Improved Response in High-Risk Neuroblastoma With Protracted Topotecan Administration Using a Pharmacokinetically Guided Dosing Approach
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《临床肿瘤学》
the Departments of Hematology-Oncology, Biostatistics, Radiological Sciences, Surgery, Molecular Pharmacology, and Pharmaceutical Sciences, St Jude Children's Research Hospital
Department of Pediatrics and Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, T
ABSTRACT
PURPOSE: To estimate the response rate and toxicity associated with intravenous topotecan when it is administered on a protracted schedule according to a pharmacokinetically guided dosing approach to treat childhood high-risk neuroblastoma.
PATIENTS AND METHODS: In this prospective phase II trial, topotecan was administered intravenously daily for 5 days for each of 2 consecutive weeks for two cycles. On the basis of topotecan systemic clearance, doses were individualized to attain a single-day topotecan lactone area under the plasma concentration-time curve (AUC) of 80 to 120 ng/mL · h. Patients subsequently received standard treatment.
RESULTS: Both cycles were administered to 28 (93%) of the 30 enrolled patients (median age, 3.1 years). Target topotecan AUCs were achieved in 92 (72%) of the 127 measurements conducted after pharmacokinetically guided adjustment; the median dosage required to achieve target AUCs was 2.7 mg/m2 (range, 0.95 to 3.8 mg/m2). The response rate was 60% (95% CI, 41% to 77%); there were one complete and 17 partial responses. No patient experienced disease progression during initial topotecan therapy. Primary tumor volumes decreased (median decrease, –58.2%; range, –95.1% to –4.9%) in the 26 patients with available size data. Homovanillic acid levels in 16 (89%) of 18 patients and vanillylmandelic acid levels in 14 (78%) of 18 patients were lower (P = .002 and P = .018, respectively) after topotecan therapy. Reversible grade 4 myelosuppression occurred in all patients, but no deaths occurred as a result of infection or toxicity.
CONCLUSION: Topotecan is active against neuroblastoma when it is administered on a protracted schedule and targeted systemic exposure is achieved.
INTRODUCTION
Successful treatment of high-risk neuroblastoma remains challenging in pediatric oncology; fewer than half of the children receiving current therapy will achieve long-term survival.1 Recently, topotecan has emerged as an active agent against recurrent neuroblastoma; response rates (complete response [CR], partial response [PR], and stable disease) of approximately 30% have been observed in patients with relapsed disease.2 Furthermore, activity as a single agent, when administered daily for 5 consecutive days, has been documented in chemotherapy-naive patients with neuroblastoma.3 This promising antitumor activity observed in patients is consistent with that reported in preclinical models of neuroblastoma.4,5
Our approach to the introduction of topotecan in neuroblastoma treatment is based on the evaluation of a protracted schedule of administration (daily administration for 5 consecutive days for each of 2 consecutive weeks) and the evaluation of systemic drug exposure associated with antitumor activity in xenograft mouse models.5-7 Using a panel of neuroblastoma xenografts, Zamboni et al7 showed that protracted topotecan therapy (10 doses for 12 days) results in greater antitumor activity than intermittent administration of the same total dosage over a shorter schedule. Moreover, at a topotecan systemic exposure of 88 ng/mL · h, CRs or PRs were observed in four of five neuroblastoma xenografts evaluated. The systemic exposure versus antitumor effect curve is steep, and minimal decreases in systemic exposure result in significant decreases in antitumor effect.7
Another factor to consider in optimizing clinical studies of topotecan is the significant interpatient variability in topotecan pharmacokinetics. A 12-fold range in the systemic clearance of topotecan lactone has been noted, and standard dosing based on surface area has yielded large interpatient variability in topotecan systemic exposure.8-10 This variability limits our ability to attain what could be considered cytotoxic plasma systemic exposure required for optimal antitumor effects. In a previous clinical study, we reduced interpatient variability by individualizing the topotecan dosage to achieve a topotecan systemic exposure of 80 to 120 ng/mL · h in children with refractory solid tumors.11 Using this approach, we successfully adjusted individual topotecan systemic exposure to reduce interpatient variability; 78% (46 of 59 values) of the measured area under concentration-time curve (AUC) values were within the target range.11
These observations formed the basis for our current investigation that incorporated topotecan administered intravenously on a protracted schedule (daily administration for 5 consecutive days for each of 2 consecutive weeks) and used pharmacokinetically guided dose adjustments to achieve a predefined topotecan systemic exposure in children with newly diagnosed disseminated neuroblastoma. The primary goals were to estimate the response rate to two cycles of topotecan administered intravenously as initial therapy and in dosages adjusted to attain a target systemic exposure of 80 to 120 ng/mL · h and to determine the toxicity of this treatment. Secondary objectives were to evaluate the disposition of topotecan in these patients and to estimate survival and progression-free survival rates.
PATIENTS AND METHODS
Patient Selection
Patients were eligible for this prospective, single-arm, phase II trial if they had previously untreated neuroblastoma, were 1 year of age, had International Neuroblastoma Staging System (INSS) stage 3 or 4 disease or were younger than 1 year, had INSS stage 3 or 4 disease, and tumor-specific MYCN amplification. Other eligibility requirements included a serum creatinine concentration less than 2 mg/dL and an aspartate transaminase level that was less than 3x the upper limit of the normal range. The protocol was approved by the St Jude Institutional Review Board, and all patients, parents, or guardians, as appropriate, were required to provide written informed consent or permission in accordance with institutional and federal guidelines.
Dose and Drug Administration
Before therapy began, long-term central venous access was established in each patient. Topotecan was administered intravenously as a daily 30-minute infusion in a schedule of daily administration for 5 consecutive days for each of 2 consecutive weeks (Fig 1). The initial dosage (3 mg/m2/d) was adjusted to attain a target topotecan systemic exposure (AUC) of 80 to 120 ng/mL · h. A second cycle of topotecan was administered approximately 16 days from the end of the first cycle (day 28). The initial dosage for the second cycle of topotecan was based on the dosage required in the preceding cycle to attain the target AUC. Patients were also administered filgrastim subcutaneously or intravenously at 5 μg/kg/d beginning on study day 13 and continuing for a minimum of 10 days or until the absolute neutrophil count exceeded 500/μL in two consecutive measurements after the expected nadir. Patients with progressive disease or nonhematologic grade 4 toxicity (excluding diarrhea lasting < 72 hours) during the initial topotecan therapy did not receive further topotecan treatment. All patients received prophylactic antiemetic agents, such as ondansetron, at the discretion of the treating physician. Trimethoprim-sulfamethoxazole as Pneumocystis carinii prophylaxis was withheld during the 12 days of topotecan therapy.12
Treatment After Topotecan Chemotherapy
After the topotecan treatment phase, all patients received standard induction chemotherapy consisting of one cycle of cyclophosphamide, doxorubicin, and etoposide; two cycles of cisplatin and etoposide; and one cycle of ifosfamide, carboplatin, and etoposide. This chemotherapy was followed by surgical evaluation and possible resection of the primary tumor and accessible lymph nodes. Patients underwent bone marrow or peripheral-blood stem-cell harvest either at resection or after recovery from the surgical resection. Patients then received consolidation therapy consisting of either high-dose cyclophosphamide and topotecan or carboplatin and etoposide (if the tumor did not respond to the initial topotecan treatment) and subsequent unpurged autologous marrow/peripheral-blood stem-cell rescue (minimum dose of nucleated bone marrow cells, 1 x 108/kg).13 Full-dose therapy was administered to all patients. Chemotherapy was delayed when necessary until the absolute neutrophil count exceeded 500/μL. After consolidation therapy, patients could receive oral retinoic acid for 6 months at the discretion of the treating physician. This report only describes data relevant to the antitumor activity, toxicity, and pharmacokinetics of topotecan administered during cycles 1 and 2.
Pharmacokinetically Guided Topotecan Dosing
Figure 1 illustrates our pharmacokinetically guided dosing strategy.11 During the first cycle, plasma samples were obtained after doses 1 and 6, processed immediately, and analyzed. If the single-day topotecan lactone AUC was within the target range after the first dose, then no dose adjustment was required. If not, then the topotecan dosage was adjusted linearly, on the basis of the patient's topotecan lactone clearance, to attain the target AUC on day 2, and repeat pharmacokinetic studies were performed until the patient's topotecan systemic exposure was within the target range. Regardless of day 1 results, the same pharmacokinetic testing strategy was repeated on day 8 (ie, sixth dose) using the topotecan dosage that attained the target AUC during the first week.
During the second cycle of therapy, plasma samples were collected on days 1 and 8, and decisions about dosing were made as described for the first treatment cycle. The topotecan dosage was adjusted only if the single-day target AUC was outside the target range. Additional plasma samples were taken to determine the adequacy of the modification, if necessary (Fig 1, hatched arrows).
As in previous studies, we made a distinction between AUC values resulting from a pharmacokinetically based dose adjustment and those solely reflecting a predetermined dosage, such as the first dose of cycle 1.11 In the latter instance, we refer to the AUC value as a dose success or a dose failure, and we reserve the terms pharmacokinetic targeting success and pharmacokinetic targeting failure for situations in which the dose adjustment did or did not place the patient's topotecan lactone AUC within the target range, respectively.
Sampling Strategy and Sample Analysis
Plasma samples were collected before and at 0.25, 1, and 6 hours after completion of the topotecan infusion. At each time point, 3 mL of whole blood was collected in a heparinized tube. Within 2 minutes of collection, the blood was centrifuged in a microfuge for 2 minutes at 7,000 x g, the plasma was separated, and 200 μL of plasma was added to 800 μL of cold (–30°C) methanol. The methanolic mixture was vortex mixed for 10 seconds and then centrifuged for 2 minutes at 7,000 x g. The supernatant was decanted into a screw-top tube and analyzed by isocratic high-performance liquid chromatography detection with fluorescence (RF551; Shimadzu, Columbia, MO); the excitation and emission wavelengths were 370 and 530 nm, respectively. Calibration curves were constructed with the use of human plasma from a single donor. The lower limit of quantitation for topotecan lactone in plasma is 0.25 ng/mL.11
Pharmacokinetic Analysis
A two-compartment model was fit to the plasma concentrations of topotecan lactone by using a maximum a posteriori Bayesian algorithm as implemented in ADAPT II.14 Estimated model parameters included the volume of the central compartment, elimination rate constant, and the intercompartment rate constants. We used published values (mean and variance) for the Bayesian priors.11 Standard equations were used to calculate systemic clearance and the volume of distribution at steady-state from parameter estimates.15 The model parameters for each patient were used to simulate the plasma concentration-time profile, from which the AUC from time zero to infinity was calculated by using a log-linear trapezoidal method. Because topotecan disposition is linear,16,17 we used the following equation to adjust topotecan dosage: adjusted dosage (mg/m2) = current topotecan dosage (mg/m2)/current AUC x target AUC.
Patient Monitoring and Toxicity Assessment
Before the start of treatment, tumor status was assessed by physical examination and the collection of each patient's medical history; appropriate diagnostic imaging; bone marrow aspiration and biopsy; complete and differential blood counts; liver function tests; measurement of serum creatinine, electrolytes, total protein, and albumin; and measurement of urine catecholamines.
During topotecan therapy, patients were examined at least weekly, and complete blood counts were obtained twice weekly; serum creatinine and liver function were evaluated as clinically indicated. At the completion of two cycles of topotecan therapy, patients underwent diagnostic imaging of the primary and metastatic sites, bone marrow examination, and measurement of urine catecholamines. The absolute primary tumor volume was calculated on the basis of the length, width, and depth of the tumor by using the following formula to calculate ellipsoid volume: V = (4 x ÷ 3) x a x b x c = (4 x ÷ 3) x (0.5 x length) x (0.5 x width) x (0.5 x depth) = 0.52 x length x width x depth.
Response to two cycles of topotecan therapy (the primary outcome) was described as follows: CR, complete resolution of metastatic tumor and more than 90% regression of the primary tumor attained by and maintained through initial induction phases; very good PR, more than 90% regression of primary tumor and clearing of metastatic disease except for persistent, bone scan–positive lesions; PR, more than 50% regression of all tumor; objective response, more than 25% but less than 50% regression of all disease; stable disease, less than 25% regression but no disease progression; and progressive disease, appearance of tumor in a previously uninvolved site. Patients with a CR, very good PR, or PR after two cycles of topotecan were classified as responders. Toxicities were evaluated on the basis of the National Cancer Institute Common Toxicity Criteria, version 2.0.
Statistical Considerations
On the basis of Simon's two-stage design with a type I error rate of 10% and a power of 80%, the statistical plan was to accrue 24 patients.18 Topotecan therapy would be considered unacceptable if sufficient evidence showed that the true response rate was less than 20%; a response rate of 40% was considered promising. Considering that the targeted systemic exposure might not be reached in as many as 15% of patients (based on previous data), as many as 34 patients could be enrolled.11 The estimated response rate was presented with an exact binomial 95% CI. The Wilcoxon signed-rank test was used to compare changes in laboratory values (lactic dehydrogenase [LDH], urinary homovanillic acid [HVA], and vanillylmandelic acid [VMA]) from diagnosis to evaluation after completion of topotecan therapy. The survival period was defined as the interval from enrollment to date of death from any cause or the date of last contact. The period of progression-free survival was defined as the time interval from enrollment to date of relapse, progressive disease, or last follow-up. Survival and outcome distributions were estimated by using the Kaplan-Meier method; associated SEs were based on the method of Peto and Pike.19,20 Follow-up data were current as of July 31, 2004.
RESULTS
Patient Characteristics
Thirty patients were enrolled. The median age at enrollment was 3.1 years (range, < 1 month to 16.9 years). Twenty-seven (90%) of 30 patients had INSS stage 4 disease (Table 1). Adrenal tissue was the most common primary site (20 of 30 patients, 67%). The oncogene MYCN was amplified in 12 (40%) of 30 tumors. Other demographic data are listed in Table 1.
Table 2 lists tumor volumes and selected laboratory results (LDH, urine HVA, and urine VMA) at diagnosis and after the completion of topotecan therapy. The laboratory value obtained within 1 week after the evaluation was used for the post-topotecan assessment. Most values were lower after two cycles. In 24 of 25 patients for whom LDH data was available, the values obtained after the completion of topotecan therapy were less than the values obtained at diagnosis (P < .001). Between diagnosis and the post-topotecan evaluation, the urine HVA values significantly decreased in 16 (89%) of 18 patients for whom such data were known (P = .002). Similarly, the known VMA values of 14 (78%) of 18 patients were lower after topotecan therapy than at diagnosis (P = .018).
Pharmacokinetic Parameters
Pharmacokinetic parameters were derived from the mixed-effects model for all patients (Table 3). Further analysis was based on cycles in which the topotecan dosage was adjusted or unadjusted; no resulting intergroup statistical comparison indicated a significant bias.
We assessed the interpatient and intrapatient variability by using the mixed-effect model, which allowed us to account for possible correlations between topotecan lactone clearance and cycle with repeated measurements within each subject. The estimated intersubject and intrasubject variances were 17.1% and 19.8%, respectively.9,17 This finding is different from those of previous studies in which intersubject variability in topotecan clearance exceeded intrasubject variability.10
Targeting of Topotecan Systemic Exposure
Presented in Figure 2 is a representative topotecan lactone plasma concentration-time plot for a patient studied after the administration of the initial predetermined topotecan dosage and then after a pharmacokinetically guided dose adjustment. The initial AUC (171 ng/mL · h) was above the maximum target value, and because the topotecan dosage was predetermined, this initial value was considered a dosing failure. The topotecan AUC corresponding to the second concentration-time curve was the result of a pharmacokinetically guided dose adjustment. The subsequent topotecan AUC value reached the target level (ie, 95 ng/mL · h) and, therefore, represented a pharmacokinetic targeting success. The median topotecan dosage in the cycles in which the target range of AUC values was achieved was 2.7 mg/m2 (range, 0.95 to 3.8 mg/m2).
We performed a total of 157 pharmacokinetic studies in 30 children (Fig 3). The first 30 studies were performed after a fixed topotecan dosage (3 mg/m2) was administered. Of these studies, only 16 (53%) yielded values that were considered a dosing success; the remainder indicated a dosing failure. In subsequent studies using pharmacokinetically guided dosing, the overall pharmacokinetic targeting success rate was 72% (AUCs in 92 of 127 assessable studies were in the target range). By cycle 2, 98% of AUCs (from 54 of 55 determinations) were in the target range after the second pharmacokinetic study.
Time Required to Receive Two Cycles of Topotecan Treatment
Only two of the 30 patients were unable to receive the second cycle because of gastrointestinal toxicity. For the 28 patients (93%) who completed both cycles, the median time from the start of cycle 1 to the start of standard chemotherapy (cycle 3) was 58 days (range, 44 to 73 days). The median time from the start of cycle 1 to the start of cycle 2 for the 28 patients was 25.5 days (range, 21 to 33 days), and the median time from the start of cycle 2 to the start of cycle 3 was 31 days (range, 23 to 42 days).
Response to Topotecan
Responses after two cycles of topotecan therapy were excellent; one patient had a CR, 17 had PRs, two had objective responses, and eight had stable disease. Two patients were considered to have response failures because they were unable to receive both cycles of topotecan. Therefore, the rate of CR + PR was 60% (95% CI, 41% to 77%).
Tumor Volume
Of the 30 patients, four did not have available data concerning tumor size; two patients were unable to complete the two cycles of topotecan therapy, and two other patients had liver or bone metastases at diagnosis that could not be measured accurately (primary tumor had been removed before chemotherapy). The median tumor volume of the other 26 patients at diagnosis was 307.2 mL (range, 12.0 to 1,578.4 mL; Table 2). All volumes decreased (median change in volume, –58.2%; range, –95.1% to –4.9%), and the median tumor volume after the completion of topotecan therapy was 126.6 mL (range, 2.5 to 805.1 mL).
Toxicity During Topotecan Treatment
The following sections focus on toxicity in the 28 patients who completed both cycles of topotecan therapy.
Neutropenia, thrombocytopenia, and diarrhea. Table 4 lists the incidence and duration of grade 4 neutropenia, thrombocytopenia, and diarrhea by cycle. All 28 patients who completed two cycles of topotecan therapy had two episodes of grade 4 neutropenia (one per cycle); median durations during both cycles were similar (15 and 14 days). Similarly, most patients had two episodes of grade 4 thrombocytopenia during the therapy (one per cycle); two patients had only one episode each. Median durations of grade 4 thrombocytopenia for cycles 1 and 2 were 4 and 8 days, respectively.
Of the seven patients with grade 4 diarrhea during topotecan therapy, one received only one cycle of topotecan therapy. Of the six patients who completed two cycles, four had grade 4 diarrhea during cycle 1, and the other two experienced toxicity during cycle 2. Two patients developed neutropenic colitis during the first cycle of topotecan therapy and were excluded from further topotecan treatment.
Transfusions of platelets and packed RBCs. All but one patient received at least one transfusion of packed RBCs (pRBC) and platelets during each cycle of topotecan therapy. One patient did not receive a pRBC transfusion during cycle 2. The median numbers of transfusions administered were similar for the two cycles (three and 2.5 pRBC transfusions per patient during cycles 1 and 2, respectively; two platelet transfusions each for cycles 1 and 2; Table 4).
Incidence of febrile neutropenia and duration of intravenous antibiotic administration. During the topotecan phase, all patients had at least one episode of febrile neutropenia (FN; median, two episodes; range, one to three episodes). A total of 52 FN episodes during the topotecan phase was observed in the 28 patients who received both topotecan cycles. All patients received intravenous antibiotics during treatment; the median duration of intravenous antibiotic administration per patient was 12.5 days (range, 4 to 28 days). During the 52 episodes of FN, intravenous antibiotics were administered for a median of 7 days (range, 3 to 16 days). We found no relationship between topotecan systemic exposure and toxicity.
Outcome
Twelve (40%) of the 30 patients were alive at the time this article was written. The median follow-up period from the enrollment date is 4.0 years (range, 2.1 to 6.5 years). All but one survivor has been evaluated or contacted within 1 year of the analysis date. All survivors had been evaluated or contacted within the past 2 years. No subsequent malignancies or deaths occurred before relapse or progression. Three-year and 4-year survival rate estimates are 66.2% ± 8.6% and 43.7% ± 11.6%, respectively. Estimates of 3-year and 4-year progression-free survival rates are 26.7% ± 7.6% and 23.3% ± 11.8%, respectively.
DISCUSSION
Results of our phase II trial demonstrate that topotecan has significant activity in children with neuroblastoma when administered on a protracted schedule in which pharmacokinetically guided dose adjustments achieve a predefined level of systemic exposure. The response rate (60%) in our high-risk neuroblastoma patients was excellent. The number of patients who achieved a CR or PR is higher than that achieved with only 5 days of administration and with traditional dosing based on a surface area calculation.3 A response rate of 39% (13 CRs and PRs in 33 patients) after two cycles of single-agent therapy was observed in a Pediatric Oncology Group study in which topotecan was administered as an intravenous bolus infusion (2 mg/m2/d) for only 5 days.3 However, disease in seven patients progressed during the topotecan phase. The response rate in our study was 1.5 times higher, as documented by careful evaluation of tumor volume and adherence to strict response criteria (only CR and PR). Furthermore, no patient experienced disease progression during topotecan therapy. The quality of the response was substantial; radiographic assessment of locoregional disease indicated that tumors in 16 of 24 patients were potentially surgically resectable after the completion of topotecan therapy.21 Because earlier tumor removal may decrease the risk of subsequent chemotherapy-resistant disease, it was important that our patients achieved a significant early decrease in tumor size and volume. These results, although encouraging, must be interpreted within the context of the limited sample size of a phase II study. Furthermore, the potential impact of modifications in schedule of administration or dosing parameters on the toxicity profile of topotecan, such as neutropenia, must be considered. Although myelotoxicity was observed, life-threatening infectious complications were uncommon in our study.
The results of the present study extend the findings of our previous study of pharmacokinetically guided topotecan dosing in patients with newly diagnosed neuroblastoma and confirm the feasibility of this approach to dosing topotecan. We separated the results of the pharmacokinetic studies conducted after the first dose of cycle 1 from those obtained by the remainder of the pharmacokinetic studies. This separation was done because the first topotecan dose of cycle 1 is fixed and the achievement of the desired systemic exposure is not a measure of the success of the targeting method. With extensive data from prior topotecan pharmacokinetic studies, we predicted that a topotecan dose of 3 mg/m2 would result in a topotecan lactone systemic exposure of 80 to 120 ng/mL · h. However, the AUCs for only 16 (53%) of 30 patients were within the target range after the first dose. In contrast, the dose adjustments based on our targeting approach resulted in 72% of patients having AUCs within the target range. Even for those patients whose AUCs were outside of the target range after the first adjustment, further adjustment resulted in AUCs within the target range in most patients.
Of the 21 dose adjustments that were judged pharmacokinetic targeting failures, 13 were attempted in children younger than 2 years. The one child who required more than four studies to attain the target range of AUCs was 2 weeks old at diagnosis. This observation highlights the importance of age as a critical factor that must be accounted for in this young population. All AUCs for all patients except one were within the target range after one dose adjustment (ie, by cycle 2).
In our study, we observed a 10-fold range in topotecan systemic clearance, a result that is consistent with previous experience showing that intersubject variability in topotecan clearance is substantial. If the present study population of children had been administered every dose as a fixed topotecan dose, one could expect a 10-fold range in topotecan plasma systemic exposure. However, our individualized approach to dosing resulted in a narrow range of topotecan systemic exposure (eg, 80 to 120 ng/mL · h). Thus, we presumably decreased the topotecan dosage for children with slow clearance rates and avoided excessive toxicity and increased the dosage for children with high clearance rates and reached what our preclinical models suggested were cytotoxic exposure levels.
A clinically relevant question for this approach to dosing topotecan is whether or not the day 1 pharmacokinetic study could be used to guide subsequent topotecan dosing. First, the results of the mixed effects modeling of the topotecan clearance suggest that the variability among patients (eg, intraoccasion variability [IOV]) is slightly greater than the variability between patients (eg, interindividual variability), which is different from our previous studies in which we have found that the interpatient variability is much greater than the intrapatient variability. Many sources of variability may account for the IOV in our patient population, and we are conducting studies to identify them. Many have suggested that if the IOV is greater than the interindividual variability, then the pharmacokinetically guided dosing would be problematic (ie, more variability within patients than between patients would lead to frequent dose adjustments). However, the results from the present study convincingly show that we are able to attain the target topotecan systemic exposure in more than 70% of the assessable topotecan studies (92 of 127 studies). These results, which were obtained using an approach in which we measured topotecan pharmacokinetic studies after dose 1 of cycle 1 to adjust the topotecan dose for subsequent doses, were highly encouraging and provided support for further applications of this approach.
The lack of response in a subset of patients suggests camptothecin resistance. In neuroblastoma cell lines, low intracellular accumulation of topotecan can be attributed to the presence of P-glycoprotein and multidrug resistance–associated proteins.22,23 The fact that topotecan is a substrate of P-glycoprotein and breast cancer resistance protein (ABCG2) implicates ATP-binding cassette transporters in clinical resistance.24-30
Our encouraging results serve as the basis of a current pilot study conducted by the Children's Oncology Group to investigate the use of topotecan with pharmacokinetically guided dose adjustments (and cyclophosphamide as a second agent) as initial therapy in children with newly diagnosed disseminated neuroblastoma. This strategy is resource and labor intensive and is difficult for the patient and family. Therefore, this approach may be limited in its applicability and is now only feasible in centers with expertise in pharmacokinetically guided dosing. To further address the wide interpatient variability in topotecan systemic clearance and its impact on efficacy and toxicity, we are conducting a population-based pharmacokinetic analysis to identify patient-specific covariates related to topotecan lactone systemic clearance that could be used to help guide topotecan dosing. The end point will be the creation of a nomogram based on patient-specific covariates that the pediatric oncologist could use to individualize the topotecan dosage. Further studies are evaluating the contribution of ATP-binding cassette transporters to camptothecin resistance in neuroblastoma patients. Moreover, we are evaluating other factors (eg, those that increase oral absorption or decrease systemic clearance) that will enhance the use of camptothecins in treating childhood neuroblastoma.
The results of this clinical study further support the use of preclinical model systems to compare the systemic drug exposures in mouse models and man and their tumor-specific predictive value.31 Finally, our observations are in agreement with data in pediatric xenograft models and in pediatric leukemia suggesting that increased duration of therapy (protracted administration) is important for topotecan efficacy and produces superior responses rates.32
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Peter J. Houghton, GlaxoSmithKline. Stock Ownership: Victor M. Santana, GlaxoSmithKline. Honoraria: Peter J. Houghton, GlaxoSmithKline. Research Funding: Clinton F. Stewart, GlaxoSmithKline. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
Acknowledgment
We thank Valerie McPherson, CRA, for data management and the physicians, nurses, and other personnel who provided excellent patient care. We are indebted to Drs Margaret Ma, Mark Kirstein, Lisa Iacono, Burgess Freeman, and members of the Department of Pharmaceutical Sciences for their invaluable assistance in conducting this study.
NOTES
Supported by the US Public Health Service Childhood Solid Tumor Program Project Grant No. CA 23099, by Cancer Center Support Grant No. CA 21765 from the National Cancer Institute, and by the American Lebanese Syrian Associated Charities.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Matthay KK, Villablanca JG, Seeger RC, et al: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid: Children's Cancer Group. N Engl J Med 341:1165-1173, 1999
Nitschke R, Parkhurst J, Sullivan J, et al: Topotecan in pediatric patients with recurrent and progressive solid tumors: A Pediatric Oncology Group phase II study. J Pediatr Hematol Oncol 20:315-318, 1998
Kretschmar C, Kletzel M, Murray K, et al: Response to paclitaxel, topotecan, and topotecan-cyclophosphamide in children with untreated disseminated neuroblastoma treated in an upfront phase II investigational window: A Pediatric Oncology Group study. J Clin Oncol 22:4119-4126, 2004
Houghton PJ, Chesire PJ, Myers L, et al: Evaluation of 9-dimethylaminomethyl-10-hydroxycamptothecin against xenografts derived from adult and childhood solid tumors. Cancer Chemother Pharmacol 31:229-239, 1992
Houghton PJ, Cheshire PJ, Hallman JD II, et al: Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother Pharmacol 36:393-403, 1995
Zamboni WC, Gajjar AJ, Mandrell TD, et al: A four-hour topotecan infusion achieves cytotoxic exposure throughout the neuraxis in the nonhuman primate model: Implications for treatment of children with metastatic medulloblastoma. Clin Cancer Res 4:2537-2544, 1998
Zamboni WC, Stewart CF, Thompson J, et al: Relationship between topotecan systemic exposure and tumor response in human neuroblastoma xenografts. J Natl Cancer Inst 90:505-511, 1998
Tubergen DG, Stewart CF, Pratt CB, et al: Phase I trial and pharmacokinetic (PK) and pharmacodynamics (PD) study of topotecan using a five-day course in children with refractory solid tumors: A Pediatric Oncology Group study. J Pediatr Hematol Oncol 18:352-361, 1996
Stewart CF, Liu CY, Zamboni WC, et al: Population pharmacokinetics of topotecan in children and adolescents. Proc Am Soc Clin Oncol 19:177a, 2000 (abstr 687)
Montazeri A, Boucaud M, Lokiec F, et al: Population pharmacokinetics of topotecan: Intra-individual variability in total drug. Cancer Chemother Pharmacol 46:375-381, 2000
Santana VM, Zamboni WC, Kirstein MN, et al: A pilot study of protracted topotecan dosing using a pharmacokinetically guided dosing approach in children with solid tumors. Clin Cancer Res 9:633-640, 2003
Zamboni WC, Houghton PJ, Johnson RK, et al: Probenecid alters topotecan systemic and renal disposition by inhibiting renal tubular secretion. J Pharmacol Exp Ther 284:89-94, 1998
Santana VM, Schell MJ, Williams R, et al: Escalating sequential high-dose carboplatin and etoposide with autologous marrow support in children with relapsed solid tumors. Bone Marrow Transplant 10:457-462, 1992
d'Argenio DZ, Schumitzky A: ADAPT II User's Guide. Los Angeles, CA, University of Southern California, Los Angeles, Biomedical Simulations Resource, 1990
Gibaldi M, Perrier D: Pharmacokinetics. New York, NY, Marcel Dekker, 1982
van Warmerdam LJ, Verweij J, Schellens JH, et al: Pharmacokinetics and pharmacodynamics of topotecan administered daily for 5 days every 3 weeks. Cancer Chemother Pharmacol 35:237-245, 1995
Zamboni WC, Bowman LC, Tan M, et al: Interpatient variability in bioavailability of the intravenous formulation of topotecan given orally to children with recurrent solid tumors. Cancer Chemother Pharmacol 43:454-460, 1999
Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1-10, 1989
Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958
Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II. Analysis and examples. Br J Cancer 35:1-39, 1977
Davidoff AM, Corey BL, Santana VM, et al: Radiographic assessment of locoregional disease in children with high-risk neuroblastoma during neoadjuvant chemotherapy. Pediatr Blood Cancer 44:158-162, 2005
Turner PK, Johnston BJ, Wingo S, et al: MRP4 and P-glycoprotein (PgP) expression associated with topotecan (TPT) sensitivity in neuroblastoma (NB) cell lines. Proc Am Assoc Cancer Res 44:705, 2003 (abstr R3549)
Hirschmann-Jax C, Foster AE, Wulf GG, et al: A distinct "side population" of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci U S A 101:14228-14233, 2004
Keshelava N, Groshen S, Reynolds CP: Cross-resistance of topoisomerase I and II inhibitors in neuroblastoma cell lines. Cancer Chemother Pharmacol 45:1-8, 2000
Dhooge CR, De Moerloose BM, Benoit YC, et al: Expression of the MDR1 gene product P-glycoprotein in childhood neuroblastoma. Cancer 80:1250-1257, 1997
Maliepaard M, van Gastelen MA, de Jong LA, et al: Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res 59:4559-4563, 1999
Mattern MR, Hofmann GA, Polsky RM, et al: In vitro and in vivo effects of clinically important camptothecin analogues on multidrug-resistant cells. Oncol Res 5:467-474, 1993
Norris MD, Bordow SB, Marshall GM, et al: Expression of the gene for multidrug-resistance-associated protein and outcome in patients with neuroblastoma. N Engl J Med 334:231-238, 1996
Schellens JH, Maliepaard M, Scheper RJ, et al: Transport of topoisomerase I inhibitors by the breast cancer resistance protein: Potential clinical implications. Ann NY Acad Sci 922:188-194, 2000
Houghton PJ, Germain GS, Harwood FC, et al: Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro. Cancer Res 64:2333-2337, 2004
Houghton PJ, Adamson PC, Blaney S, et al: Testing of new agents in childhood cancer preclinical models: Meeting summary. Clin Cancer Res 8:3646-3657, 2002
Furman WL, Stewart CF, Kirstein M, et al: Protracted intermittent schedule of topotecan in children with refractory acute leukemia: A Pediatric Oncology Group study. J Clin Oncol 20:1617-1624, 2002(Victor M. Santana, Wayne )
Department of Pediatrics and Surgery, College of Medicine, University of Tennessee Health Science Center, Memphis, T
ABSTRACT
PURPOSE: To estimate the response rate and toxicity associated with intravenous topotecan when it is administered on a protracted schedule according to a pharmacokinetically guided dosing approach to treat childhood high-risk neuroblastoma.
PATIENTS AND METHODS: In this prospective phase II trial, topotecan was administered intravenously daily for 5 days for each of 2 consecutive weeks for two cycles. On the basis of topotecan systemic clearance, doses were individualized to attain a single-day topotecan lactone area under the plasma concentration-time curve (AUC) of 80 to 120 ng/mL · h. Patients subsequently received standard treatment.
RESULTS: Both cycles were administered to 28 (93%) of the 30 enrolled patients (median age, 3.1 years). Target topotecan AUCs were achieved in 92 (72%) of the 127 measurements conducted after pharmacokinetically guided adjustment; the median dosage required to achieve target AUCs was 2.7 mg/m2 (range, 0.95 to 3.8 mg/m2). The response rate was 60% (95% CI, 41% to 77%); there were one complete and 17 partial responses. No patient experienced disease progression during initial topotecan therapy. Primary tumor volumes decreased (median decrease, –58.2%; range, –95.1% to –4.9%) in the 26 patients with available size data. Homovanillic acid levels in 16 (89%) of 18 patients and vanillylmandelic acid levels in 14 (78%) of 18 patients were lower (P = .002 and P = .018, respectively) after topotecan therapy. Reversible grade 4 myelosuppression occurred in all patients, but no deaths occurred as a result of infection or toxicity.
CONCLUSION: Topotecan is active against neuroblastoma when it is administered on a protracted schedule and targeted systemic exposure is achieved.
INTRODUCTION
Successful treatment of high-risk neuroblastoma remains challenging in pediatric oncology; fewer than half of the children receiving current therapy will achieve long-term survival.1 Recently, topotecan has emerged as an active agent against recurrent neuroblastoma; response rates (complete response [CR], partial response [PR], and stable disease) of approximately 30% have been observed in patients with relapsed disease.2 Furthermore, activity as a single agent, when administered daily for 5 consecutive days, has been documented in chemotherapy-naive patients with neuroblastoma.3 This promising antitumor activity observed in patients is consistent with that reported in preclinical models of neuroblastoma.4,5
Our approach to the introduction of topotecan in neuroblastoma treatment is based on the evaluation of a protracted schedule of administration (daily administration for 5 consecutive days for each of 2 consecutive weeks) and the evaluation of systemic drug exposure associated with antitumor activity in xenograft mouse models.5-7 Using a panel of neuroblastoma xenografts, Zamboni et al7 showed that protracted topotecan therapy (10 doses for 12 days) results in greater antitumor activity than intermittent administration of the same total dosage over a shorter schedule. Moreover, at a topotecan systemic exposure of 88 ng/mL · h, CRs or PRs were observed in four of five neuroblastoma xenografts evaluated. The systemic exposure versus antitumor effect curve is steep, and minimal decreases in systemic exposure result in significant decreases in antitumor effect.7
Another factor to consider in optimizing clinical studies of topotecan is the significant interpatient variability in topotecan pharmacokinetics. A 12-fold range in the systemic clearance of topotecan lactone has been noted, and standard dosing based on surface area has yielded large interpatient variability in topotecan systemic exposure.8-10 This variability limits our ability to attain what could be considered cytotoxic plasma systemic exposure required for optimal antitumor effects. In a previous clinical study, we reduced interpatient variability by individualizing the topotecan dosage to achieve a topotecan systemic exposure of 80 to 120 ng/mL · h in children with refractory solid tumors.11 Using this approach, we successfully adjusted individual topotecan systemic exposure to reduce interpatient variability; 78% (46 of 59 values) of the measured area under concentration-time curve (AUC) values were within the target range.11
These observations formed the basis for our current investigation that incorporated topotecan administered intravenously on a protracted schedule (daily administration for 5 consecutive days for each of 2 consecutive weeks) and used pharmacokinetically guided dose adjustments to achieve a predefined topotecan systemic exposure in children with newly diagnosed disseminated neuroblastoma. The primary goals were to estimate the response rate to two cycles of topotecan administered intravenously as initial therapy and in dosages adjusted to attain a target systemic exposure of 80 to 120 ng/mL · h and to determine the toxicity of this treatment. Secondary objectives were to evaluate the disposition of topotecan in these patients and to estimate survival and progression-free survival rates.
PATIENTS AND METHODS
Patient Selection
Patients were eligible for this prospective, single-arm, phase II trial if they had previously untreated neuroblastoma, were 1 year of age, had International Neuroblastoma Staging System (INSS) stage 3 or 4 disease or were younger than 1 year, had INSS stage 3 or 4 disease, and tumor-specific MYCN amplification. Other eligibility requirements included a serum creatinine concentration less than 2 mg/dL and an aspartate transaminase level that was less than 3x the upper limit of the normal range. The protocol was approved by the St Jude Institutional Review Board, and all patients, parents, or guardians, as appropriate, were required to provide written informed consent or permission in accordance with institutional and federal guidelines.
Dose and Drug Administration
Before therapy began, long-term central venous access was established in each patient. Topotecan was administered intravenously as a daily 30-minute infusion in a schedule of daily administration for 5 consecutive days for each of 2 consecutive weeks (Fig 1). The initial dosage (3 mg/m2/d) was adjusted to attain a target topotecan systemic exposure (AUC) of 80 to 120 ng/mL · h. A second cycle of topotecan was administered approximately 16 days from the end of the first cycle (day 28). The initial dosage for the second cycle of topotecan was based on the dosage required in the preceding cycle to attain the target AUC. Patients were also administered filgrastim subcutaneously or intravenously at 5 μg/kg/d beginning on study day 13 and continuing for a minimum of 10 days or until the absolute neutrophil count exceeded 500/μL in two consecutive measurements after the expected nadir. Patients with progressive disease or nonhematologic grade 4 toxicity (excluding diarrhea lasting < 72 hours) during the initial topotecan therapy did not receive further topotecan treatment. All patients received prophylactic antiemetic agents, such as ondansetron, at the discretion of the treating physician. Trimethoprim-sulfamethoxazole as Pneumocystis carinii prophylaxis was withheld during the 12 days of topotecan therapy.12
Treatment After Topotecan Chemotherapy
After the topotecan treatment phase, all patients received standard induction chemotherapy consisting of one cycle of cyclophosphamide, doxorubicin, and etoposide; two cycles of cisplatin and etoposide; and one cycle of ifosfamide, carboplatin, and etoposide. This chemotherapy was followed by surgical evaluation and possible resection of the primary tumor and accessible lymph nodes. Patients underwent bone marrow or peripheral-blood stem-cell harvest either at resection or after recovery from the surgical resection. Patients then received consolidation therapy consisting of either high-dose cyclophosphamide and topotecan or carboplatin and etoposide (if the tumor did not respond to the initial topotecan treatment) and subsequent unpurged autologous marrow/peripheral-blood stem-cell rescue (minimum dose of nucleated bone marrow cells, 1 x 108/kg).13 Full-dose therapy was administered to all patients. Chemotherapy was delayed when necessary until the absolute neutrophil count exceeded 500/μL. After consolidation therapy, patients could receive oral retinoic acid for 6 months at the discretion of the treating physician. This report only describes data relevant to the antitumor activity, toxicity, and pharmacokinetics of topotecan administered during cycles 1 and 2.
Pharmacokinetically Guided Topotecan Dosing
Figure 1 illustrates our pharmacokinetically guided dosing strategy.11 During the first cycle, plasma samples were obtained after doses 1 and 6, processed immediately, and analyzed. If the single-day topotecan lactone AUC was within the target range after the first dose, then no dose adjustment was required. If not, then the topotecan dosage was adjusted linearly, on the basis of the patient's topotecan lactone clearance, to attain the target AUC on day 2, and repeat pharmacokinetic studies were performed until the patient's topotecan systemic exposure was within the target range. Regardless of day 1 results, the same pharmacokinetic testing strategy was repeated on day 8 (ie, sixth dose) using the topotecan dosage that attained the target AUC during the first week.
During the second cycle of therapy, plasma samples were collected on days 1 and 8, and decisions about dosing were made as described for the first treatment cycle. The topotecan dosage was adjusted only if the single-day target AUC was outside the target range. Additional plasma samples were taken to determine the adequacy of the modification, if necessary (Fig 1, hatched arrows).
As in previous studies, we made a distinction between AUC values resulting from a pharmacokinetically based dose adjustment and those solely reflecting a predetermined dosage, such as the first dose of cycle 1.11 In the latter instance, we refer to the AUC value as a dose success or a dose failure, and we reserve the terms pharmacokinetic targeting success and pharmacokinetic targeting failure for situations in which the dose adjustment did or did not place the patient's topotecan lactone AUC within the target range, respectively.
Sampling Strategy and Sample Analysis
Plasma samples were collected before and at 0.25, 1, and 6 hours after completion of the topotecan infusion. At each time point, 3 mL of whole blood was collected in a heparinized tube. Within 2 minutes of collection, the blood was centrifuged in a microfuge for 2 minutes at 7,000 x g, the plasma was separated, and 200 μL of plasma was added to 800 μL of cold (–30°C) methanol. The methanolic mixture was vortex mixed for 10 seconds and then centrifuged for 2 minutes at 7,000 x g. The supernatant was decanted into a screw-top tube and analyzed by isocratic high-performance liquid chromatography detection with fluorescence (RF551; Shimadzu, Columbia, MO); the excitation and emission wavelengths were 370 and 530 nm, respectively. Calibration curves were constructed with the use of human plasma from a single donor. The lower limit of quantitation for topotecan lactone in plasma is 0.25 ng/mL.11
Pharmacokinetic Analysis
A two-compartment model was fit to the plasma concentrations of topotecan lactone by using a maximum a posteriori Bayesian algorithm as implemented in ADAPT II.14 Estimated model parameters included the volume of the central compartment, elimination rate constant, and the intercompartment rate constants. We used published values (mean and variance) for the Bayesian priors.11 Standard equations were used to calculate systemic clearance and the volume of distribution at steady-state from parameter estimates.15 The model parameters for each patient were used to simulate the plasma concentration-time profile, from which the AUC from time zero to infinity was calculated by using a log-linear trapezoidal method. Because topotecan disposition is linear,16,17 we used the following equation to adjust topotecan dosage: adjusted dosage (mg/m2) = current topotecan dosage (mg/m2)/current AUC x target AUC.
Patient Monitoring and Toxicity Assessment
Before the start of treatment, tumor status was assessed by physical examination and the collection of each patient's medical history; appropriate diagnostic imaging; bone marrow aspiration and biopsy; complete and differential blood counts; liver function tests; measurement of serum creatinine, electrolytes, total protein, and albumin; and measurement of urine catecholamines.
During topotecan therapy, patients were examined at least weekly, and complete blood counts were obtained twice weekly; serum creatinine and liver function were evaluated as clinically indicated. At the completion of two cycles of topotecan therapy, patients underwent diagnostic imaging of the primary and metastatic sites, bone marrow examination, and measurement of urine catecholamines. The absolute primary tumor volume was calculated on the basis of the length, width, and depth of the tumor by using the following formula to calculate ellipsoid volume: V = (4 x ÷ 3) x a x b x c = (4 x ÷ 3) x (0.5 x length) x (0.5 x width) x (0.5 x depth) = 0.52 x length x width x depth.
Response to two cycles of topotecan therapy (the primary outcome) was described as follows: CR, complete resolution of metastatic tumor and more than 90% regression of the primary tumor attained by and maintained through initial induction phases; very good PR, more than 90% regression of primary tumor and clearing of metastatic disease except for persistent, bone scan–positive lesions; PR, more than 50% regression of all tumor; objective response, more than 25% but less than 50% regression of all disease; stable disease, less than 25% regression but no disease progression; and progressive disease, appearance of tumor in a previously uninvolved site. Patients with a CR, very good PR, or PR after two cycles of topotecan were classified as responders. Toxicities were evaluated on the basis of the National Cancer Institute Common Toxicity Criteria, version 2.0.
Statistical Considerations
On the basis of Simon's two-stage design with a type I error rate of 10% and a power of 80%, the statistical plan was to accrue 24 patients.18 Topotecan therapy would be considered unacceptable if sufficient evidence showed that the true response rate was less than 20%; a response rate of 40% was considered promising. Considering that the targeted systemic exposure might not be reached in as many as 15% of patients (based on previous data), as many as 34 patients could be enrolled.11 The estimated response rate was presented with an exact binomial 95% CI. The Wilcoxon signed-rank test was used to compare changes in laboratory values (lactic dehydrogenase [LDH], urinary homovanillic acid [HVA], and vanillylmandelic acid [VMA]) from diagnosis to evaluation after completion of topotecan therapy. The survival period was defined as the interval from enrollment to date of death from any cause or the date of last contact. The period of progression-free survival was defined as the time interval from enrollment to date of relapse, progressive disease, or last follow-up. Survival and outcome distributions were estimated by using the Kaplan-Meier method; associated SEs were based on the method of Peto and Pike.19,20 Follow-up data were current as of July 31, 2004.
RESULTS
Patient Characteristics
Thirty patients were enrolled. The median age at enrollment was 3.1 years (range, < 1 month to 16.9 years). Twenty-seven (90%) of 30 patients had INSS stage 4 disease (Table 1). Adrenal tissue was the most common primary site (20 of 30 patients, 67%). The oncogene MYCN was amplified in 12 (40%) of 30 tumors. Other demographic data are listed in Table 1.
Table 2 lists tumor volumes and selected laboratory results (LDH, urine HVA, and urine VMA) at diagnosis and after the completion of topotecan therapy. The laboratory value obtained within 1 week after the evaluation was used for the post-topotecan assessment. Most values were lower after two cycles. In 24 of 25 patients for whom LDH data was available, the values obtained after the completion of topotecan therapy were less than the values obtained at diagnosis (P < .001). Between diagnosis and the post-topotecan evaluation, the urine HVA values significantly decreased in 16 (89%) of 18 patients for whom such data were known (P = .002). Similarly, the known VMA values of 14 (78%) of 18 patients were lower after topotecan therapy than at diagnosis (P = .018).
Pharmacokinetic Parameters
Pharmacokinetic parameters were derived from the mixed-effects model for all patients (Table 3). Further analysis was based on cycles in which the topotecan dosage was adjusted or unadjusted; no resulting intergroup statistical comparison indicated a significant bias.
We assessed the interpatient and intrapatient variability by using the mixed-effect model, which allowed us to account for possible correlations between topotecan lactone clearance and cycle with repeated measurements within each subject. The estimated intersubject and intrasubject variances were 17.1% and 19.8%, respectively.9,17 This finding is different from those of previous studies in which intersubject variability in topotecan clearance exceeded intrasubject variability.10
Targeting of Topotecan Systemic Exposure
Presented in Figure 2 is a representative topotecan lactone plasma concentration-time plot for a patient studied after the administration of the initial predetermined topotecan dosage and then after a pharmacokinetically guided dose adjustment. The initial AUC (171 ng/mL · h) was above the maximum target value, and because the topotecan dosage was predetermined, this initial value was considered a dosing failure. The topotecan AUC corresponding to the second concentration-time curve was the result of a pharmacokinetically guided dose adjustment. The subsequent topotecan AUC value reached the target level (ie, 95 ng/mL · h) and, therefore, represented a pharmacokinetic targeting success. The median topotecan dosage in the cycles in which the target range of AUC values was achieved was 2.7 mg/m2 (range, 0.95 to 3.8 mg/m2).
We performed a total of 157 pharmacokinetic studies in 30 children (Fig 3). The first 30 studies were performed after a fixed topotecan dosage (3 mg/m2) was administered. Of these studies, only 16 (53%) yielded values that were considered a dosing success; the remainder indicated a dosing failure. In subsequent studies using pharmacokinetically guided dosing, the overall pharmacokinetic targeting success rate was 72% (AUCs in 92 of 127 assessable studies were in the target range). By cycle 2, 98% of AUCs (from 54 of 55 determinations) were in the target range after the second pharmacokinetic study.
Time Required to Receive Two Cycles of Topotecan Treatment
Only two of the 30 patients were unable to receive the second cycle because of gastrointestinal toxicity. For the 28 patients (93%) who completed both cycles, the median time from the start of cycle 1 to the start of standard chemotherapy (cycle 3) was 58 days (range, 44 to 73 days). The median time from the start of cycle 1 to the start of cycle 2 for the 28 patients was 25.5 days (range, 21 to 33 days), and the median time from the start of cycle 2 to the start of cycle 3 was 31 days (range, 23 to 42 days).
Response to Topotecan
Responses after two cycles of topotecan therapy were excellent; one patient had a CR, 17 had PRs, two had objective responses, and eight had stable disease. Two patients were considered to have response failures because they were unable to receive both cycles of topotecan. Therefore, the rate of CR + PR was 60% (95% CI, 41% to 77%).
Tumor Volume
Of the 30 patients, four did not have available data concerning tumor size; two patients were unable to complete the two cycles of topotecan therapy, and two other patients had liver or bone metastases at diagnosis that could not be measured accurately (primary tumor had been removed before chemotherapy). The median tumor volume of the other 26 patients at diagnosis was 307.2 mL (range, 12.0 to 1,578.4 mL; Table 2). All volumes decreased (median change in volume, –58.2%; range, –95.1% to –4.9%), and the median tumor volume after the completion of topotecan therapy was 126.6 mL (range, 2.5 to 805.1 mL).
Toxicity During Topotecan Treatment
The following sections focus on toxicity in the 28 patients who completed both cycles of topotecan therapy.
Neutropenia, thrombocytopenia, and diarrhea. Table 4 lists the incidence and duration of grade 4 neutropenia, thrombocytopenia, and diarrhea by cycle. All 28 patients who completed two cycles of topotecan therapy had two episodes of grade 4 neutropenia (one per cycle); median durations during both cycles were similar (15 and 14 days). Similarly, most patients had two episodes of grade 4 thrombocytopenia during the therapy (one per cycle); two patients had only one episode each. Median durations of grade 4 thrombocytopenia for cycles 1 and 2 were 4 and 8 days, respectively.
Of the seven patients with grade 4 diarrhea during topotecan therapy, one received only one cycle of topotecan therapy. Of the six patients who completed two cycles, four had grade 4 diarrhea during cycle 1, and the other two experienced toxicity during cycle 2. Two patients developed neutropenic colitis during the first cycle of topotecan therapy and were excluded from further topotecan treatment.
Transfusions of platelets and packed RBCs. All but one patient received at least one transfusion of packed RBCs (pRBC) and platelets during each cycle of topotecan therapy. One patient did not receive a pRBC transfusion during cycle 2. The median numbers of transfusions administered were similar for the two cycles (three and 2.5 pRBC transfusions per patient during cycles 1 and 2, respectively; two platelet transfusions each for cycles 1 and 2; Table 4).
Incidence of febrile neutropenia and duration of intravenous antibiotic administration. During the topotecan phase, all patients had at least one episode of febrile neutropenia (FN; median, two episodes; range, one to three episodes). A total of 52 FN episodes during the topotecan phase was observed in the 28 patients who received both topotecan cycles. All patients received intravenous antibiotics during treatment; the median duration of intravenous antibiotic administration per patient was 12.5 days (range, 4 to 28 days). During the 52 episodes of FN, intravenous antibiotics were administered for a median of 7 days (range, 3 to 16 days). We found no relationship between topotecan systemic exposure and toxicity.
Outcome
Twelve (40%) of the 30 patients were alive at the time this article was written. The median follow-up period from the enrollment date is 4.0 years (range, 2.1 to 6.5 years). All but one survivor has been evaluated or contacted within 1 year of the analysis date. All survivors had been evaluated or contacted within the past 2 years. No subsequent malignancies or deaths occurred before relapse or progression. Three-year and 4-year survival rate estimates are 66.2% ± 8.6% and 43.7% ± 11.6%, respectively. Estimates of 3-year and 4-year progression-free survival rates are 26.7% ± 7.6% and 23.3% ± 11.8%, respectively.
DISCUSSION
Results of our phase II trial demonstrate that topotecan has significant activity in children with neuroblastoma when administered on a protracted schedule in which pharmacokinetically guided dose adjustments achieve a predefined level of systemic exposure. The response rate (60%) in our high-risk neuroblastoma patients was excellent. The number of patients who achieved a CR or PR is higher than that achieved with only 5 days of administration and with traditional dosing based on a surface area calculation.3 A response rate of 39% (13 CRs and PRs in 33 patients) after two cycles of single-agent therapy was observed in a Pediatric Oncology Group study in which topotecan was administered as an intravenous bolus infusion (2 mg/m2/d) for only 5 days.3 However, disease in seven patients progressed during the topotecan phase. The response rate in our study was 1.5 times higher, as documented by careful evaluation of tumor volume and adherence to strict response criteria (only CR and PR). Furthermore, no patient experienced disease progression during topotecan therapy. The quality of the response was substantial; radiographic assessment of locoregional disease indicated that tumors in 16 of 24 patients were potentially surgically resectable after the completion of topotecan therapy.21 Because earlier tumor removal may decrease the risk of subsequent chemotherapy-resistant disease, it was important that our patients achieved a significant early decrease in tumor size and volume. These results, although encouraging, must be interpreted within the context of the limited sample size of a phase II study. Furthermore, the potential impact of modifications in schedule of administration or dosing parameters on the toxicity profile of topotecan, such as neutropenia, must be considered. Although myelotoxicity was observed, life-threatening infectious complications were uncommon in our study.
The results of the present study extend the findings of our previous study of pharmacokinetically guided topotecan dosing in patients with newly diagnosed neuroblastoma and confirm the feasibility of this approach to dosing topotecan. We separated the results of the pharmacokinetic studies conducted after the first dose of cycle 1 from those obtained by the remainder of the pharmacokinetic studies. This separation was done because the first topotecan dose of cycle 1 is fixed and the achievement of the desired systemic exposure is not a measure of the success of the targeting method. With extensive data from prior topotecan pharmacokinetic studies, we predicted that a topotecan dose of 3 mg/m2 would result in a topotecan lactone systemic exposure of 80 to 120 ng/mL · h. However, the AUCs for only 16 (53%) of 30 patients were within the target range after the first dose. In contrast, the dose adjustments based on our targeting approach resulted in 72% of patients having AUCs within the target range. Even for those patients whose AUCs were outside of the target range after the first adjustment, further adjustment resulted in AUCs within the target range in most patients.
Of the 21 dose adjustments that were judged pharmacokinetic targeting failures, 13 were attempted in children younger than 2 years. The one child who required more than four studies to attain the target range of AUCs was 2 weeks old at diagnosis. This observation highlights the importance of age as a critical factor that must be accounted for in this young population. All AUCs for all patients except one were within the target range after one dose adjustment (ie, by cycle 2).
In our study, we observed a 10-fold range in topotecan systemic clearance, a result that is consistent with previous experience showing that intersubject variability in topotecan clearance is substantial. If the present study population of children had been administered every dose as a fixed topotecan dose, one could expect a 10-fold range in topotecan plasma systemic exposure. However, our individualized approach to dosing resulted in a narrow range of topotecan systemic exposure (eg, 80 to 120 ng/mL · h). Thus, we presumably decreased the topotecan dosage for children with slow clearance rates and avoided excessive toxicity and increased the dosage for children with high clearance rates and reached what our preclinical models suggested were cytotoxic exposure levels.
A clinically relevant question for this approach to dosing topotecan is whether or not the day 1 pharmacokinetic study could be used to guide subsequent topotecan dosing. First, the results of the mixed effects modeling of the topotecan clearance suggest that the variability among patients (eg, intraoccasion variability [IOV]) is slightly greater than the variability between patients (eg, interindividual variability), which is different from our previous studies in which we have found that the interpatient variability is much greater than the intrapatient variability. Many sources of variability may account for the IOV in our patient population, and we are conducting studies to identify them. Many have suggested that if the IOV is greater than the interindividual variability, then the pharmacokinetically guided dosing would be problematic (ie, more variability within patients than between patients would lead to frequent dose adjustments). However, the results from the present study convincingly show that we are able to attain the target topotecan systemic exposure in more than 70% of the assessable topotecan studies (92 of 127 studies). These results, which were obtained using an approach in which we measured topotecan pharmacokinetic studies after dose 1 of cycle 1 to adjust the topotecan dose for subsequent doses, were highly encouraging and provided support for further applications of this approach.
The lack of response in a subset of patients suggests camptothecin resistance. In neuroblastoma cell lines, low intracellular accumulation of topotecan can be attributed to the presence of P-glycoprotein and multidrug resistance–associated proteins.22,23 The fact that topotecan is a substrate of P-glycoprotein and breast cancer resistance protein (ABCG2) implicates ATP-binding cassette transporters in clinical resistance.24-30
Our encouraging results serve as the basis of a current pilot study conducted by the Children's Oncology Group to investigate the use of topotecan with pharmacokinetically guided dose adjustments (and cyclophosphamide as a second agent) as initial therapy in children with newly diagnosed disseminated neuroblastoma. This strategy is resource and labor intensive and is difficult for the patient and family. Therefore, this approach may be limited in its applicability and is now only feasible in centers with expertise in pharmacokinetically guided dosing. To further address the wide interpatient variability in topotecan systemic clearance and its impact on efficacy and toxicity, we are conducting a population-based pharmacokinetic analysis to identify patient-specific covariates related to topotecan lactone systemic clearance that could be used to help guide topotecan dosing. The end point will be the creation of a nomogram based on patient-specific covariates that the pediatric oncologist could use to individualize the topotecan dosage. Further studies are evaluating the contribution of ATP-binding cassette transporters to camptothecin resistance in neuroblastoma patients. Moreover, we are evaluating other factors (eg, those that increase oral absorption or decrease systemic clearance) that will enhance the use of camptothecins in treating childhood neuroblastoma.
The results of this clinical study further support the use of preclinical model systems to compare the systemic drug exposures in mouse models and man and their tumor-specific predictive value.31 Finally, our observations are in agreement with data in pediatric xenograft models and in pediatric leukemia suggesting that increased duration of therapy (protracted administration) is important for topotecan efficacy and produces superior responses rates.32
Authors' Disclosures of Potential Conflicts of Interest
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Peter J. Houghton, GlaxoSmithKline. Stock Ownership: Victor M. Santana, GlaxoSmithKline. Honoraria: Peter J. Houghton, GlaxoSmithKline. Research Funding: Clinton F. Stewart, GlaxoSmithKline. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
Acknowledgment
We thank Valerie McPherson, CRA, for data management and the physicians, nurses, and other personnel who provided excellent patient care. We are indebted to Drs Margaret Ma, Mark Kirstein, Lisa Iacono, Burgess Freeman, and members of the Department of Pharmaceutical Sciences for their invaluable assistance in conducting this study.
NOTES
Supported by the US Public Health Service Childhood Solid Tumor Program Project Grant No. CA 23099, by Cancer Center Support Grant No. CA 21765 from the National Cancer Institute, and by the American Lebanese Syrian Associated Charities.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Matthay KK, Villablanca JG, Seeger RC, et al: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid: Children's Cancer Group. N Engl J Med 341:1165-1173, 1999
Nitschke R, Parkhurst J, Sullivan J, et al: Topotecan in pediatric patients with recurrent and progressive solid tumors: A Pediatric Oncology Group phase II study. J Pediatr Hematol Oncol 20:315-318, 1998
Kretschmar C, Kletzel M, Murray K, et al: Response to paclitaxel, topotecan, and topotecan-cyclophosphamide in children with untreated disseminated neuroblastoma treated in an upfront phase II investigational window: A Pediatric Oncology Group study. J Clin Oncol 22:4119-4126, 2004
Houghton PJ, Chesire PJ, Myers L, et al: Evaluation of 9-dimethylaminomethyl-10-hydroxycamptothecin against xenografts derived from adult and childhood solid tumors. Cancer Chemother Pharmacol 31:229-239, 1992
Houghton PJ, Cheshire PJ, Hallman JD II, et al: Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother Pharmacol 36:393-403, 1995
Zamboni WC, Gajjar AJ, Mandrell TD, et al: A four-hour topotecan infusion achieves cytotoxic exposure throughout the neuraxis in the nonhuman primate model: Implications for treatment of children with metastatic medulloblastoma. Clin Cancer Res 4:2537-2544, 1998
Zamboni WC, Stewart CF, Thompson J, et al: Relationship between topotecan systemic exposure and tumor response in human neuroblastoma xenografts. J Natl Cancer Inst 90:505-511, 1998
Tubergen DG, Stewart CF, Pratt CB, et al: Phase I trial and pharmacokinetic (PK) and pharmacodynamics (PD) study of topotecan using a five-day course in children with refractory solid tumors: A Pediatric Oncology Group study. J Pediatr Hematol Oncol 18:352-361, 1996
Stewart CF, Liu CY, Zamboni WC, et al: Population pharmacokinetics of topotecan in children and adolescents. Proc Am Soc Clin Oncol 19:177a, 2000 (abstr 687)
Montazeri A, Boucaud M, Lokiec F, et al: Population pharmacokinetics of topotecan: Intra-individual variability in total drug. Cancer Chemother Pharmacol 46:375-381, 2000
Santana VM, Zamboni WC, Kirstein MN, et al: A pilot study of protracted topotecan dosing using a pharmacokinetically guided dosing approach in children with solid tumors. Clin Cancer Res 9:633-640, 2003
Zamboni WC, Houghton PJ, Johnson RK, et al: Probenecid alters topotecan systemic and renal disposition by inhibiting renal tubular secretion. J Pharmacol Exp Ther 284:89-94, 1998
Santana VM, Schell MJ, Williams R, et al: Escalating sequential high-dose carboplatin and etoposide with autologous marrow support in children with relapsed solid tumors. Bone Marrow Transplant 10:457-462, 1992
d'Argenio DZ, Schumitzky A: ADAPT II User's Guide. Los Angeles, CA, University of Southern California, Los Angeles, Biomedical Simulations Resource, 1990
Gibaldi M, Perrier D: Pharmacokinetics. New York, NY, Marcel Dekker, 1982
van Warmerdam LJ, Verweij J, Schellens JH, et al: Pharmacokinetics and pharmacodynamics of topotecan administered daily for 5 days every 3 weeks. Cancer Chemother Pharmacol 35:237-245, 1995
Zamboni WC, Bowman LC, Tan M, et al: Interpatient variability in bioavailability of the intravenous formulation of topotecan given orally to children with recurrent solid tumors. Cancer Chemother Pharmacol 43:454-460, 1999
Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1-10, 1989
Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958
Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II. Analysis and examples. Br J Cancer 35:1-39, 1977
Davidoff AM, Corey BL, Santana VM, et al: Radiographic assessment of locoregional disease in children with high-risk neuroblastoma during neoadjuvant chemotherapy. Pediatr Blood Cancer 44:158-162, 2005
Turner PK, Johnston BJ, Wingo S, et al: MRP4 and P-glycoprotein (PgP) expression associated with topotecan (TPT) sensitivity in neuroblastoma (NB) cell lines. Proc Am Assoc Cancer Res 44:705, 2003 (abstr R3549)
Hirschmann-Jax C, Foster AE, Wulf GG, et al: A distinct "side population" of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci U S A 101:14228-14233, 2004
Keshelava N, Groshen S, Reynolds CP: Cross-resistance of topoisomerase I and II inhibitors in neuroblastoma cell lines. Cancer Chemother Pharmacol 45:1-8, 2000
Dhooge CR, De Moerloose BM, Benoit YC, et al: Expression of the MDR1 gene product P-glycoprotein in childhood neuroblastoma. Cancer 80:1250-1257, 1997
Maliepaard M, van Gastelen MA, de Jong LA, et al: Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res 59:4559-4563, 1999
Mattern MR, Hofmann GA, Polsky RM, et al: In vitro and in vivo effects of clinically important camptothecin analogues on multidrug-resistant cells. Oncol Res 5:467-474, 1993
Norris MD, Bordow SB, Marshall GM, et al: Expression of the gene for multidrug-resistance-associated protein and outcome in patients with neuroblastoma. N Engl J Med 334:231-238, 1996
Schellens JH, Maliepaard M, Scheper RJ, et al: Transport of topoisomerase I inhibitors by the breast cancer resistance protein: Potential clinical implications. Ann NY Acad Sci 922:188-194, 2000
Houghton PJ, Germain GS, Harwood FC, et al: Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro. Cancer Res 64:2333-2337, 2004
Houghton PJ, Adamson PC, Blaney S, et al: Testing of new agents in childhood cancer preclinical models: Meeting summary. Clin Cancer Res 8:3646-3657, 2002
Furman WL, Stewart CF, Kirstein M, et al: Protracted intermittent schedule of topotecan in children with refractory acute leukemia: A Pediatric Oncology Group study. J Clin Oncol 20:1617-1624, 2002(Victor M. Santana, Wayne )