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© 2001 American Society for Clinical Oncology Phase I Trial of Multiple Cycles of High-Dose Carboplatin, Paclitaxel, and Topotecan With Peripheral-Blood Stem-Cell Support as Front-Line TherapyFrom the Fox Chase Cancer Center, Philadelphia, PA. Address reprint requests to Russell J. Schilder, MD, 7701 Burholme Ave, Philadelphia, PA 19111.
PURPOSE: To determine the safety and feasibility of delivering multiple cycles of front-line high-dose carboplatin, paclitaxel, and topotecan with peripheral-blood stem-cell (PBSC) support. PATIENTS AND METHODS: Patients were required to have a malignant solid tumor for which they had received no prior chemotherapy. Mobilization of PBSC was achieved with either filgrastim alone or in combination with cyclophosphamide and paclitaxel. Patients then received three or four cycles of high-dose carboplatin (area under the concentration-time curve [AUC] 16), paclitaxel (250 mg/m2), and topotecan (10-15 mg/m2), with the latter two agents administered as 24-hour infusions and supported with PBSC and filgrastim. Cycles were repeated every 28 days. RESULTS: Twenty patients were enrolled onto the trial and were assessable for toxicity and clinical outcome. Dose-limiting toxicities were stomatitis and prolonged hematopoietic recovery. The maximum-tolerated dose of topotecan was 12.5 mg/m2 when given with high-dose carboplatin and paclitaxel for three cycles. Four cycles were able to be given with a dose of topotecan of 10 mg/m2. The pharmacokinetics of each compound were not affected by the other agents. Eleven (85%) of 13 patients with assessable disease responded. CONCLUSION: Multiple cycles of high-dose carboplatin, paclitaxel, and topotecan can be safely administered with filgrastim and PBSC support. The recommended doses for phase II study are carboplatin AUC 16, paclitaxel 250 mg/m2, and topotecan 10 mg/m2. Trials are currently being conducted with this regimen as front-line treatment in patients with advanced ovarian cancer and extensive small-cell carcinoma. This approach remains experimental and should be used only in the context of a clinical trial.
SEVERAL NEW classes of chemotherapeutic agents have been brought into clinical use during the past decade. Among these drugs, two of the most exciting are paclitaxel and topotecan. These agents have been combined with platinum compounds to form active regimens. Paclitaxel has been approved in the United States on the basis of its activity in epithelial ovarian, breast, and lung cancers. It also has demonstrated clinically important activity in a variety of other disease settings including endometrial and bladder cancers.1 In a phase III trial, the regimen of paclitaxel and cisplatin was found to be superior to cyclophosphamide and cisplatin in advanced ovarian cancer.2 Substitution of carboplatin for cisplatin achieved reduced toxicity,3 and the clinical activity of carboplatin and paclitaxel was confirmed in two phase III trials leading to the widespread adoption of the regimen as primary therapy for ovarian cancer.4,5 The same combination was shown to be active in metastatic non–small-cell lung cancer.6,7 Topotecan is a camptothecin analog that inhibits topoisomerase I. As a single agent, activity was demonstrated against ovarian and small-cell carcinoma.8 In a phase III trial, topotecan was shown to have similar activity compared with paclitaxel in patients with ovarian cancer previously treated with cisplatin and cyclophosphamide.9 Activity also has been confirmed in patients with progressive ovarian cancer resistant to platinum and taxane compounds.10 Its principal dose-limiting toxicities are neutropenia and thrombocytopenia. The duration of this toxicity is brief, noncumulative, and rarely associated with infections. Clinically relevant nonhematologic toxicities are uncommon. Preclinical data suggest that topotecan would act synergistically with platinum compounds because of inhibition of repair of platinum-DNA adducts.11 Preclinical in vivo data also suggest a synergistic interaction. Mice bearing Lewis lung carcinoma treated with topotecan and cisplatin had a longer median survival than mice treated with either agent alone.12 Various phase I trials have demonstrated that cisplatin and topotecan can be administered together, although with significant myelosuppression.12,13 The sequence in which the drugs are administered can affect the toxicity and possible efficacy of the regimen.14 Similar observations have been made with the combination of topotecan and carboplatin.15 The combination of topotecan with paclitaxel has been less well evaluated. These drugs have distinct mechanisms of action with nonoverlapping, nonhematologic toxicities with incomplete cross-resistance. The dose-limiting toxicity of this doublet in patients previously treated with cisplatin-based chemotherapy was myelosuppression, even with hematopoietic cytokine support.16 The dose of topotecan in this regimen was less than two thirds of its single-agent dose. Nonetheless, this combination resulted in a 40% response rate in patients with recurrent ovarian cancer who had relapsed after platinum-based front-line chemotherapy. A dose-response relationship for topotecan has been demonstrated in preclinical models.17,18 Phase I trials have evaluated the potential for escalation of the dose of topotecan using filgrastim but without much success because of the emergence of dose-limiting thrombocytopenia.19-21 Nonhematologic toxicities were similar among the various dosing schedules. Thus, the dose of topotecan could be further escalated in combination with other active agents if given with peripheral blood stem cell (PBSC) support. For this study, a 24-hour topotecan infusion was favored because it permits early reinfusion of the PBSC (on day 5 rather than on day 8 if a daily times 5-day schedule had been used). Recent data show that single-agent topotecan used on this schedule has less activity compared with the daily times 5 day schedule.22-24 However, schedule may have less impact on efficacy when topotecan is administered in combination with other chemotherapeutic agents with which it can interact synergistically. In a previous phase I trial, we established the feasibility of administering multiple cycles of high-dose carboplatin and paclitaxel with hematopoietic cytokine and cellular support.25 The maximum-tolerated dose (MTD) of carboplatin was established at an area under the concentration-time curve (AUC) of 16, similar to that also determined by other groups.26,27 Several groups have attempted to combine topotecan with paclitaxel and a platinum compound without hematopoietic cellular support.28-36 All combinations have required substantial reductions in dosage of one or more agents, raising questions about optimal tumor exposure to these agents. We hypothesized that the administration of these agents with hematopoietic cell support would permit delivery of full doses or greater for each drug over multiple cycles. These factors support the development of this high-dose triplet regimen for initial use as front-line treatment in patients with ovarian and small-cell carcinomas. The pharmacokinetics of topotecan given over this dose range and schedule with high-dose carboplatin and paclitaxel was studied as well, because there is evidence to suggest that the pharmacokinetics of topotecan may not be linear at higher doses.19
Eligible patients were enrolled from September 1996 through June 1998. Patients were required to have a histologic diagnosis of a malignant solid tumor and not had prior chemotherapy. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were required to have fully recovered from any prior radiotherapy or surgery. Before the initiation of treatment, a comprehensive medical history and physical examination, complete blood cell count, biochemical profile, ECG, urinalysis, audiogram, viral titers (herpes simplex virus, cytomegalovirus, human immunodeficiency virus, hepatitis A, B, and C), chest x-ray (computed tomography scans when appropriate), and appropriate tumor markers, eg, CA-125, were performed. All patients had adequate bone marrow (absolute neutrophil count [ANC]  1,500/µL, platelets 100,000/µL), hepatic (bilirubin  1.5 mg/dL and transaminases two times the upper limit of normal), and renal (serum creatinine 1.5 mg/dL) function. Patients with known human immunodeficiency virus infection, CNS metastases, or other serious medical conditions were not eligible. Written informed consent was obtained in accordance with federal, state, and institutional guidelines. Complete blood cell counts were obtained during the mobilization cycle every 3 days until day 10 and then daily through the PBSC collection. Biochemical panels, complete blood cell counts, and tumor markers were checked before each cycle. Radiographic studies were not routinely repeated until all the treatment cycles were completed. Doses of the chemotherapy agents were not escalated in individual patients. If a patient suffered significant but reversible toxicity, treatment was delayed a week. Patients with grade 3 (irreversible) or 4 nonhematologic vital organ toxicity or hematologic toxicity resulting in more than a 2-week delay in receiving the next treatment cycle were removed from study.
Treatment Plan
Cycle 1: Mobilization of PBSC For the last five patients, PBSC were mobilized with cyclophosphamide 3 g/m2, paclitaxel 250 mg/m2 (as a 24-hour infusion), and filgrastim 5 µg/kg/d. Filgrastim began on day 3 and continued through the night before the last collection until a minimum of 8 x 106 CD34+ cells/kg were obtained. The chemotherapy and filgrastim-induced mobilization of PBSC was performed on the last five patients to improve PBSC yield to support a fourth high-dose cycle. Premedications for paclitaxel were given as per Bookman et al.37
PBSC Collection
High-Dose Cycles Once the MTD of topotecan was established, a fourth cycle was added with a topotecan dose of 10 mg/m2 for the last five patients. This change represented a logical progression toward developing this regimen as a completely high-dose front-line treatment because all chemotherapy regimens used to treat advanced disease have used at least four cycles of induction therapy.
Patients did not receive the next cycle of high-dose chemotherapy until they had regained normal renal and hepatic function and peripheral-blood cell counts. Patients who still required granulocyte colony-stimulating factor 22 days after infusion of PBSC or had not yet recovered their platelet count enough to receive the next cycle of treatment (
PBSC Reinfusion
Definition of MTD Analysis of variance (ANOVA) and ANOVA with repeated measurements were used to model the effect of the administered topotecan dose and the dose effect across multiple cycles for different variables, respectively. The statistical analysis was performed using standard computer software statistical packages (SAS, Cary, NC; Minitab, State College, PA). The critical significance level of 5% was chosen.
Supportive Care
Pharmacokinetics Pharmacokinetic parameters of topotecan were determined in 19 patients by noncompartmental analysis using the computer program, NCOMP.43 A modified log trapezoidal algorithm was used to estimate the areas under the zero (ie, AUC) and first (AUMC) moments that incorporated a log-linear regression method to determine the terminal areas by extrapolation to time infinity.44 These areas were used to calculate total systemic clearance (CL) and the volume of distribution at steady-state (Vss) by standard formulas.45 The terminal elimination half-life was also calculated from the slope of the terminal elimination phase of topotecan. Carboplatin. Blood samples (5 mL) for the measurement of platinum were collected at 0 (predose), 2 (end of infusion), 2.25, 2.5, 3, 4, 6, 8, and 24 hours and analyzed by a previously described method.46 Approximately half the volume of collected plasma was placed in a filter device (Ultrafree, MW cutoff 30 kd; Millipore Corporation, Bedford, MA) and centrifuged to obtain an ultrafiltrate that was stored at -80°C until analyzed for platinum. Ultrafiltrate platinum concentrations were determined by flameless atomic absorption spectrophotometry (Perkin Elmer/Cetus model 3,100 equipped with HGA 600 graphite furnace). The ultrafiltrate samples were prepared in triplicate by dilution with appropriate volumes of 0.2% nitric acid/0.1% Triton-X 100, and then aliquots were injected onto the atomic absorption spectrophotometer. Pharmacokinetic parameters of carboplatin were determined in 19 patients with the noncompartmental methods described above. Total clearance and AUC values derived from ultrafiltrate platinum concentrations are reported. Paclitaxel. A single end of infusion paclitaxel concentration was determined in 19 patients according to a previously reported method.47 The method consisted of a solid-phase extraction of paclitaxel and the internal standard (cephalomannine) from 1 mL of plasma. Final solid-phase column eluents were evaporated to dryness under nitrogen at 40°C, reconstituted in 150 µL of 50:50 (v:v) acetonitrile:water, and injected onto an HPLC system. The HPLC system used a Hypersil C18 analytic (5 µm, 150 x 4.6 mm) and guard columns (5 µm, 45 x 4.6 mm) fitted with an ultraviolet detector set at a wavelength of 230 nm. Paclitaxel was eluted by an isocratic mobile phase (55:45 [v:v] acetonitrile:water) at a flow rate of 1.0 mL/min and a run time of 14 minutes.
The demographics of the 20 patients enrolled onto this trial are summarized in Table 1. None of the patients had received prior chemotherapy. One patient had prior pelvic irradiation. Twelve patients had ovarian cancer, reflecting the activity of these drugs in this patient population and the selection priorities at our institution. All patients received at least one high-dose chemotherapy treatment. Two patients with ovarian cancer received only one cycle because of progressive disease and/or toxicity. Four patients received only two cycles because of toxicity. These patients had endometrial (one), ovarian (two), or fallopian tube (one) carcinoma. A total of 56 cycles of high-dose chemotherapy were administered. Four of five patients scheduled to receive four cycles at the recommended phase II dose did so. The other patient received only two cycles due to delayed recovery of her performance status.
Toxicity There was one death on this trial attributed to respiratory failure in the setting of progressive Aspergillus pneumonia despite amphotericin B therapy. The patient also had Bacteroides fragilis bacteremia, presumed secondary to a pelvic source. She had rapidly progressive pulmonary and abdominopelvic metastases before initiating treatment. No radiographic response was observed during the 3 weeks between initiating high-dose chemotherapy and her death. One additional patient died of progressive disease during the first cycle. In both cases, their neutrophil counts had recovered, demonstrating at least partial bone marrow engraftment. The initial 15 patients were mobilized with filgrastim only ( Fig 1A). During mobilization, there were no significant toxicities other than self-limited bone pain managed with mild analgesics. Some patients required parenteral electrolyte repletion postapheresis. Five additional patients had their PBSC mobilized with cyclophosphamide, paclitaxel, and filgrastim (Fig 1B). All five of these patients had expected grade 4 granulocytopenia, but only one patient required hospitalization for an indwelling catheter infection. The patient recovered without incident after the line was removed. Two patients had grade 3 thrombocytopenia and anemia. There were no grade 3 or 4 nonhematologic toxicities during the mobilization phase.
The major toxicities for the high-dose carboplatin, paclitaxel, and topotecan cycles were neutropenic fever and stomatitis. Grade 4 myelosuppression was commonly seen but was manageable. The median number of days required to achieve a neutrophil count 500/µL and to a transfusion-independent platelet count of 20,000/µL per cycle per dose are listed in Table 2. The association of dose and days to neutrophil recovery trended toward significance (P = .08) during the first cycle but was not significant across cycles (P = .55). There was a significant correlation between dose and the days to platelet recovery during the first cycle (P = .03) and across cycles (P = .01). The median number of units of PRBCs and platelets transfused per cycle is listed in Table 3. There was no correlation between topotecan dose and the number of units of PRBCs or platelets transfused (P = .24 and P = .17, respectively). Also, there was no association between these parameters and the number of cycles of high-dose chemotherapy administered (PRBC, P = .77; platelets, P = .43).
Based on the data of Tricot et al,48 a minimum target of 2 x 106 CD34 cells/kg was selected to support each cycle of this highly myelosuppressive but not myeloablative regimen. In the first cycle, there were five patients who received less than 2 x 106 CD34+ cells/kg ( Table 4). Two of these patients received 3 x 106 CD34+ cells/kg on subsequent cycles when the marrow would require greater support. Two patients received 1.6 x 106 and 1.9 x 106 CD34+ cells/kg per cycle and had hematologic recovery no different from the rest. They also required no more blood bank support than the group as a whole. One patient received less than 1 x 106 CD34+ cells/kg and recovered her neutrophil count production on time. She did require greater blood bank support because of a prolonged platelet recovery.
In the second and third cycles, only two patients received less than 2 x 106 CD34+ cells/kg (1.6 x 106 and 1.8 x 106 CD34+ cells/kg) but had similar rates of hematologic reconstitution compared with those who receive greater than 2 x 106 CD34+ cells/kg. All four patients who underwent four cycles of high-dose chemotherapy received greater than 2 x 106 CD34+ cells/kg with a median of 9.35 x 106 CD34+ cells/kg per reinfusion (range, 4.3 x 106 to 16.6 x 106). No association was detected between the number of CD34+ cells/kg reinfused and the units of PRBCs (P = .56) or platelets (P = .75) reinfused. There also was no association between the dose of CD34 cells/kg reinfused and the days to ANC recovery (P = .6) and platelet recovery (P = .61).
The primary dose-limiting nonhematologic toxicity was hemorrhagic stomatitis at the 15-mg/m2 dose of topotecan ( Table 5). This patient expectorated bloody casts of exfoliated esophageal and oral mucosa for approximately 5 days during her second high-dose cycle. However, she did not require intubation to maintain patency of her airway. This patient also required 30 days to recover her platelet count, which met one of the criteria for dose-limiting toxicity. The dose of topotecan used to treat this patient was deemed to exceed MTD. Stomatitis also was evident at the lower doses but was easily managed with total parenteral nutrition and parenteral morphine, usually for less than 7 days. There were only isolated instances of other grade
Based on our previous experience,25 outpatient prophylactic fluids and electrolyte replacement were routinely ordered for patients after hospital discharge following the administration of the chemotherapy and PBSC. Hypomagnesemia was the most common electrolyte pertubation observed and was successfully addressed with IV supplementation at home. With one exception, all patients developed neutropenic fever and/or significant stomatitis requiring hospitalization for each of the high-dose cycles. One patient avoided readmission and/or extended hospitalization after receiving chemotherapy and PBSC for two of the high-dose cycles. Approximately 70% of these admissions lasted 7 days or less. The median length of stay for each dose level by cycle is provided in Table 6. The association between increasing dose and increasing length of stay was at the threshold of significance (P = .05). The number of cycles did not significantly impact on the length of stay (P = .11).
Responses Thirteen of the 20 patients, all of whom had ovarian or primary peritoneal carcinoma, had disease assessable for response. All these patients were suboptimally debulked. The remaining seven patients with other diagnoses had no measurable disease after resection but were considered at high risk for recurrence. Eleven of the 13 assessable patients responded (85%; 95% confidence interval, 60.5% to 97.1%). Two patients were documented to have a pathologic complete response at second-look laparotomy. Both of these patients were deemed too bulky to undergo initial cytoreductive surgery and proceeded directly with study treatment. A third patient, also with initially unresectable disease, was found to have minimal macroscopic disease at second-look surgery with negative radiographic studies and normalization of the CA-125. In addition, there were three clinical complete responses and five partial responses. One patient progressed and one had no response during the first (and only) high-dose cycle. The remaining patients with primary sites other than ovarian or primary peritoneal cancer were not assessable for response. Time to progression was not an end point because patients were permitted to receive additional therapies at the completion of study treatment.
Pharmacokinetics
The dose of carboplatin was fixed at a target AUC 16. Seventy-three percent of patients received the targeted AUC dose or greater of carboplatin. The clearance and AUC of carboplatin were independent of the dose of topotecan ( Table 9).
The 24-hour end-of-infusion paclitaxel concentrations ranged from 225 ng/mL to 830 ng/mL (Table 7) and did not vary with increasing doses of topotecan.
Topotecan has demonstrated activity in patients with cancers resistant to platinum compounds and paclitaxel.9,10 In preclinical models, topotecan has shown synergy with these compounds.11,12,49 It is logical to attempt to incorporate agents with such activity into front-line therapy. However, attempts to combine topotecan with platinum and paclitaxel-containing regimens have been limited by significant myelosuppression.28-36 In developing these combinations, some investigators have chosen to use cisplatin instead of carboplatin to minimize the degree of myelosuppression but with limited success. For example, one study determined the MTD to be cisplatin 75 mg/m2 (on day 2) with paclitaxel at 110 mg/m2 (on day 1) and topotecan at 0.4 mg/m2/d x 5 days with filgrastim.29 The Gynecologic Oncology Group (GOG) phase I trial of this combination is ongoing. Current doses are 175 mg/m2 over 3 hours for paclitaxel followed by cisplatin 50 mg/m2 and topotecan 0.5 mg/m2/d for 3 consecutive days followed by filgrastim.28 Several phase I trials using carboplatin achieved similar total doses of topotecan per cycle as used in the cisplatin-containing phase I trials.30-34 For example, nine patients with metastatic or recurrent head and neck cancer were treated with this three-drug combination.34 None had received prior treatment for relapsed metastatic disease. All patients received paclitaxel (135 mg/m2) and carboplatin (AUC 4) on day 4. Topotecan was administered on days 1 to 3 at 0.5, 0.75, or 1.0 mg/m2/d for 3 days. Dose-limiting toxicity has not yet been reached. Another group of investigators determined the MTD of this three-drug regimen using carboplatin AUC 5 or 6, paclitaxel 175 mg/m2 administered on day 1, along with topotecan 0.5 mg/m2/d to 1.25 mg/m2/d x 4 or 5 days.30 During the next cycle, the carboplatin and paclitaxel were then switched to day 4 or 5. The dose-limiting toxicity for the early sequence was neutropenia occurring with 50% of the cycles at paclitaxel 175 mg/m2, carboplatin AUC 5, and topotecan 0.75 mg/m2/d x 5 days; for the late sequence, the same dose-limiting toxicity was observed at the same doses of paclitaxel and carboplatin and a topotecan dose of 1 mg/m2/d x 4 days without filgrastim. The authors concluded that the late sequence was less toxic and recommended the doses of paclitaxel 175 mg/m2, carboplatin AUC 5, and topotecan 0.75 mg/d for 5 days without filgrastim as the phase II dose. With filgrastim, the authors were able to go to topotecan 1 mg/m2/d but only for 4 days. Finally, Thompson et al32 treated 33 patients with these three drugs. Carboplatin was given at AUC 5 with paclitaxel 135 or 175 mg/m2 over 1 hour on day 1; topotecan was administered at 0.75 to 1 mg/m2/d on days 1 to 3. Dose-limiting toxicity was still myelosuppression, especially thrombocytopenia, even with filgrastim and oprelvekin support. It is not surprising that this combination was active in all these studies, but the common theme of dose-limiting myelotoxicity, even at low-to-standard doses of each drug, is evident. PBSC with hematopoietic growth factor support clearly allows the delivery of each drug at or exceeding their conventional MTD. The dose-limiting toxicity of this regimen in the current trial was stomatitis. It is interesting that in our previous phase I trial with high-dose carboplatin and paclitaxel, severe stomatitis was not observed.25 Also, in a previous trial with topotecan administered as a 24-hour infusion every 21 days, the dose-limiting toxicity was myelosuppression without significant stomatitis.21,50 The emergence of dose-limiting stomatitis within this regimen suggests a biologic interaction among these agents. Synergy has been demonstrated in vitro between each doublet combination of these three drugs.49,51-53 In particular, the current triplet demonstrated significant synergy in vitro compared with other combinations evaluated.53 Of note, the CTC version 1.0 that was used as the toxicity-grading criteria for this study did not differentiate between the toxicities of high-dose treatment compared with conventional-dose chemotherapy. It was therefore common to support patients through what was then called grade 4 stomatitis. Today, these patients would have had only grade 3 toxicity as defined by the new CTC version 2.0 for bone marrow transplant patients, with grade 4 toxicity for bone marrow transplant patients now requiring intubation. Thus, the dose at which the patient with hemorrhagic stomatitis was treated during her second cycle would also not have been considered to have been grade 4 by the new criteria. It was believed at that time that this level of stomatitis exceeded the MTD. This small increase in topotecan dose to 15 mg/m2 did not warrant this level of toxicity in the face of these already high doses of all three drugs. As expected, the activity of this aggressive front-line treatment is evident. The majority of the patients had advanced, suboptimally debulked stage III or IV ovarian cancer. Eleven (85%) of 13 patients with ovarian or primary peritoneal papillary serous carcinoma responded, including two pathologic complete responses, four clinical complete responses, one pathologic partial response, and five clinical partial responses. Although these numbers are small and not overwhelming, these patients represented a poor-prognosis group with advanced disease. Obviously, a randomized trial would be required to compare directly the efficacy of this approach with conventional therapy such as carboplatin and paclitaxel. The GOG has initiated a pilot trial to explore the feasibility of this regimen in a limited, multicenter trial in patients with optimally debulked stage III ovarian cancer. This study also includes assessment of response by second-look laparotomy and will help to determine whether further testing is appropriate. The mean total clearance (CL = 11.3 ± 3.2 L/h/m2) and volume of distribution (Vss = 59.2 ± 40.4 L/m2) values for topotecan are within the broad range of values previously reported.54 These comparisons include all types of topotecan dose ranges and schedules, with the majority being the typical daily times five 30-minute infusions. Specifically, AUC and CL values obtained in this study were in the same range as those previously reported for a 24-hour infusion of topotecan as a single agent. It seems unlikely that the administration of high-dose carboplatin and paclitaxel preceding the topotecan infusion affected the total clearance and volume of distribution of topotecan. The pharmacokinetics of topotecan at these high doses appears linear over the relatively narrow dose range studied. Collection of more pharmacokinetic data using the current drug combination regimen will be important to establish the population pharmacokinetic behavior of these drugs and useful pharmacokinetic-pharmacodynamic relationships. Carboplatin pharmacokinetic parameters were evaluated in 19 of 20 patients during the first triplet cycle. Carboplatin was delivered at a target dose or greater in 73% of patients. We currently are constructing a limited sampling model for the delivery of high-dose carboplatin which can be used to confirm the delivery of the targeted AUC dose. The 24 hour end-of-infusion values for the plasma concentration of paclitaxel in this trial were similar across the various topotecan dose levels and in agreement with values already published. Two groups of investigators previously reported mean end-of-infusion plasma concentrations of 0.88 µmol/L and 1.57 µmol/L.55,56 Our range of 0.26 to 0.97 µmol/L (mean ± SD, 0.59 ± 0.2) is consistent with these values and shows that the pharmacokinetics of paclitaxel were not altered by the subsequent administration of high-dose carboplatin and topotecan. However, more extensive paclitaxel concentration measurements would be needed to study in detail what effects, if any, the coadministration of high-dose carboplatin and topotecan had on the pharmacokinetics of paclitaxel. Some readers may question the schedule of topotecan used in this trial. Topotecan as a single agent administered as a 24-hour infusion has less activity than topotecan administered on a daily times 5-day schedule.22-24 Schedule may not be as critical for efficacy when topotecan is used along with other antineoplastic agents. In combination, synergy with other drugs such as carboplatin and paclitaxel still may prove beneficial. Such synergy has been demonstrated in vitro. The toxicity profile seen in this study, which differs from our previous high-dose trial, may represent a biologic interaction among these three drugs. Cancers such as ovarian cancer and small-cell carcinoma are often initially responsive to chemotherapy; however, the vast majority are not cured due to relapse with development of resistant disease. The approach of using multiple cycles of high-dose chemotherapy as front-line therapy has been shown to be successful in the treatment of non-Hodgkin’s lymphoma.57 Many new drugs have come into the field during the past decade. Several of these drugs have been shown to have favorable interactions with older drugs such as the platinum compounds. Combining these drugs, in general and specifically, as front-line regimens has proven difficult, usually because of excessive myelotoxicity. This toxicity can be overcome by using maximum hematopoietic support with cytokines and PBSC. The dose-toxicity relationship for topotecan is steep, and greater advantage might be gained by adding a fourth high-dose cycle rather than pushing the dose of topotecan to the MTD. A fourth cycle at the MTD of 12.5 mg/m2 was believed to exceed patient tolerance. Consequently, this regimen is being taken forward into phase II trials with the dose of topotecan of 10 mg/m2 in ovarian and small-cell carcinomas. At this time, it is unclear whether the degree of toxicity generated by this complex regimen will be justified, or if this approach will meaningfully prolong survival and increase cure rates in these malignancies. If the current phase II trials are successful, this regimen will need to be tested prospectively in randomized trials compared with standard therapy.
Supported in part by grant no. UO1-CA70024-03 from the National Cancer Institute, National Institutes of Health, and SmithKline Beecham Corporation. We thank Barbara Arrighy for her excellent secretarial support, the nurses of the Mary S. Schinagl Clinical Research Unit and the Apheresis Unit for their dedicated patient care, Dottie Shields for her superb technical support, Eileen Keenan for her outstanding data management skills, and, mostly, the patients who participated in this trial.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
