved drug-related toxicities is recommended for patients receiving IFL or other intensive chemotherapy regimens.

Commentary concerning demonstration of safety and efficacy of investigational anticancer agents in clinical trials.

Expeditious clinical development and approval of new drugs that are beneficial to patients are matters of high priority. There has been a great deal of discussion within the oncology community about what should constitute evidence of effectiveness of new anticancer agents for purposes of drug approval. This commentary is intended to illustrate a variety of end points that can lead to approval of new anticancer agents for specific clinical situations. Although the ultimate hope of antineoplastic therapy is prolongation of life, there are other effects of anticancer drugs that constitute clear clinical benefit and represent evidence of effectiveness. The guiding principle is that the beneficial effects obtained from a new drug should sufficiently outweigh the adverse effects such that the potential risk:benefit ratio achieved by an individual patient is favorable. The assessment of a new drug should flexibly evaluate safety and efficacy in the context of the specific clinical condition being treated. Early discussions with the Food and Drug Administration (FDA) and the National Cancer Institute (NCI) are recommended to identify prospectively the end points and trial designs needed to demonstrate effectiveness of a new drug. The general principles discussed will likely apply to the drug approval process for other medical disciplines as well.

Phase I and pharmacokinetic trial of weekly CPT-11.

PURPOSE: We conducted a phase I and pharmacokinetic trial of CPT-11 (irinotecan) to characterize the maximum-tolerated dose (MTD), toxicities, pharmacokinetic profile, and antitumor effects in patients with refractory solid malignancies. PATIENTS AND METHODS: We treated 32 patients with CPT-11 administered as a 90-minute intravenous infusion every week for 4 consecutive weeks followed by a 2-week rest period. Dose levels ranged from 50 to 180 mg/m2/wk. We determined concentrations of the lactone (active) and total (lactone plus carboxylate) forms of CPT-11 and its metabolite, SN-38, in the plasma and urine of selected patients during and after drug infusion. RESULTS: Grade 4 diarrhea was the dose-limiting toxicity (DLT) at the 180-mg/m2/wk dose level. Other toxicities attributed to CPT-11 included dehydration, nausea, vomiting, and asthenia. Hematologic toxicity was mild in most patients. The terminal plasma half-life for CPT-11 (total) was 7.9 +/- 2.8 hours, for CPT-11 (lactone) 6.3 +/- 2.2 hours, for SN-38 (total) 13.0 +/- 5.8 hours, and for SN-38 (lactone) 11.5 +/- 3.8 hours. We observed significant correlations between drug dose and peak plasma concentration (Cpmax) and between drug dose and area under the concentration curve (AUC) for CPT-11, but not for SN-38. CONCLUSION: The MTD for CPT-11 in this patient population was 150 mg/m2/wk when administered on a weekly-times-four schedule repeated every 6 weeks. At dose levels greater than 150 mg/m2/wk, diarrhea is dose-limiting.

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.

Phase I and pharmacokinetic trial of oral irinotecan administered daily for 5 days every 3 weeks in patients with solid tumors.

PURPOSE: We conducted a phase I dose-escalation trial of orally administered irinotecan (CPT-11) to characterize the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetic profile, and antitumor effects in patients with refractory malignancies. PATIENTS AND METHODS: CPT-11 solution for intravenous (IV) use was mixed with CranGrape juice (Ocean Spray, Lakeville-Middleboro, MA) and administered orally once per day for 5 days every 3 weeks to 28 patients. Starting dosages ranged from 20 to 100 mg/m2/d. RESULTS: Grade 4 delayed diarrhea was the DLT at the 80 mg/m2/d dosage in patients younger than 65 years of age and at the 66 mg/m2/d dosage in patients 65 or older. The other most clinically significant toxicity of oral CPT-11 was neutropenia. A linear relationship was found between dose, peak plasma concentration, and area under the concentration-time curve (AUC) for both CPT-11 and SN-38 lactone, implying no saturation in the conversion of irinotecan to SN-38. The mean metabolic ratio ([AUC(SN-38 total) + AUC(SN-38G total)]/AUC(CPT-11 total)) was 0.7 to 0.8, which suggests that oral dosing results in presystemic conversion of CPT-11 to SN-38. An average of 72% of SN-38 was maintained in the lactone form during the first 24 hours after drug administration. One patient with previously treated colorectal cancer and liver metastases who received oral CPT-11 at the 80 mg/m2/d dosage achieved a confirmed partial response. CONCLUSION: The MTD and recommended phase II dosage for oral CPT-11 is 66 mg/m2/d in patients younger than 65 years of age and 50 mg/m2/d in patients 65 or older, administered daily for 5 days every 3 weeks. The DLT of diarrhea is similar to that observed with IV administration of CPT-11. The biologic activity and favorable pharmacokinetic characteristics make oral administration of CPT-11 an attractive option for further clinical development.

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.

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.

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.

The role of nonrandomized trials in the evaluation of oncology drugs.

Although randomized trials provide the most reliable evidence of a drug's safety and efficacy, there are situations where randomized trials are not possible or ethical. In this article we discuss when and how single-arm trials can be used to support full approval of oncology drugs. These include situations in which an unprecedented effect on tumor response is observed in a setting of high unmet medical need, clinical trial patients have been well characterized, enabling a target population to be clearly defined, experience exists in a sufficient number of patients to allow adequate assessment of the risk:benefit relationship, and a proper historical context can be provided for analysis. We also discuss how response rates might be considered predictive of long-term outcomes or clinically meaningful in and of themselves in certain contexts.

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.

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.