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Randomized Phase II Study of Two Irinotecan Schedules for Patients With Metastatic Breast Cancer Refractory to an Anthracycline, a Taxane, or Both

From the Mayo Clinic and Mayo Foundation, Jacksonville, FL; Mayo Clinic, Rochester; Duluth Community Clinical Oncology Program (CCOP), Duluth, MN; Missouri Valley Cancer Consortium, Omaha, NE; Scottsdale CCOP, Scottsdale, AZ; Carle Cancer Center CCOP, Urbana; Illinois Oncology Research Association CCOP, Peoria, IL; Ochsner CCOP, New Orleans, LA; and Wichita HCCOP, Wichita, KS

Address reprint requests to Edith A. Perez, MD, Division of Hematology/Oncology, Mayo Clinic Jacksonville, 4500 San Pablo Rd, Jacksonville, FL 32224; e-mail: perez.edith{at}mayo.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
PURPOSE: A pressing need exists for agents active against anthracycline- or taxane-refractory metastatic breast cancer (MBC), or both. Previous clinical trials suggested that irinotecan might have such activity. We conducted this multicenter phase II study to assess efficacy and tolerability of two irinotecan schedules.

PATIENTS AND METHODS: MBC patients who experienced disease progression after one to three chemotherapy regimens, including at least one anthracycline- or taxane-based regimen, were randomly assigned to irinotecan in 6-week cycles comprising 100 mg/m² weekly for 4 weeks, then a 2-week rest (weekly) or 240 mg/m² every 3 weeks.

RESULTS: The weekly arm had 52 assessable patients; the every-3-weeks arm had 51 assessable patients. In the weekly arm, the objective response (complete regression [CR] + partial regression [PR]) rate was 23% (one CR, 11 PR; 95% CI, 13% to 37%). Median response duration was 4.9 months (range, 1.9 to 15.9 months), and median overall survival was 9.7 months (95% CI, 8.0 to 14.2 months). In the every-3-weeks arm, the objective response rate was 14% (nine PR; 95% CI, 6% to 26%), median response duration was 4.2 months (range, 3.1 to 13.9 months), and median overall survival was 8.6 months (95% CI, 7.0 to 12.3 months). Treatment generally was well tolerated, especially in the weekly arm. Grade 3 to 4 adverse events with 10% incidence included neutropenia (29%) and diarrhea (17%) in the weekly arm and neutropenia (36%), vomiting (20%), dyspnea (18%), nausea (16%), and diarrhea (12%) in the every-3-weeks arm.

CONCLUSION: Irinotecan is active with good tolerability in refractory MBC. Irinotecan (especially weekly) warrants additional study as monotherapy and in combination regimens in this setting.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
The preferred front-line chemotherapy for metastatic breast cancer (MBC) typically is based on anthracycline or taxane.^1,2 Response rates range from 20% to 41% for single agents from either drug class and increase to 70% to 80% when an anthracycline, a taxane, or both are used in combination with each other or with drugs of other classes. Nevertheless, the majority of patients with MBC who receive anthracycline- or taxane-based treatment experience disease progression or recurrence. The 5-year survival rate as of 2002 of only 21% among women with distant metastases emphasizes the critical need for agents with efficacy against anthracycline- and taxane-refractory MBC.³

Potentially, one such agent is the semisynthetic camptothecin derivative, irinotecan. Irinotecan is an inhibitor of topoisomerase I, an enzyme necessary for DNA replication. The irinotecan metabolite, SN-38, binds to the topoisomerase I-DNA complex, preventing the enzyme from resealing the DNA during replication and transcription, and thereby producing DNA breaks, leading to apoptosis.⁴

Irinotecan has demonstrated single-agent activity in advanced colorectal cancer in multicenter, international phase III studies.^5,6 Likewise, the drug has shown single-agent clinical activity in a variety of other solid tumors, including advanced breast cancer, in phase I and II studies.^7-11 Studies involving patients with MBC and other solid tumors used two different schedules of irinotecan administration: weekly on day 1 each of 4 consecutive weeks, followed by a 2-week rest period (hereafter referred to as weekly)⁸ or on the first of every 21 days (hereafter referred to as every 3 weeks).⁹ Given the clear need for agents active against refractory MBC, and suggestions of efficacy in earlier clinical trials in this setting, we conducted a randomized phase II study to assess further these schedules of irinotecan monotherapy in women with breast cancer refractory to an anthracycline, a taxane, or both.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
Study Design and Patient Selection
This was a multicenter, randomized, open-label, two-stage trial designed to evaluate, but not to compare, the antitumor activity and safety of two schedules of irinotecan (Camptosar; Pfizer Inc, New York, NY) in women whose metastatic breast cancer had recurred or progressed after anthracycline- or taxane-based therapy, or both. The study was conducted by the North Central Cancer Treatment Group (NCCTG) at 19 North American centers.

Eligibility criteria included histologically confirmed adenocarcinoma of the breast with progressing locoregional or metastatic disease and at least one bidimensionally measurable indicator lesion with a diameter of at least 1.0 cm if assessed by physical examination or chest x-ray, or of at least 2.0 cm if assessed by computed tomography, magnetic resonance imaging, or ultrasonography. Prior treatment with at least one regimen, whether adjuvant or for metastatic disease, and containing an anthracycline, an anthraquinone, a taxane, or doxorubicin, was also required. Patients were allowed to have received at most one adjuvant regimen and two regimens for metastatic disease, whether or not all of these were based on anthracycline or taxane. Other eligibility criteria included age 18 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2, and life expectancy more than 3 months. Within 14 days of study registration (hereafter referred to as baseline), patients had to have an absolute neutrophil count 1,500/mm³ and platelets 100,000/mm³. Also at baseline, creatinine had to be 1.0 mg/dL above, total bilirubin had to be 0.3 mg/dL above, and AST had to be 3x the respective upper limit of institutional normal.

Patients who had undergone major surgery or chemotherapy within 4 weeks of study registration, who had received radiation to more than 25% of their bone marrow, or who had received strontium-89 were excluded. Also precluded from participation were patients with uncontrolled infection, chronic debilitating illness, New York Heart Association class 3 or 4 heart disease, or CNS metastases not rendered free of symptoms or progression by surgery or radiation within the 2 months before study entry. In addition, women who were pregnant, lactating, or unwilling to use adequate contraception were excluded.

The study was performed according to precepts established by the Helsinki Declaration, the protocol was approved by the institutional review boards of all study centers, and each patient gave written informed consent to participate.

Stratification, Random Assignment, and Treatment
Patients were stratified prospectively according to dominant metastatic site (visceral v nonvisceral), ECOG PS (0 to 1 v 2), and prior chemotherapy for metastatic disease (yes v no). They then were randomly assigned using a dynamic allocation procedure¹² to either of two treatment schedules comprising 6-week cycles: weekly irinotecan 100 mg/m² on day 1 in each of 4 consecutive weeks, followed by a 2-week rest, or irinotecan 240 mg/m² every 3 weeks on days 1 and 22 of a 42-day period. Irinotecan was diluted in 500 mL of 5% dextrose and infused intravenously during 90 minutes.

In both arms, starting dosage was lower than the respective maximum-tolerated dose determined by phase I studies^8,9 because of preliminary tolerability findings of another NCCTG investigation.¹³ On the basis of the presence and intensity of treatment-related adverse events, subsequent dosage in this study was subject to modification according to a prospective scheme derived from product labeling and clinical experience. According to this scheme, dosage was increased to 125 mg/m² in the weekly arm and 280 mg/m² in the every-3-weeks arm if toxicity was absent in the first cycle. Treatment was withheld, and dosage decreased up to three times in the weekly arm to a minimum of 40 mg/m², and up to two times in the every-3-weeks arm to a minimum of 160 mg/m², in response to toxicity grade 2. Treatment was discontinued when the maximum number of dosage reductions took place.

At the investigator's discretion, treatment was permitted with analgesics, antiemetics, or growth factors. Atropine or loperamide regimens developed in irinotecan phase I studies^8,14 were suggested to treat diarrhea during and between irinotecan infusions, respectively.

Treatment continued until unacceptable toxicity, patient refusal, patient removal for clinical cause at the investigator's discretion, intercurrent illness preventing continuation of therapy or regular follow-up, progressive disease (PROG), or death. Patients with complete regression (CR) received an additional four treatment cycles and patients with partial regression (PR) or stable disease (STAB) could continue therapy indefinitely, at the investigator's discretion. Once a patient discontinued therapy, evaluation for PROG and survival continued at 6-month intervals, for a maximum of 3 years.

Efficacy and Tolerability Assessments and Response Criteria
A history was taken, physical examination with weight measurement was performed, and ECOG PS was calculated¹⁵ at baseline and before each dose and cycle of irinotecan. Blood counts were obtained and safety assessed weekly starting at baseline. We evaluated toxicity via investigator observation and patient queries, according to National Cancer Institute Common Toxicity Criteria.¹⁶ Height measurement and standard chemistry panel were performed at baseline and before each cycle. Chest x-ray was taken at baseline and as clinically indicated subsequently. Women of childbearing potential underwent pregnancy testing within 7 days before study registration.

Tumor size was measured bidimensionally at baseline and before each irinotecan cycle by physical examination, chest x-ray, computed tomography, magnetic resonance imaging, or ultrasonography of the prospectively selected indicator lesion(s); the same method was used for all serial measurements. We used standard NCCTG-North American intergroup response criteria. CR was defined as disappearance of all evidence of tumor. PR was defined as a 50% reduction from baseline values in the sum of the products of the largest perpendicular diameters of the indicator lesion(s). To be considered an objective response, a CR or PR had to be sustained during at least two consecutive evaluations over an interval of at least 6 weeks. STAB was defined as not meeting the definitions of CR, PR, or PROG. Criteria for PROG included any of the following: appearance of any new lesion(s), a 25% increase in the measurements of the indicator lesion(s) compared with baseline values or with the smallest measurements while enrolled onto the study, or a decline in ECOG PS by more than one level or significant worsening of tumor-related symptoms that could not be attributed to treatment or intercurrent illness.

Study End Points and Statistical Analysis
The primary end point was the objective response (CR + PR) rate of each irinotecan regimen among assessable patients, defined as all individuals who satisfied the eligibility criteria and received one or more doses of irinotecan within the corresponding treatment arm. The study was designed to test the null hypothesis that the objective response rate to an irinotecan regimen was less than 0.10, a rate that was deemed to indicate that the regimen offered insufficient benefit, where the smallest response probability that would suggest that the regimen merited further study was .25. With a two-sided of .10 and a power of 0.90 to detect a true response probability of .25, a minimum sample size of 21 patients was needed for each schedule. It was deemed that 50 patients would be required to evaluate each irinotecan regimen. Therefore, a two-stage design^17,18 was used for both treatment schedules examined, with 21 patients entered into each study arm in the first stage. If in the first stage, objective response rate to a regimen was more than 10%, and the regimen's tolerability, response duration, and survival were judged adequate by the investigators, the corresponding arm passed to the second stage, with an additional 29 patients recruited.

Secondary end points included median response duration, median progression-free survival, median overall survival, 1-year survival, and toxicity of each regimen. Response duration was calculated from the first date of objective response until the date of PROG. Time to progression and survival were calculated from the date of randomization to the dates of PROG or death, respectively. Patients clearly documented not to have PROG on the date of death were censored for PROG on that date. Patients living as of the most-recent follow-up were censored for survival on the date of that follow-up. Distributions of times to progression and death were estimated with the Kaplan-Meier method.¹⁹ The 95% CIs for objective response rates were calculated using the Duffy and Santner method.²⁰ Toxicity incidence rates were calculated using the maximum grade of intensity recorded for each patient for each toxicity.

	RESULTS

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Patient Characteristics
A total of 104 patients enrolled onto the study between November 1998 and December 2001. Of these, 53 patients were randomly assigned to receive irinotecan weekly and 51 patients were randomly assigned to receive irinotecan every 3 weeks. One patient was removed from the weekly arm before receiving any treatment because she was found to have hemangiomas instead of MBC. Therefore, the weekly arm had 52 assessable patients and the every-3-weeks arm had 51 assessable patients.

Table 1 shows patient characteristics for each study arm. In both arms, a high percentage of patients (> 85%) had visceral disease. Although taxane treatment of MBC only was beginning to become widespread at the time patients were enrolled, a substantial minority (> 20%) had received this modality. Although the study was not designed to balance or compare the treatment arms for these characteristics, the every-3-weeks arm had substantially higher proportions of patients who had received at least two prior chemotherapy regimens (74% v 55%); who had ECOG PS 1 (65% v 54%); and who were positive for the estrogen or progesterone receptor, or both (63% v 50%).

View larger version (18K): [in this window] [in a new window]   Fig 1. Objective response and stable disease 6 months events for irinotecan given weekly and every 3 weeks. CR, complete regression; PR, partial regression; STAB, stable disease for 6 months.

In the weekly arm, eight (27%) of 30 patients who previously had received both anthracycline- and taxane-containing regimens had an objective response to irinotecan, as did two (18%) of 11 patients in each of the subgroups previously receiving only an anthracycline or only a taxane. In the every-3-weeks arm, four (13%) of 32 patients previously receiving both an anthracycline and a taxane had an objective response to irinotecan. The corresponding figures were one (17%) of six and two (15%) of 13, respectively, in the subgroups that had been given a prior anthracycline or taxane only.

Time to Progression and Overall Survival
In the weekly irinotecan arm, the median progression-free survival was 2.8 months (95% CI, 1.6 to 3.5 months) and median overall survival was 9.7 months (95% CI, 8.0 to 14.2 months; Fig 2A). One-year survival was 42% (95% CI, 30% to 58%).

View larger version (10K): [in this window] [in a new window]   Fig 2. Overall and progression-free survival for irinotecan given (A) weekly and (B) every 3 weeks.

Tolerability
Treatment-related toxicity was generally modest and manageable, especially in the weekly irinotecan arm. In that arm, the most common grade 3 to 4 adverse event was neutropenia (29%); however, febrile neutropenia occurred in only two patients (4%) and never exceeded grade 3 intensity. The only other grade 3 to 4 adverse event with an incidence 10% was diarrhea (17%), which reached grade 4 intensity in only two patients (4%; Table 2). Grade 1 alopecia occurred in 12 patients (24%) and grade 2 alopecia occurred in 27 patients (53%) in the study arm. During the course of the study, only seven patients (13%) experienced at least one grade 4 adverse event.

In both arms, the primary reason for study drug discontinuation was PROG (85% of discontinuations in the weekly and 82% in the every-3-weeks arm). In the weekly arm, other reasons for study drug discontinuation were adverse events in 10% of patients and patient refusal, and alternative treatment or other medical problems in 2% each (total exceeds 100% because of rounding). In the every-3-weeks arm, other reasons for discontinuation were patient refusal in 8%, and death as a result of PROG, death as a result of pulmonary fibrosis, adverse events, other medical problems, or removal because of lack of response in 2% each.

Dose-Intensity
Patients in the weekly irinotecan arm received a median of two (range, one to 14) treatment cycles. Patients in the every-3-weeks arm were given a median of one (range, one to 13) 6-week treatment cycle (median, two; range, two to 26 every-3-week doses). Dose escalation was allowed if the patient did not experience any adverse events during the first treatment cycle. One patient (2%) in the weekly irinotecan arm dose was escalated to a dose of 125 mg/m². Over the course of the study, 30 patients (59%) in the weekly irinotecan arm and 20 patients (39%) in the every-3-weeks arm required dose reduction. We examined the percentage of patients receiving a full dose and the median irinotecan dose per week actually received in each treatment arm (Table 3). Although no statistical comparison was made, during each cycle, the percentage of patients receiving full dose and the median weekly dose were higher for the every-3-weeks arm than for the weekly arm.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

The results in our weekly arm are in agreement with those of a multicenter phase II Japanese study¹¹ using the same irinotecan schedule and involving 65 assessable patients with advanced breast cancer, nearly two thirds of whom had received a prior anthracycline. The Japanese study observed response rates of 23% in the overall population and 26% in the anthracycline-refractory subgroup.

However, our experience contrasts sharply with that of a single-center, retrospective phase II Japanese study²¹ involving 20 patients refractory to both an anthracycline and a taxane, and again using the same weekly regimen as ours. This trial observed a 5% response rate (95% CI, 0% to 15.5%), median time to PROG of 35 days, and median overall survival of 124 days. However, 45% of its population had ECOG PS 2, in contrast to 12% in our weekly arm. Perhaps most importantly, the Japanese investigators gave only a median of one treatment cycle, whereas we gave a median of two treatment cycles in our weekly arm. Therefore, the discrepant observations of our trials may result from the Japanese investigators studying a shorter duration of therapy in a clinically more advanced patient population.

In the other arm of our study, the irinotecan regimen given every 3 weeks also proved to have activity and a manageable safety profile. Although the study was not designed to compare the weekly and every-3-weeks arms, the latter had a numerically lower objective response rate (14%; 95% CI, 6% to 26%), and a numerically shorter median response duration (4.2 months; range, 3.1 to 13.9 months), time to PROG (1.9 months; 95% CI, 1.4 to 3.3 months), and overall survival (8.6 months; 95% CI, 7.0 to 12.3 months). In addition, although most toxicity was mild to moderate, grade 3 to 4 treatment-related adverse events occurred more often and in greater variety than was observed in the weekly arm. Grade 3 to 4 neutropenia (36%), vomiting (20%), dyspnea (18%), nausea (16%), and diarrhea (12%) all were noted in 10% of patients. The incidence of dyspnea, which was higher than normally observed with irinotecan, may be attributable to the high percentage of patients in this trial with lung metastases.

The greater incidence of more marked toxicity in the every-3-weeks arm is perhaps unsurprising, given that patients in this arm consistently received a higher median weekly dose and a greater percentage of the planned dose than did their counterparts in the weekly group. In addition, by virtue of the dosing-related schedule of physical examinations, clinical follow-up in the every-3-weeks arm may have been less intense than in the weekly arm, perhaps allowing toxicity to progress further before it was identified and treated.

The 23% objective response rate in our weekly arm falls slightly below the 25% minimum that we prospectively had deemed to merit further investigation. However, the 23% rate was achieved in a study population with substantially higher prevalence of visceral metastasis or prior taxane therapy than were anticipated when our protocol was developed. In addition, the 95% CI for objective response rate in our weekly arm, 13% to 37%, comfortably encompasses the original 25% target.

In our study, weekly irinotecan had a single-agent objective response rate and tolerability that appears comparable to those of capecitabine—the only drug currently approved for refractory MBC—in phase II trials in this setting.^22-24 In addition, weekly irinotecan seemed to have similar, and in some instances, superior, single-agent phase II efficacy and safety, to those of vinorelbine^25-28 and gemcitabine,^29-31 drugs widely considered to warrant intense clinical development in refractory MBC. However, definitive conclusions about relative single-agent activity and tolerability of these agents await comparative trials.

Irinotecan has a distinct mechanism of action from that of other agents frequently used to treat MBC, and relatively limited cross-resistance as well as nonoverlapping toxicities with those drugs. Given these characteristics and the efficacy and tolerability of the weekly schedule demonstrated in this trial, we conclude that weekly irinotecan merits additional study as monotherapy and in combination therapies for refractory MBC. The strong topoisomerase I–inhibitory activity of irinotecan and its in vitro synergy in combination with fluorouracil in breast cancer cell lines and tumor models make irinotecan an excellent candidate for investigation in combination with capecitabine and other fluoropyrimidines. We have started a phase II study of weekly irinotecan plus weekly docetaxel for patients with MBC refractory to an anthracycline, a taxane, or both, and are developing combination and sequential studies with capecitabine.

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
The appendix is included in the full-text version of this article, available on-line at www.jco.org. It is not included in the PDF (via Adobe® Acrobat Reader®) version.

In addition to the authors, the following investigators and institutions participated in the study: L.P. Ebbert, MD, Rapid City Regional Oncology Group, Rapid City, SD; P.J. Flynn, MD, Metro-Minnesota Community Clinical Oncology Program (CCOP), St Louis Park, MN; R. Levitt, MD, Meritcare Hospital CCOP, Fargo, ND; M. Salim, MD, Saskatchewan Cancer Foundation, Saskatoon Cancer Centre, Saskatoon, and Allan Blair Cancer Centre, Regina, Saskatchewan, Canada; P.L. Schaefer, MD, Toledo Community Hospital Oncology Program CCOP, Toledo, OH; P.J. Stella, MD, Michigan Cancer Consortium, Ann Arbor, MI; L.K. Tschetter, MD, Sioux Community Cancer Consortium, Sioux Falls, SD; D. Wender, MD, Siouxland Hematology-Oncology Associates, Sioux City, IA; M. Wiesenfeld, MD, Cedar Rapids Oncology Project CCOP, Cedar Rapids, IA; and E. Wos, MD, Medcenter One Health Systems and Mid Dakota Clinic, Bismarck, ND.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We gratefully acknowledge the contributions of our patients, their families, our fellow investigators, the nurses, and other caregivers in this study.

	NOTES

 
Conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic and supported in part by Public Health Service grants CA-25224, CA-35103, CA-35113, CA-35195, CA-35267, CA-35269, CA-35272, CA-35415, CA-35431, CA-37404, CA-37417, CA-52352, CA-60276, CA-63848, and CA-63849 from the National Cancer Institute, US Department of Health and Human Services, Bethesda, MD. Irinotecan and loperamide were supplied by Pharmacia & Upjohn, Peapack, NJ, now Pfizer Inc, New York, NY.

Preliminary results from this study were presented in an abstract for the 38th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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Submitted October 8, 2003; accepted April 17, 2004.

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