Irinotecan in Lymphoma, Leukemia, and Breast, Pancreatic, Ovarian, and Small-Cell Lung Cancers

Introduction

Extensive preclinical work has demonstrated the efficacy of irinotecan(Drug information on irinotecan) (CPT-11 [Camptosar]) against many cancer cell lines and human tumor xenografts. In addition, numerous phase I clinical trials have included case reports of responses in different tumor types. Minor, partial, and/or complete responses to varying schedules of irinotecan have been reported in patients with cancers of the head and neck, esophagus, stomach, pancreas, liver, colon/rectum, kidney, lymph nodes, ovary, and uterine cervix.[1-8] These papers also have described responses in sarcoma, melanoma, acute and chronic leukemia, mesothelioma, and cancers of unknown primary site. Isolated cases are helpful in the design of future phase II trials but, of course, need to be interpreted with caution.

Most of the phase II and III trials of irinotecan have been conducted in patients with colorectal and other gastrointestinal, non-small-cell lung, and cervical cancers. These trials are discussed in other articles in this monograph. This article discusses the limited number of studies of irinotecan in other diseases. Specifically, phase II trials in lymphoma, leukemia, breast, pancreas, ovarian, and small-cell lung cancers are presented.

As will become evident from this discussion, the information gleaned from such preliminary work is subject to many limitations. The number of patients enrolled in the studies is small, and often patients with different disease histologies, stages, and number of prior treatments are included, thereby diluting the reproducibility of the results even further. In many of the early Japanese trials, two or sometimes more dosing regimens are employed in the same trial. When response or toxicity information is eventually reported, rates are based on numbers of patients evaluable rather than number of patients enrolled. Many patients, either because of advanced disease and/or extreme toxicity, are not included in the efficacy analysis.

Most of the trials discussed in this article have been published in abstract form only, itself a limitation on the amount of information that can be presented. When several publications appear in the same year with similar but not identical lists of authors, one cannot be sure whether two separate trials are being summarized or whether the same study is being updated with additional patient numbers. Finally, response duration or length of survival often is not presented, limiting the value of the information that is included.

Despite these drawbacks, which are fairly typical of preliminary data, these studies contain some interesting information. They appear to show a broad range of clinical activity of irinotecan. These studies leave much room open for further study to discover the precise diseases in which the drug may be useful and in which combinations.

Lymphoma

Several phase I trials hinted that irinotecan has clinical activity against the lymphomas; these included one complete response in a patient with previously treated non-Hodgkin’s lymphoma who received 500 mg/m² every 3 weeks.[9] Often, such publications did not provide precise details about disease histology, previous treatment, response duration, and survival. A few phase II trials, conducted in Japan, were limited in that they involved patients with several histologic types and degrees of prior therapy. Two previously published trials included patients with both non-Hodgkin’s lymphoma and Hodgkin’s disease, and one of these studies also included patients with acute leukemias. (With regard to the latter study, the lymphoma patients will be discussed here and the leukemia patients, in the following section.)

Irinotecan Alone

Ohno et al described a series of 29 patients with non-Hodgkin’s lymphoma and 3 with Hodgkin’s disease enrolled at 14 Japanese institutions between December 1987 and October 1989.[10] This study population included 3 patients with follicular lymphoma, 2 with diffuse small-cell lymphoma, 7 with diffuse medium-cell lymphoma, 2 with diffuse mixed large- and small-cell lymphoma, 10 with diffuse large-cell lymphoma, 4 with lymphoblastic lymphoma, and 1 with an immunoblastic lymphoma. The Hodgkin’s disease patients were not characterized by subtype. Although not specifically mentioned in the study, it can be assumed that all of the patients were pretreated, as 10 were characterized as primarily refractory and 21 as both relapsed and refractory.

In the initial treatment phase of the study, patients were randomly assigned to 200 mg/m² of irinotecan every 3 to 4 weeks (schedule A) or 40 mg/m² for 5 days every 3 to 4 weeks (schedule B). An interim analysis showed no response to the first dosing regimen and early relapses (ie, before recovery of normal hematopoietic cells) in patients given the second regimen. Subsequent patients, therefore, were randomized to 40 mg/m² of irinotecan for 3 days every week (schedule C) or 20 mg/m² twice daily for 7 days every 3 to 4 weeks (schedule D).

Results by histology are detailed in Table 1 and by schedule in Table 2. Overall response rates were 24% in the non-Hodgkin’s group (four complete and three partial responses) and 33% in those with Hodgkin’s disease (one partial response in three patients). Toxicities were predictable, with myelo- suppression, diarrhea, nausea, vomiting, and anorexia being the most common.

The authors concluded that a single monthly dose of irinotecan was ineffective for these diseases and that only divided doses given daily (for 3 or 7 days) produced responses. These conclusions are consistent with the theoretical notion that a mechanism of action dependent on cell proliferation would require more frequent dosing.

A follow-up phase II study in lymphoma, conducted by the same group, was published in 1992.[11] This phase II study enrolled 59 patients (56 evaluable for toxicity and 51 for efficacy) who were treated with the prior study’s schedule C, 40 mg/m² of irinotecan for 3 days repeated weekly. Again, multiple histologies were included, with 44 patients described as having non-Hodgkin’s lymphoma, 8 having adult T-cell leukemia/lymphoma (ATLL), and 4 having Hodgkin’s disease. The patients appear to have been heavily pretreated, and had fairly good Eastern Cooperative Oncology Group (ECOG) performance status.

In the non-Hodgkin’s group, 8 complete and 15 partial responses were recorded (44%); no responses were noted in the Hodgkin’s group. Interestingly, there was a 50% response rate (four partial responses) in the ATLL group. The regimen was reasonably well tolerated in this trial.

The results of this trial were updated by Ota et al in 1994.[12] Of 79 patients with lymphoma, 66 completed treatment. The overall response rate was 42% (95% confidence interval [CI], 30% to 54%), including nine complete responses in patients with non-Hodgkin’s lymphoma and no responses in the four individuals with Hodgkin’s disease. The ATLL subgroup of NHL patients (reported separately in another publication[13]) had a response rate of 39% (one complete response, four partial responses).

Irinotecan Combined With Carboplatin(Drug information on carboplatin)

The Japanese study group conducted a phase I/II trial in which carboplatin (Paraplatin) was added to irinotecan.[14] Irinotecan was given at a dose of 20 mg/m² for 3 days every week (with dose escalation planned), and carboplatin dose was fixed at 300 mg/m² on day 1. The first dose level was declared to be the maximum tolerated dose (MTD). In the eight patients treated at that level, the response rate was 25%, which was clearly not superior to the response rate achieved with irinotecan alone. As a result, the regimen was not pursued further.

Summary

The limited studies conducted to date (Table 3) suggest evidence of irinotecan’s activity against a number of lymphoma subtypes, albeit with numbers too small to answer questions with sufficient statistical power. No trials have examined the irinotecan dosing regimens currently approved for other diseases in the United States and Europe. Controlled investigations in patients with similar lymphoma subtypes and amounts of prior therapy should clarify the role of irinotecan, alone and in combination, in lymphoma.