Intermittent chemotherapy in patients with metastatic androgen-independent prostate cancer

Results from ASCENT, a double-blinded, randomized comparison of high-dose calcitriol plus docetaxel with placebo plus docetaxel

Authors


  • The Oregon Health and Science University (OHSU) and Dr. Beer have a significant financial interest in Novacea, Inc, a company that may have a commercial interest in the results of this research and technology. This potential conflict was reviewed and a management plan approved by the OHSU Conflict of Interest in Research Committee and the Integrity Program Oversight Council was implemented.

    The following were participating investigators who are not included among the authors. Canada (Investigators of the Canadian Urologic Oncology Group): Scott Berry (Toronto-Sunnybrook Regional Cancer Centre, Toronto, Ontario), Piotr Czaykowski (CancerCare Manitoba, Winnipeg, Manitoba), D. Scott Ernst (London Regional Cancer Centre, London, Ontario), Malcolm Moore (Princess Margaret Hospital-University Health Network, Toronto, Ontario), and Fred Saad (Centre Hospitalier de I'Université de Montréal Hôpital Notre-Dame, Montréal, Qué bec). U.S.: Frederick R. Ahmann (University of Arizona Cancer Center, Tucson, AZ), Ari D. Baron (California Pacific Medical Center, San Francisco, CA), William R. Berry (Raleigh Hematology Oncology Clinic, Cary, NC), Maria B. Bishop (Southern Arizona VA Health Care Sustek, Tucson, AZ), James A. Brown (Associates in Oncology/Hematology, Rockville, MD), Michael A. Carducci (The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD), Tarek A. Chidiac (Mid-Ohio Oncology/Hematology, Inc, Columbus, OH), Luis Chu (Oncology Hematology Consultants, Sarasota, FL), Steven L. Davidson (Montgomery Cancer Center, Montgomery, AL), Robert Dreicer (The Cleveland Clinic Foundation, Cleveland, OH), David M. Ellison (Charleston Hematology Oncology, Charleston, SC), Louis Fehrenbacher (Kaiser Permanente Medical Center, Vallejo, CA), Patrick J. Flynn (Metro-Minnesota CCOP, St. Louis Park, MN), Michael S. Gordon (Arizona Cancer Center, Scottsdale, AZ), Leland M. Green (Tower Cancer Research Foundation, Beverly Hills, CA), Ralph J. Hauke (University of Nebraska Medical Center, Omaha, NE), Celestia S. Higano (Seattle Cancer Care Alliance, Seattle, WA), David H. Irwin (Alta Bates Comprehensive Cancer Center, Berkeley, CA), Vahan S. Kassabian (Georgia Oncology, Atlanta, GA), Manish Kohli (Central Arkansas Veterans Healthcare System, Little Rock, AR), Primo N. Lara, Jr (University of California, Davis Cancer Center, Sacramento, CA), Ellis G. Levine (Roswell Park Cancer Institute, Buffalo, NY), Timothy M. Lopez (New Mexico Cancer Center Associates, Santa Fe, NM), Joseph J. Muscato (Missouri Cancer Associates, Columbia, MO), Ira A. Oliff (Midwest Cancer Research Group, Skokie, IL), Ray D. Page (Texas Cancer Care, Fort Worth, TX), Jonathan A. Polikoff (Southern California Permanente Medical Group, San Diego, CA), Mark U. Rarick (Kaiser Permanente Northwest, Portland, OR), Charles H. Redfern (Sharp Health- Care, San Diego, CA), Donald A. Richards (Tyler Cancer Center, Tyler, TX), Mansoor N. Saleh (Georgia Cancer Specialists, Tucker, GA), Michael A. Savin (Texas Cancer Center at Medical City, Dallas, TX), Mark C. Scholz (Prostate Oncology Specialists, Marina Del Rey, CA), Rakesh Singal (University of Miami Hospital and Clinics, Miami, FL), Daniel Vicario (San Diego Cancer Center, Vista, CA), David M. Waterhouse (Oncology Hematology Care, Cincinnati, OH), and Furhan Yunus (University of Tennessee Cancer Institute, Memphis, TN).

Abstract

BACKGROUND.

Survival in patients with metastatic, chemotherapy-naive, androgen-independent prostate cancer (AIPC) is improved with 10 to 12 cycles of docetaxel-containing chemotherapy but further management is undefined. In the current study, the authors examined retreatment with the same regimen after a treatment holiday.

Methods.

Patients treated with docetaxel at a dose of 36 mg/m2 plus either high-dose calcitriol (DN-101; 45 μg) or placebo administered weekly for 3 of every 4 weeks could suspend treatment if their serum prostate-specific antigen (PSA) level was reduced ≥50% and reached a level ≤4 ng/mL. PSA was monitored every 4 weeks (computed tomography scans were administered every 8 weeks in patients with measurable disease) during the treatment holiday. Treatment was resumed when the serum PSA rose by ≥50% and was ≥2 ng/mL or when there was other evidence of disease progression. The study was not powered to compare treatment holiday outcomes between the 2 arms.

RESULTS.

A total of 250 patients were randomized 1:1. Overall, 18% of patients (20% in the high-dose calcitriol group and 16% in the placebo group) entered the intermittent chemotherapy arm. The median duration of the first chemotherapy holiday was 18 weeks (range, 4%70 weeks). On resumption of treatment after the first holiday, 45.5% of evaluable patients responded with a ≥50% reduction in serum PSA from their postholiday baseline, 45.5% met the criteria for stable PSA for at least 12 weeks, and 9.1% of patients developed disease progression.

CONCLUSIONS.

To the authors' knowledge, the current study is the first report of intermittent chemotherapy in patients with AIPC who were prospectively tested in a large multi-institutional trial. This strategy results in a clinically significant duration of chemotherapy holidays and can be offered to a minority of patients. At the time of retreatment, the majority of patients again respond to treatment or their PSA levels stabilized. Additional studies of intermittent chemotherapy are needed to better characterize the optimal patient population and the optimal approach. Cancer 2008. © 2007 American Cancer Society.

Docetaxel-based chemotherapy is the standard treatment of androgen-independent prostate cancer (AIPC) and is associated with an overall survival benefit.1, 2 Approximately 46% of patients treated with docetaxel on a schedule of once every 3 weeks and 35% of patients treated with weekly docetaxel completed the planned initial course of chemotherapy without disease progression or unacceptably toxicity on Taxotere Study 327. To our knowledge, the literature provides no guidance regarding the optimal long-term management of such patients because the available studies called for a fixed initial treatment period (30 weeks and 36 weeks, respectively,) and did not address treatment beyond this initial course of chemotherapy.1, 2

Previously, we formulated a hypothesis that intermittent chemotherapy may be feasible in selected AIPC patients. We tested this hypothesis in a single-institution, phase 2 study of calcitriol plus docetaxel that was performed in 37 patients with metastatic AIPC.3 Results from 8 of these patients who received intermittent chemotherapy after responding to initial chemotherapy with a reduction in their prostate-specific antigen (PSA) level to <4 ng/mL suggest that intermittent chemotherapy is feasible in carefully selected patients.4, 5

ASCENT (AIPC Study of Calcitriol Enhancing Taxotere) was a placebo-controlled randomized clinical trial that compared DN-101, a high-dose formulation of calcitriol, plus weekly docetaxel with placebo plus weekly docetaxel in the treatment of patients with metastatic AIPC. The rationale for this study, its design, and primary outcomes have been reported previously.6 The design of the study incorporated intermittent chemotherapy for selected patients and therefore provided what to our knowledge is the first opportunity to prospectively examine outcomes with intermittent chemotherapy in a large multi-institutional trial.

MATERIALS AND METHODS

Detailed eligibility criteria and the treatment regimen have been reported previously.7 Briefly, men with chemotherapy-naive, metastatic AIPC were treated with calcitriol (Asentar™; Novacea Inc, South San Francisco, CA) at a dose of 45 μg or placebo by mouth on Day 1 followed by docetaxel at a dose of 36 mg/m2 intravenously on Day 2 with dexamethasone (4 mg orally given 12 hours before, 1 hour before, and 12 hours after docetaxel administration). This regimen was administered weekly for 3 consecutive weeks of a 4-week cycle.

Treatment on the ASCENT trial continued until disease progression was evident (either by serum PSA measurements or tumor assessments on imaging), unacceptable toxicity, or patient request. Disease progression based on the serum PSA level was defined by consensus criteria.8 Tumor progression was defined by Response Evaluation Criteria In Solid Tumors (RECIST) criteria.9 Patients enrolled in the ASCENT trial who reached a confirmed PSA level ≤4.0 ng/mL and met the criteria for PSA response had the option of continuing their treatment in the form of intermittent chemotherapy as previously described.4 Treatment was suspended until the PSA level rose by 50% and was ≥2 ng/mL or until there was any other evidence of disease progression. At that time, treatment was then resumed. Patients continued to undergo regular monitoring during this intermittent therapy phase (monthly clinical and laboratory assessments including serum PSA, computed tomography scans every 8 weeks in patients who had measurable disease at baseline, and bone scans as clinically indicated).

After chemotherapy was resumed, patients whose response to retreatment allowed them to meet eligibility criteria again could have additional chemotherapy holidays. The number of such holidays and retreatment cycles was not restricted. The study was approved by the Institutional Review Board of the Oregon Health and Science University and participating institutions.

Descriptive statistics were used to present outcomes with intermittent chemotherapy. The correlation between pretreatment patient characteristics and participation in intermittent chemotherapy was examined using the Student t test for comparisons of continuous variables and the chi-square test for comparisons of categoric variables. The study was not powered to measure differences in intermittent chemotherapy outcomes between patients assigned to high-dose calcitriol and those assigned to placebo.

RESULTS

Patients

After responding to initial treatment, 45 of 250 patients (18%) became eligible for and participated in intermittent chemotherapy on the ASCENT trial. Approximately 20% of patients treated with high-dose calcitriol and 16% of placebo-treated patients received intermittent chemotherapy. Patients became eligible and began intermittent chemotherapy after a median of 22 weeks (in both treatment arms) from randomization.

An additional 11 patients responded to therapy and reached a serum PSA level ≤4 ng/mL and therefore were potentially eligible for intermittent chemotherapy but did not participate. Reasons for nonparticipation were not collected prospectively; however, a review of the study records revealed that 5 of these patients had only a single PSA value <4 ng/mL and another 2 were experiencing significant treatment-related toxicity near the time when their treatment was discontinued. Unless specifically indicated, these 11 patients are not included in further analyses.

As shown in Table 1, patients who received intermittent chemotherapy had a better performance status (Eastern Cooperative Oncology Group); a higher hemoglobin, lower alkaline serum phosphatase, and lower serum PSA level; and were less likely to have measurable disease than patients who did not receive intermittent chemotherapy. There were no differences with regard to age, race, serum lactate dehydrogenase, or specific sites of disease between the 2 groups. Similar results were obtained when the 11 patients who were eligible for intermittent chemotherapy, but did not receive it, were included in this analysis.

Table 1. Baseline Characteristics of All Patients, Patients Who Participated, and Patients Who Did Not Participate in Intermittent Chemotherapy
 All patientsPatients who received intermittent chemotherapyPatients who did not receive intermittent chemotherapyP*
  • NA indicates not applicable; ECOG, Eastern Cooperative Oncology Group; PSA, prostate-specific antigen; LDH, lactate dehydrogenase.

  • *

    The Student t test was used for comparisons of continuous variables, whereas the chi-square test was used for comparisons of categoric variables.

  • Values in bold are statistically significant.

No. randomized250 (100%)45 (18.0%)205 (82.0%)NA
Median age (range), y69.5 (45–92)70 (52–82)69 (45–92).88
Race (%)   .253
 White82.0%88.9%80.5% 
 African American11.6%4.4%13.2% 
 Other6.4%6.7%6.3% 
ECOG performance status   <.001
 050.4%82.2%43.4% 
 145.2%17.8%51.2% 
 24.4%0.0%5.4% 
Site of disease
 Bone88.0%80.0%89.8%.068
 Lymph node39.6%33.3%41.0%.343
 Liver6.0%2.2%6.8%.239
Measurable disease45.2%28.9%48.8%.015
Median PSA (range), ng/mL104.65 (4.2–4452.8)25.28 (5.8–1029.7)137 (4.2–4452.8).013
Median hemoglobin (range), g/dL12.6 (7.6–15.5)13.5 (9.4–15.1)12.5 (7.6–15.5)<.001
Median LDH (range), U/L216 (82–2537)213 (82–837)216 (93–2537).176
Alkaline phosphatase, median (range)126 (34–3739)97 (49–978)136 (34–3739).016

First Chemotherapy Holiday

Of the 45 patients, 38 completed the first treatment holiday (36 were retreated whereas 2 were removed from the study before treatment was reinitiated). At the time of last follow-up, 7 patients remained on a treatment holiday. The median duration of the first chemotherapy holiday, including patients who were still on holiday at the time of the analysis, was 18 weeks (range, 4–70 weeks) (20 weeks for high-dose calcitriol and 16 weeks for placebo). The distribution of the duration of the first chemotherapy holiday is shown in Figure 1. This figure shows that the chemotherapy holiday lasted ≥20 weeks in a significant fraction of patients.

Figure 1.

Duration of the first chemotherapy holiday.

Thirty-three of the 36 patients who resumed treatment after an initial treatment holiday were evaluable for PSA response to treatment resumption. Of these, 15 patients (45.5%) responded with a ≥50% reduction in the serum PSA from their postholiday baseline, 15 patients (45.5%) met the criteria for stable PSA for at least 12 weeks, and 3 patients (9.1%) developed disease progression while receiving therapy.

Subsequent Chemotherapy Holidays

Our previous study demonstrated that multiple cycles of intermittent chemotherapy were feasible in selected patients.5 Complete information regarding the outcomes of patients who took >1 chemotherapy holiday on the ASCENT trial was not available at the time of last follow-up. To date, 13 patients have taken ≥2 chemotherapy holidays and 10 patients have completed their second chemotherapy holiday. The median duration of the second chemotherapy holiday for those 10 patients was 12 weeks (range, 7–22 weeks) (15 weeks for high-dose calcitriol and 11 weeks for placebo). An example of a patient whose disease has been maintained: with multiple cycles of chemotherapy is shown in Figure 2.

Figure 2.

Changes in serum prostate-specific antigen (PSA) over time in a patient treated with intermittent chemotherapy (Chemo). Closed arrows indicate when chemotherapy was initiated and open arrows show when chemotherapy was withdrawn.

DISCUSSION

Although durable complete remission remains an elusive goal in the treatment of patients with AIPC, substantial responses to therapy are frequently reported. The optimal approach to the treatment of AIPC patients whose disease is in response status when a full course of chemotherapy is completed remains unclear. In a phase 2 study, we previously reported that intermittent chemotherapy is a feasible treatment strategy in selected patients and that several measures of quality of life improved during a chemotherapy holiday.4 To our knowledge, the ASCENT trial was the first prospective multicenter clinical trial in patients with prostate cancer that incorporated intermittent chemotherapy into its treatment plan.

This strategy results in a clinically significant duration of chemotherapy holidays and was offered to a minority (18%) of patients. Among those patients who took chemotherapy holidays and resumed treatment, a substantial majority of evaluable patients (90.9%) retained their sensitivity to chemotherapy as indicated by a second response or disease stabilization after treatment was resumed. Although the data regarding multiple chemotherapy holidays are incomplete, the feasibility of multiple breaks in treatment was demonstrated in a small number of patients as well.

The criteria for offering intermittent chemotherapy to patients in the current study were relatively stringent in that a reduction in the serum PSA of ≤4 ng/mL was required. The decision to require a PSA level <4 ng/mL was arbitrary and it is not known whether this requirement is either optimal or necessary. Not all patients who have docetaxel-sensitive prostate cancer as they complete the initial treatment course achieve such a low PSA level. Therefore, more liberal criteria for offering intermittent chemotherapy could allow a somewhat larger proportion of patients to participate. However, it is not known whether the treatment holidays would be equally durable if patients were less carefully selected. The selection of patients is apparent when the baseline characteristics of those patients who received intermittent chemotherapy are compared with those of the patients who did not. Several of the factors that distinguished the 2 groups (performance status, hemoglobin, and alkaline phosphatase level) also are known prognostic factors for overall survival in AIPC.10 Although the range of patients who received intermittent chemotherapy on the ASCENT trial was broad, overall, patients who participated in intermittent chemotherapy appeared to have had more favorable prognostic features prior to chemotherapy than those who did not. All these patients were chemotherapy naive at the time of study entry. We did not attempt to analyze associations between participation in intermittent chemotherapy and prior exposure to first-line and subsequent hormonal therapies or other cancer-directed therapies.

The role of intermittent chemotherapy in the management of AIPC remains to be fully defined. Data from the current study demonstrate that this approach is feasible. This knowledge is of practical importance because docetaxel-based chemotherapy was approved for a fixed number of cycles and indefinite therapy in responding patients is not practical. Our results should provide a measure of confidence to patients and physicians regarding stopping chemotherapy in carefully selected patients. The overall impact of intermittent chemotherapy on the duration of survival and quality of life remains to be fully defined and the current study did not permit us to compare intermittent with continuous chemotherapy. A direct comparison of these 2 strategies in a randomized trial would be necessary to determine which approach is optimal. Until therapy that can durably control AIPC is developed, this approach appears to be a practical method with which to balance disease control and quality of life in a subset of AIPC patients whose disease is very sensitive to docetaxel. Additional studies of intermittent chemotherapy are needed to better characterize the optimal patient population and the optimal approach.

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