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© 1999 American Society for Clinical Oncology Phase I Trial of Multiple Cycles of High-Dose Chemotherapy Supported by Autologous Peripheral-Blood Stem CellsFrom the Fox Chase Cancer Center, Philadelphia, PA. Address reprint requests to Russell J. Schilder, MD, Fox Chase Cancer Center, 7701 Burholme Ave, Philadelphia, PA 19111; email rj_schilder{at}fccc.edu
PURPOSE: To determine the safety and feasibility of delivering multiple cycles of front-line high-dose carboplatin and paclitaxel with hematopoietic 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 cyclophosphamide, etoposide, and granulocyte-macrophage colony-stimulating factor (GM-CSF). After one cycle of conventional-dose carboplatin and cyclophosphamide with GM-CSF, patients received multiple cycles of high-dose carboplatin (area under the concentration-time curve [AUC], 12 to 20) and paclitaxel (250 mg/m2) with PBSC and GM-CSF repeated every 28 days. RESULTS: Twenty-four of 28 patients were assessable for toxicity and clinical outcome. Dose-limiting toxicitieswere dehydration, diarrhea, and electrolyte imbalances. The maximum-tolerated dose of carboplatin was AUC 16 (equivalent to a median of 1,189 mg/m2). The relationship of target AUC to measured AUC was linear (r2 = .29; P = .0011). The overall response rate was 96%, with a complete clinical response rate of 67%. The median time to progression from the first PBSC reinfusion was 49.5 weeks (range, 8 to 156+ weeks). CONCLUSION: Multiple cycles of high-dose carboplatin (AUC 16) and paclitaxel (250 mg/m2) can be safely administered with GM-CSF and PBSC support. Although this regimen is safe, feasible, and active, the use of multiple cycles of high-dose chemotherapy as front-line treatment remains experimental and should only be used in the context of a clinical trial.
HIGH-DOSE CHEMOTHERAPY with autologous hematopoietic cell support is capable of inducing long-term remissions and cures in a variety of neoplasms. Recently, several randomized trials have shown the benefit of this approach in non-Hodgkin's acute lymphoma, leukemia, breast cancer, and myeloma.1-4 Nonrandomized trials have suggested improved outcome with high-dose chemotherapy in testicular cancer, high-risk early-stage breast cancer, and ovarian cancer.5-7 Traditionally, high-dose chemotherapy has consisted of a single course administered as consolidation, with rescue provided by reinfusion of bone marrow cells. Advances in hematopoietic support, including the development of colony-stimulating factors (CSFs) and peripheral-blood stem-cell (PBSC) technology, have dramatically reduced the toxicity, complexity, and expense of such treatment. These new tools allow patients to receive multiple high-dose cycles as front-line chemotherapy. Preclinical data have shown that repetitive administration of chemotherapy with a short-cycle interval can improve efficacy and therapeutic indices compared with single applications.8 In addition, most solid tumors have relatively low growth fractions that favor a strategy using repeated cycles of high-dose chemotherapy. Two large, randomized trials have established cisplatin and paclitaxel as active front-line treatment for ovarian carcinoma. The Gynecologic Oncology Group (GOG) demonstrated that this combination improved survival in patients with advanced ovarian cancer compared with cisplatin and cyclophosphamide.9 Similar results have since been reported from another large, multicenter trial.10 We have previously shown that standard-dose combinations of paclitaxel and carboplatin have significant activity in the treatment of solid tumors,11,12 with response rates of 75% and 62% in advanced ovarian and metastatic non–small-cell lung cancer, respectively. The dose-limiting toxicity of this regimen is myelosuppression, even with the incorporation of hematopoietic cytokines such as filgrastim (granulocyte CSF). Nonhematologic toxicities are generally mild, and further dose escalation would be possible with hematopoietic cellular support. The steep dose-response relationship observed with carboplatin makes it attractive to evaluate at high doses for responsive diseases such as ovarian cancer. Nonhematologic toxicities of carboplatin were minimal up to 2,000 mg/m2 when supported with autologous bone marrow reinfusion.13 Shea et al14 subsequently treated patients with high-dose carboplatin and granulocyte-macrophage (GM)-CSF for up to three cycles with and without PBSC. Hematologic recovery, especially of platelets, was significantly faster in patients supported with GM-CSF and PBSC. Other advantages included decreased blood bank support, maintenance of full-dose chemotherapy, and a reduction in toxic deaths. Prospective randomized trials have not shown an advantage of higher platinum doses compared with standard therapy. However, the degree of actual delivered dose escalation in these studies has been minimal.15-18 The development of a safe and well-tolerated regimen using multiple cycles of high-dose chemotherapy with stem-cell support potentially would be attractive for comparison with standard therapy. In addition, this approach builds a framework for integration of new agents in combination.
Eligible patients were enrolled between September 1992 and September 1996. Patients were required to have a histologic diagnosis of a malignant solid tumor and with no prior chemotherapy. All patients were between 18 and 65 years of age with 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 count, biochemical profile, electrocardiogram, urinalysis, audiogram, viral titers (herpes simplex virus, cytomegalovirus, and hepatitis A, B, and C), bone marrow aspirate and biopsy, chest radiograph (computed tomography scans where appropriate and appropriate tumor markers, eg, CA-125) were performed. All patients had adequate bone marrow (WBC count  4,000/µL, platelet count 100,000/µL), hepatic (bilirubin level  2 mg/dL and transaminase levels two times the upper limit of normal), and renal (serum creatinine concentration 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 counts were obtained during the mobilization cycle every 3 days until day 10 and then daily through the PBSC collection period. Biochemical panels, complete blood counts, and tumor markers were checked before each cycle. Radiographic studies were not routinely repeated until all treatment cycles were completed. Carboplatin doses were not escalated in individual patients. If a patient suffered significant but reversible toxicity, treatment was delayed a week. Only one patient received a dose reduction because of a prolonged hospital stay for refractory diarrhea.
Treatment Plan
Cycle 1: Mobilization of PBSC GM-CSF was started 24 hours after completion of either of the aforementioned chemotherapy regimens to enhance mobilization. Either the Escherichia coli–derived product (Schering, Kenilworth, NJ) at 5 µg/kg/d or sargramostim (Immunex Corporation, Seattle, WA) at 250 µg/m2/d was administered subcutaneously until leukaphersis was completed. PBSC collection. Collection of PBSCs commenced when the WBC and platelet counts reached 1,000/µL and 30,000/µL, respectively, usually between days 12 and 16 (9 to 11 days for patients mobilized with paclitaxel). PBSCs were collected through a temporary double-lumen catheter placed for access for leukapheresis using a Fenwall 3000 apheresis machine (Baxter, Deerfield, IL) over 2 to 4 hours, which processed 10 to 20 L of total blood volume per leukapheresis. Cell count, differential, and enumeration of CD34+ cells were immediately performed on an aliquot of the collected specimen along with routine microbiologic studies. Apheresis continued on a daily basis until a minimum of 4 x 106 CD34+ cells/kg was collected. The product was then diluted with autologous plasma and an equal volume of freezing solution containing autologous plasma and tissue culture Medium-199 (Gibco Life Technologies, Grand Island, NY), with a final dimethyl sulfoxide concentration of 10%. The cells were cryopreserved in approximately 100-mL aliquots using a programmable freezer and stored in a liquid phase of liquid nitrogen. If the yield from the first series of aphereses was inadequate to support two high-dose cycles, then a second mobilization was performed using GM-CSF (250 µg/m2/d) for 8 days, with leukapheresis occurring on the last 3 days. CD34 analysis. One hundred microliters of 10 x 107 cells/mL or mononuclear cells isolated from peripheral blood were labeled with anti-CD45 fluorescein isothiocyanate/CD14 phycoerythrin, isotype match control, or anti-CD34 fluorescein isothiocyanate/CD33 phycoerythrin monoclonal antibodies (Becton Dickinson, Mountain View, CA). Cells were incubated for 20 minutes at 4°C, washed, and resuspended in cold Hank's balanced salt solution (Gibco) with 1% bovine serum albumin and 0.1% sodium azide. Ten microliters of propidum iodide (0.2%) were added for live gate exclusion of dead cells. Cells were analyzed on a FACScan (Becton Dickinson). The percentage of positive cells in the negative and isotype match controls were subtracted from the percentage of CD34+ cells. This percentage was multiplied by the number of mononuclear cells per kilogram to yield the CD34+ cells/kg.
Cycle 2: Induction Cycle From the PBSC Mobilization Cycle
High-Dose Cycles Once feasibility of delivering two cycles of high-dose carboplatin and paclitaxel was established, the standard-dose cycle (cycle 2) was replaced by a third cycle of high-dose carboplatin (AUC 16) and paclitaxel. This change represented a logical progression toward developing multiple cycles of high-dose carboplatin and paclitaxel as a front-line regimen.
PBSC Reinfusion Patients did not receive the next cycle of high-dose chemotherapy until they had regained normal renal and hepatic function and peripheral-blood counts. Patients who still required GM-CSF 22 days after infusion of PBSC were considered to have failure of engraftment and thus would receive the rest of their PBSCs without further chemotherapy on study. Patients who experienced grade 3 or 4 nonhematologic toxicity were required to have improvement to grade 0 or 1 by day 22 to receive the next cycle of high-dose chemotherapy.
Definition of Maximum-Tolerated Dose The maximum-tolerated dose was defined based on toxicity during the high-dose cycles of the trial. Toxicity was graded based on the Eastern Cooperative Oncology Group toxicity scale. A minimum of four patients was entered at each dose level. If none of these four patients experienced dose-limiting toxicity, then the dose was escalated to the next higher level in four subsequent patients. If one or two of these four patients suffered dose-limiting toxicity, then three more patients were accrued at the same dose. If fewer than three patients at a given dose level suffered dose-limiting toxicity, then the dose was escalated in subsequent patients. If three or more patients experienced dose-limiting toxicity, then the maximum-tolerated dose had been exceeded, and three more patients were treated at the next lower dose (if only four patients were previously treated at the prior dose). Dose-limiting toxicity was defined as requiring GM-CSF more than 21 days, nonhematologic vital organ toxicity of grade 3 or 4, or requiring hospitalization to manage nonhematologic toxicity resulting from high-dose carboplatin and paclitaxel. The probability of overescalation with a true toxicity in 50% of patients was 24.5%. The probability of erroneous early termination of the study when less than 20% of patients become toxic was 14.5%. Patients were removed from the study if life-threatening or irreversible toxicity occurred.
Supportive Care
Pharmacokinetics Analytic Procedure. Plasma and ultrafiltrate samples were diluted in duplicate with 0.2% nitric acid containing 0.1% (vol/vol) Triton X-100 and injected (20 µL) onto an atomic absorption spectrophotometer 3100 equipped with an HGA 600 graphite furnace (Perkin-Elmer, Norwalk, CT). Platinum content was determined relative to a freshly prepared standard curve for elemental platinum (0.2 to 4.0 ng). Furnace conditions were as previously published.21 Analysis. Carboplatin AUC values were computed by noncompartmental analysis using the program NCOMP.22
Twenty-eight patients were enrolled onto this trial as summarized in Table 2. None of the patients had received prior chemotherapy, although three had received prior pelvic radiation. Nearly one half of the patients had ovarian cancer, reflecting the activity of these drugs in treating this disease and selection priorities at our institution. Four patients did not receive any of the high-dose cycles. Three patients with ovarian cancer, cervical cancer, and adenocarcinoma of unknown primary tumor (one patient each) developed progressive disease, and one patient with small-cell carcinoma of the ovary wished to discontinue study therapy for personal reasons. The remaining 24 patients received 49 courses of high-dose chemotherapy. Two patients received only one cycle because of ototoxicity or progressive disease. Three of five patients received three cycles of high-dose paclitaxel and carboplatin at the maximum-tolerated dose. The other two patients received only two cycles because of insufficient CD34+ cells/kg.
Toxicity During the high-dose carboplatin/paclitaxel cycles, grade 4 myelosuppression was significant but manageable (Table 3). Nadir neutrophil counts remained less than 500/µL for a median of 5 to 7.5 days when analyzed by dose level or cycle number. Nadir platelet counts remained less than 20,000/µL from a median of 0 to 4 days, independent of dose level. There is a suggestion that the platelet nadir was prolonged with the addition of a third cycle at AUC 16; however, the small number of patients treated with three cycles precludes firm conclusions. The median number of units of packed RBCs and platelets per cycle is listed in Table 4.
Nonhematologic toxicity was minimal until the AUC-20 dose level. Only four patients developed peripheral neuropathy (all grade 1), one patient experienced grade 3 nausea/vomiting at AUC 16, and one patient had significant difficulty with hypokalemia at AUC 12. At the AUC-20 dose level, electrolyte imbalances, dehydration, and diarrhea became significant (Table 5). Dehydration resulted from diarrhea that was not responsive to loperamide or diphenoxylate/atropine (Lomotil; G.D. Searle and Co, Chicago, IL). Stomatitis was not evident. Outpatient prophylactic fluid and electrolyte replacement was initiated to decrease the severity of toxicity after hospitalization of the initial patients who received carboplatin AUC 20. However, aggressive outpatient management did not uniformly avoid the need for hospitalization. One of the latter patients received a second cycle at a reduced dose of AUC 16 after experiencing prolonged and profound diarrhea after treatment at AUC 20 that resulted in a long hospitalization (21 days) for toxicity management. The nonhematologic toxicity of an additional cycle of high-dose carboplatin and paclitaxel at a carboplatin dose of AUC 16 was not different from that observed in patients who received only two cycles.
The median length of hospital stay, including treatment days, ranged from 5 to 7.5 days for all high-dose cycles and was similar for the first two dose levels (Table 6). There was a trend toward a longer length of stay of 9 to 10 days at the AUC-20 dose level compared with the lower doses. The third cycle at AUC 16 had a similar length of stay to other cycles at AUC 12 and 16. Reasons for readmission or extending the admission beyond treatment days for the high-dose cycles were neutropenic fever (43%), dehydration with electrolyte disturbance (46%), or deep venous thrombosis (11%). Overall, 28 of 52 high-dose chemotherapy courses (53.8%) required extra hospital days for toxicity management. Eight of 30 courses (29%) for dose levels 12 and 16 and four of 19 courses (21%) for dose level 20 were admitted for neutropenic fever. However, only five of 30 courses (16.7%) at dose levels 12 and 16 resulted in admission as a result of fluid and electrolyte disturbances compared with eight of 19 courses (43%) for dose level 20.
Response
There were 12 women with advanced ovarian cancer, nine of whom were suboptimally debulked or had stage IV disease. The overall response rate was 100% with a complete clinical response rate of 67% in the subset of patients with ovarian cancer. Three patients with a complete clinical response underwent second-look surgery. One patient had a pathologic complete response, and two patients had minimal microscopic residual disease. All the patients with stage IV disease and all but two of the remaining patients with ovarian cancer received an additional three to six cycles of outpatient 3-hour paclitaxel alone after the high-dose study treatment was completed. The median time to progression from the first reinfusion was 49.5 weeks (range, 8 to 156+ weeks) for the overall group and the subset of patients with ovarian cancer (range, 8 to 142+ weeks).
Pharmacokinetics
Prospective randomized trials that examined cisplatin dose-intensity in ovarian cancer have shown that doubling the dose has no impact on disease-free or overall survival.15,16 However, the nonhematologic toxicities of cisplatin prevented significant dose escalation. More recently, two randomized trials on carboplatin dose-intensity also have shown increased toxicity with no improvement in efficacy.17,18 However, in the study by Gore et al,18 the actual delivered carboplatin dose was only 20% higher in the AUC-12 arm compared with the AUC-6 arm because of limited hematopoietic support. Thus, it remains possible that multiple cycles of high-dose chemotherapy with PBSC support may show greater activity with better management of toxicity. Hematopoietic growth factors and autologous PBSCs facilitate the delivery of multiple cycles of such high-dose treatment without increased mortality and only a modest increase in morbidity. Shea et al14 previously reported that patients could receive 1,200 mg/m2 of single-agent carboplatin for three cycles when similarly supported. Using our method of dose calculation, an AUC of 16 on the current trial was equivalent to 1,186 mg/m2. Preliminary data from Shea et al23 using multiple cycles of high-dose carboplatin together with paclitaxel in previously untreated patients established a maximum-tolerated carboplatin dose at AUC 18. The main toxicity was delayed hematologic recovery after the first cycle at AUC 20. Clinically significant neuropathy was observed in one patient each at AUC-12 and AUC-18 doses. Our data, in conjunction with the preliminary data from the trial by Shea et al,23 would suggest that full doses of paclitaxel can be added to three cycles of carboplatin without incurring additional dose-limiting toxicity. Dose-limiting toxicity in our study was not hematologic toxicity, but diarrhea and electrolyte imbalances that required aggressive IV replacement. Peripheral neuropathy was mild and reversible, consistent with the pattern associated with paclitaxel. One patient had reversible ototoxicity. Neutropenic fever was rarely the initial cause of admission at the AUC-20 dose level compared with the lower dose levels, where it is most likely the cause. However, some patients who received AUC 20 developed neutropenic fever while already hospitalized for fluid resuscitation. Only patients treated at the AUC-20 dose of carboplatin required prophylactic aggressive fluid and electrolyte repletion. However, these prophylactic measures were not always adequate to avoid hospital admission for management of these nonhematologic toxicities. Our goal was to develop a safe and tolerable outpatient regimen aside from the actual administration of therapy. Many patients who received carboplatin at the AUC-20 dose level required daily IV fluid treatments. This intensive support often was difficult for patients and family to maintain on an outpatient basis. Therefore, it was determined that a dose of carboplatin at AUC 20 exceeded the maximum-tolerated dose that could be achieved with outpatient management. Thus, we defined the maximum-tolerated dose of carboplatin as AUC 16. Other groups have determined a maximum-tolerated dose for carboplatin in the same range using similar criteria.23,24
The concordance between measured AUC and calculated AUC is confirmed in this trial even at these higher doses, with 57% of the patients receiving an actual AUC that matched or exceeded the target AUC. This observation is contrary to that of Shea et al.23 The measured AUC in their study was consistently half of that predicted for target AUC The combination of paclitaxel/carboplatin is highly active in ovarian and lung cancers. Langer et al12 obtained a 62% response rate in metastatic non–small-cell lung cancer in 53 assessable patients. In the high-dose trial of Shea et al,23 the response rate in non–small-cell lung cancer was 83% (five of six patients). A phase II trial of multiple cycles of high-dose carboplatin and paclitaxel is currently being conducted at Fox Chase Cancer Center in patients with stage III non–small-cell lung cancer before thoracotomy.25 The Cancer and Leukemia Group B have just initiated a similar trial. Bookman et al11 reported a response rate of 75% with a clinical complete response rate of 67% for carboplatin/paclitaxel at conventional doses as front-line therapy in advanced ovarian cancer. In the current trial, 91.6% of the patients with ovarian cancer responded with a clinical complete response rate of 62%. More than 75% of these patients had bulky suboptimal stage III or IV disease. Investigators at Memorial Sloan-Kettering Cancer Center recently published their experience with a similar strategy.24 The regimen consisted of carboplatin (1,000 mg/m2) with paclitaxel (250 mg/m2) approximately every 2 weeks for four cycles or for three cycles plus a cycle of high-dose melphalan. The delivery of multiple cycles of high-dose carboplatin/paclitaxel therapy was feasible, although the clinical outcome for some groups of patients was disappointing. A 55% pathologic complete response rate was observed in patients with optimal disease, but only a 20% pathologic complete response rate was observed in patients who initially had suboptimal disease. The investigators retrospectively calculated a median AUC of 15.29, which is similar to the prospective targeted dose determined to be the maximum-tolerated dose in this trial. In aggregate, the results with high-dose carboplatin and paclitaxel suggest a high level of antitumor activity but no clear indication that high doses of these agents are superior to conventional doses. In most cases, studies that involve patients with ovarian cancer have used high-dose chemotherapy only at relapse or as consolidation after a full course (six cycles) of initial standard-dose chemotherapy.26 Some trials have mixed patients with refractory and sensitive disease or bulky and minimal disease. High-dose chemotherapy is likely to have its greatest impact on minimal disease before the induction of drug resistance. The patients in the present trial were all without prior exposure to chemotherapy. The Norton-Simon model predicts that multiple cycles of chemotherapy are more likely to eradicate residual cancer cells than a single treatment.8 Higher doses also are predicted to produce a greater cell kill than lower doses in responsive disease settings. Thus, the administration of multiple high-dose cycles to previously untreated patients maximizes the likelihood of success. For example, a cure rate of less than 50% is the expected result of a single high-dose chemotherapy application, even in patients with a chemosensitive relapse of non-Hodgkin's lymphoma. Recent data reported by Gianni et al27 demonstrated that patients with previous untreated non-Hodgkin's lymphoma who were treated with high-dose sequential therapy had a superior outcome compared with those treated with a conventional-dose regimen, with disease-free survival rates of 84% versus 49% at 7 years (P < .001) with a median follow-up of 55 months. This trial confirms that multiple cycles of high-dose carboplatin and paclitaxel can be delivered safely. However, growing experience24 (D. Spriggs, personal communication, January 1998) suggests that two to four cycles of high-dose chemotherapy as front-line treatment does not offer any advantage over standard-dose chemotherapy in the treatment of advanced ovarian cancer. Most of the patients with ovarian cancer in this trial had suboptimally debulked disease and were not surgically assessed for response. Although a high clinical response rate and clinical complete response rate were observed, this was similar to the experience with standard-dose carboplatin and paclitaxel.11 The duration of response did not seem any longer than what would be expected from standard-dose chemotherapy. In the trial by Aghajanian et al,24 only a 20% pathologic complete response rate was observed in patients with suboptimally debulked disease compared with 55% in patients with optimally debulked disease. In a GOG pilot trial, a disappointingly low pathologic complete response rate was observed in patients with optimally debulked stage III ovarian cancer after mobilization of PBSCs with high-dose cyclophosphamide and paclitaxel chemotherapy with G-CSF, followed by three cycles of high-dose carboplatin and paclitaxel supported by PBSCs, and then consolidated with a PBSC-supported high-dose melphalan cycle (D. Spriggs, personal communication, January 1998). It is premature to say that this concept of multiple cycles of front-line chemotherapy is not worth further exploration or that the Norton-Simon hypothesis is invalid. Although multiple cycles of high-dose carboplatin and paclitaxel as delivered in this and similar trials has had disappointing results in ovarian cancer, it has been successful in other settings, eg, non-Hodgkin's lymphoma.27 The Norton-Simon hypothesis has been clinically validated in breast cancer.28,29 This approach, and maybe even these drugs, may find greater efficacy in other diseases, such as small-cell carcinoma. The elimination of dose-limiting myelotoxicity by PBSC support permits the development of new high-dose chemotherapy regimens as front-line therapy. It remains to be determined if other multiple-cycle approaches with other doublets or adding agents such as topotecan to high-dose carboplatin and paclitaxel will improve clinical results.
Supported in part by grant no. CA58334-02 from the National Cancer Institute, National Institutes of Health, and by Schering and Immunex Corporations. 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, Josephine Schultz for her superb technical support, and Debbie Kilpatrick, Chris Yeung, Kris Padavic-Shaller, and Eileen Keenan for outstanding data management.
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Mc Guire WP, Hoskins WJ, Brandy MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1-6, 1996 10. Stuart G, Bertelsen K, Mangioni C, et al: Updated analysis shows a highly significant improved overall survival (OS) for cisplatin-paclitaxel as first line treatment of advanced ovarian cancer: Mature results of the EORTC-GCCG, NOCOVA, NCIC CTG and Scottish Intergroup Trial. Proc Am Soc Clin Oncol 17:361a, 1998 (abstr 1394)
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Shea TC, Mason JR, Storniolo AM, et al: Sequential cycles of high-dose carboplatin administered with recombinant human granulocyte-macrophage colony-stimulating factor and repeated infusions of autologous peripheral-blood progenitor cells: A novel and effective method for delivering multiple courses of dose-intensive therapy. J Clin Oncol 10:464-473, 1992
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Schilder RJ, LaCreta FP, Perez RP, et al: Phase I pharmacokinetic study of ormaplatin (Tetraplatin, NSC 363812) administered on a day 1 and day 9 schedule. Cancer Res 54:709-717, 1994 22. Laub PB, Gallo JM NCOMP: A windows-based computer program for noncompartmental analysis of pharmacokinetic data. J Pharm Sci 85:393-395, 1996[Medline] 23. Shea TC, Graham M, Bernard S, et al: A clinical and pharmacokinetic study of high-dose carboplatin, paclitaxel, granulocyte colony-stimulating factor, and peripheral blood stem cells in patients with unresectable or metastatic cancer. Semin Oncol 22:80-85, 1995 (suppl 12) 24. Aghajanian C, Fennelly D, Shapiro F, et al: Phase II study of "dose-dense" high-dose chemotherapy treatment with peripheral-blood progenitor-cell support as primary treatment for patients with advanced ovarian cancer. J Clin Oncol 16:1852-1860, 1998[Abstract] 25. Schilder RJ, Goldberg M, Rogers B, et al: Phase II trial of high-dose induction chemotherapy in patients (pts) with stage IIIA non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 16:481a, 1997 (abstr 1732) 26. Viens P, Maraninchi D: High-dose chemotherapy and autologous marrow transplantation for common epithelial ovarian carcinoma, in Armitage JO, Antman KH (eds): High-Dose Cancer Therapy (ed 2). Baltimore, MD, Williams & Wilkins, 1995, pp 847-854
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
). The mean (•) ± SD (bars) for each dose level is indicated. Median values are indicated numerically.
