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The Oncologist, Vol. 10, No. 2, 138-149, February 2005; doi:10.1634/theoncologist.10-2-138
© 2005 AlphaMed Press

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Increasing Chemotherapy Dose Density and Intensity: Phase I Trials in Non-Small Cell Lung Cancer and Non-Hodgkin’s Lymphoma

Douglas W. Blayneya, Brian W. McGuireb, Scott E. Cruickshankb, David H. Johnsonc

a Wilshire Oncology Medical Group, Inc., Pasadena, California, USA; b Department of Medical Affairs, Amgen Inc., Thousand Oaks, California, USA; c Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA

Correspondence: Douglas W. Blayney, M.D., University of Michigan Comprehensive Cancer Center, C365 Med Inn Building, Ann Arbor, Michigan 48109-0848, USA. Telephone: 734-615-7228; Fax: 734-615-2109; e-mail: dblayney{at}med.umich.edu


   ABSTRACT
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 Additional Reading
 
Dose densification and dose escalation of cytotoxic chemotherapy may be important in improving the cure rates of chemotherapy-responsive cancers. We conducted two phase I studies, in non-small cell lung cancer (NSCLC) and in lymphoma, to explore the possibility of intensifying chemotherapy by compressing the delivery of and escalating the dose of standard combination chemotherapy. One study used etoposide and cisplatin chemotherapy in patients with unresectable stage III or IV NSCLC, intensifying chemotherapy by reducing the cycle length. The second study used cyclophosphamide, doxorubicin, vincristine, and prednisone, CHOP chemotherapy, in the treatment of stage II–IV intermediate or immunoblastic high-grade lymphoma, intensifying chemotherapy first by reducing the cycle length and then by escalating the dosages of cyclophosphamide and doxorubicin. Filgrastim support was used during dose intensification. Fifty-five patients with NSCLC and 49 with non-Hodgkin’s lymphoma (NHL) were enrolled and treated in successive cohorts. At standard dosages and intervals of chemotherapy, filgrastim support resulted in incidences of grade 3 and 4 neutropenia that were between 62% and 77% lower than those in the no-filgrastim control; the mean duration of neutropenia was, likewise, more than 80% lower. Absolute neutrophil counts were ≥2 x 109/l at day 14 in virtually 100% of patients receiving filgrastim. In the NSCLC trial, etoposide and cisplatin were intensified by >50%, and in the lymphoma trial, cyclophosphamide was intensified by 270% and doxorubicin was intensified by 87%. Chemotherapy reductions or delays for neutropenia were rare in the groups receiving filgrastim; but at higher chemotherapy intensities, dose-limiting thrombocytopenia was encountered. We conclude that the delivery of myelosuppressive chemotherapy in both a dose-intense and a dose-dense manner is feasible with filgrastim support.

Key Words. Chemotherapy • Neutropenia • Non-small cell lung carcinoma • Non-Hodgkin’s lymphoma • Drug dose-response relationships • Filgrastim


   INTRODUCTION
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 Additional Reading
 
The principle of increasing dose intensity (DI) in the treatment of human malignancies has been under investigation for over two decades [1]. DI is typically expressed as the amount of the chemotherapeutic agent (in mg) divided by the size of the patient (in m2 of body surface area) per period of time (in weeks) over which the treatment is given, referenced against a standard regimen [2]. Standard methods for calculating and analyzing DI have been published [3, 4] and are widely accepted. The DI of a chemotherapy regimen may be modified by increasing the quantity of the drug(s) in the chemotherapy regimen (dose escalation) and/or by decreasing the interval between successive treatments (increasing dose density). The most promising settings for increasing the dose density and intensity are in the curative treatment of lymphoma, breast cancer, and testicular cancer.

The potential success of dose-intense approaches to chemotherapy is predicted by mathematical modeling. The Norton-Simon hypothesis of tumor growth predicts the effects of decreasing the chemotherapy dosing interval and increasing the chemotherapy dose [5]. Smaller tumors grow faster than larger ones and thus have a greater proportion of cells undergoing mitosis. These fast-growing tumors should be more susceptible to cytotoxic chemotherapy. As the tumor becomes smaller, the hypothesis predicts a higher proportion of malignant cells susceptible to killing [5]. The rationale for increasing dose density is to limit the degree of tumor cell regrowth between cycles of chemotherapy; the rationale for dose escalation is to achieve the highest possible percentage of tumor cell kill with each application of cytotoxic chemotherapy.

Retrospective analyses of clinical trials demonstrated that relative DI (i.e., the DI that was delivered compared with the intended DI) was an important prognostic factor for survival in diffuse large cell lymphoma treated with multidrug regimens [6–8]. In particular, a high DI during the initial cycles of cyclophosphamide, doxorubicin (Adriamycin®; Bedford Laboratories; Bedford, OH), vincristine (Oncovin®; Eli Lilly and Company; Indianapolis, IN), and prednisone (Deltasone®; Pfizer Pharmaceuticals; New York, NY) (CHOP) chemotherapy had a positive impact on survival [6]. Dose intensification approaches in lymphoma, with support from autologous stem cells, have shown promise in increasing the long-term remission rate [9, 10]. Two studies of dose-dense chemotherapy have shown longer survival compared with historical controls [11] or a retrospectively defined subset of patients [12]. Prospective testing in randomized clinical trials is under way.

Recent observations in breast cancer—that increasing dose density was important [13], whereas dose escalation (i.e., with stem cell support) had not improved survival in minimal disease settings—revived interest in the question of DI. Because dose density is likely to be tested in diseases other than breast cancer, we think it is important to have detailed information on the phase I dose escalation trials in lung cancer and in lymphoma, both of which tested chemotherapy agents that are active in many tumor types. Preliminary reports of these trials have been presented [14, 15]. Here we report carefully characterized hematologic profiles of patient cohorts receiving both intensified and standard cycles of chemotherapy with and without filgrastim (Neupogen®; Amgen Inc.; Thousand Oaks, CA) support. These trials demonstrate the ability of filgrastim to facilitate both dose-dense chemotherapy and dose-escalated chemotherapy. We also characterize the nonmyeloid toxicities that have the potential of becoming dose limiting once neutropenia is ameliorated.


   PATIENTS AND METHODS
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 Additional Reading
 
Study Population
Patients eligible for the non-small cell lung cancer (NSCLC) trial had histologically confirmed unresectable stage IIIA, IIIB, or IV disease without prior chemotherapy and with at least one evaluable lesion. Patients eligible for the non-Hodgkin’s lymphoma (NHL) trial had newly diagnosed and histologically confirmed Ann Arbor stage II–IV intermediate or immunoblastic high-grade malignant lymphoma without prior chemotherapy or radiotherapy. Patients in both trials had to be at least 18 years of age with a Karnofsky performance status score of 60 or higher and with adequate organ function, adequate hematologic status (absolute neutrophil count [ANC] ≥2 x 109/l, platelets ≥100 x 109/l, and hemoglobin ≥9 g/dl), no major surgery within 2 weeks of study entry, and no active uncontrolled infection.

Study Designs and Treatment
The NSCLC trial delivered conventional dosages of etoposide (VePesid®; Bristol-Myers Squibb; Princeton, NJ) and cisplatin (Platinol®; Bristol-Myers Squibb) chemotherapy. The first cohort served as a comparative group and received a 21-day cycle of chemotherapy without filgrastim. The next sequential cohort of patients received 21-day cycles with adjunctive filgrastim in each cycle, and a third cohort received 14-day cycles with filgrastim. Etoposide was given at a dose of 120 mg/m2 on days 1–3 and cisplatin was given at a dose of 60 mg/m2 on day 1 in all cohorts. Patients received a maximum of six cycles at their assigned chemotherapy schedule. The basic elements of the study designs are summarized in Table 1Go.


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  		Table 1. Summary of study designs
 
The NHL trial, performed using CHOP chemotherapy, also intensified chemotherapy in sequentially treated cohorts of patients. The first cohort was treated with standard chemotherapy doses every 21 days, and the second cohort had a shorter cycle length—of 14 rather than 21 days—at the same doses of chemotherapy. In subsequent cohorts, the dosages of cyclophosphamide and doxorubicin were escalated in a 14-day cycle, all with adjunctive filgrastim (Table 1Go). In the initial cohorts, chemotherapy was administered as follows: cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), and vincristine (1.4 mg/m2) were all given on day 1, and prednisone (100 mg) was given on days 1–5. In subsequent cohorts, cyclophosphamide and doxorubicin were both sequentially escalated in dosage to maximums of 2,000 mg/m2 and 65 mg/m2, respectively, within a 14-day cycle; the vincristine and prednisone doses were not altered. Patients received up to six cycles at their assigned chemotherapy dose and schedule.

Filgrastim administration was planned to start 24 hours after the previous dose of chemotherapy (i.e., starting on day 4 for the NSCLC trial and on day 2 for the NHL trial), at 5 µg/kg/day by s.c. injection, and to be continued through a postnadir ANC ≥10 x 109/l. In the 14-day cycles, however, filgrastim was to be stopped on or before day 14 in order to maintain a 24-hour interval between the last filgrastim dose and the next dose of chemotherapy.

In both trials, chemotherapy cycles were delayed in the event of unresolved hematologic or nonhematologic toxicities. No dose reduction was implemented in the event of hematologic toxicity in the previous cycle, but for grade 4 nonhematologic toxicities, patients were given a 25% chemotherapy dose reduction in the next cycle (or were reassigned to the next lower dosage cohort in the dose-escalation NHL trial).

The study protocols were reviewed and approved by the institutional review board at each study site, and written informed consent was obtained from each patient before enrollment. The study was designed by Amgen in collaboration with the authors. The complete data set was held at the central data processing facility at Amgen. Statistical analyses and data interpretation were conducted by Amgen in collaboration primarily with Drs. Blayney and McGuire. The investigators had unrestricted access to the primary data and were not limited by the sponsor with regard to statements made in the final article. The lead investigator was responsible for writing the article, with editorial assistance from Amgen.

Study Observations
Study tests and observations were identical in the two studies. Blood counts (WBC with complete manual differential, platelets, hemoglobin, and hematocrit) were performed three times per week throughout the study. Physical examinations and blood chemistries were performed once per cycle, and concomitant medications and adverse events were assessed continually throughout the study. Disease evaluation was performed prestudy, every other cycle, and at completion or premature study removal.

Statistical Analysis
End points of both trials included incidence and duration of grade 3 (ANC < 1.0 x 109/l) and grade 4 (ANC < 0.5 x 109/l) neutropenia, identification of the maximum achieved dose intensity of chemotherapy, and dose-limiting toxicities.

Descriptive statistics were prepared for demographic and other baseline characteristics. Categorical variables were summarized by number and percent, and continuous variables by mean and standard deviation (SD), median, and range. For proportions, percentages and 95% confidence intervals (CIs) were generated. Daily ANC values were derived from actual ANC observations and interpolation (linear regression between two nonmissing data points), from which the duration of neutropenia was calculated. Results were assessed within cohorts by cycle and across cycles. Duration of hospitalization was calculated as the number of days between admission and discharge inclusive, unless they were the same day, in which case the duration was considered to be 0. Cumulative days of hospitalization across all cycles were summed for each patient, and cohort means were calculated.

For the dose-intensity analysis, cumulative dosages per unit time of the intensified drugs in the regimen (both etoposide and cisplatin for the NSCLC trial and cyclophosphamide and doxorubicin for the NHL trial) were individually expressed as mg/m2/week for each patient [3, 4] across all delivered cycles as follows:


This equation can be applied to each cytotoxic drug in a multidrug regimen. The actual dose delivered (as opposed to the intended dose) was used in order to account for chemotherapy dose reductions. The denominator was based on total days on treatment (from day 1 of cycle 1 through one cycle length after the date of the last chemotherapy treatment) and thus reflected all dose delays. Calculated dose intensities were then averaged across the patients in that cohort. Further, the relative dose intensity was expressed as the dose delivered divided by the dose intensity of the standard regimen. For example, in the standard CHOP regimen, cyclophosphamide was given at a dose intensity of 750 mg/m2/3 weeks or 250 mg/m2/week and doxorubicin was given at a dose intensity of 45 mg/m2/3 weeks or 15 mg/m2/week.


   RESULTS
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 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 Additional Reading
 
Patient Characteristics
Patient enrollment into these studies took place from April 1991 to February 1993. In the NSCLC trial, a total of 55 patients was sequentially assigned to one of three cohorts. Nine patients received a conventional every-21-day regimen of etoposide plus cisplatin without filgrastim (control), 24 received the same regimen with filgrastim (standard), and 22 received an accelerated 14-day regimen with filgrastim (dense). In the NHL trial, in which 49 patients were treated, five received a conventional every-21-day regimen of CHOP without filgrastim (control), 10 received the same 21-day regimen with filgrastim (standard), and 10 received an accelerated 14-day regimen with filgrastim (dense). Following this, four additional cohorts received sequentially escalated dosages of cyclophosphamide and/or doxorubicin in a 14-day regimen. Of the latter cohorts, results are presented only for the seven patients treated at the highest chemotherapy dosage level (intensified) and not for the intermediate levels.

The demographic profiles in each study are shown in Table 2Go and are representative of those commonly encountered in clinical trials. In both trials, the median age was in the 50s and most patients were male. Most patients had advanced disease, all had received surgical resection, and few had received previous radiation or chemotherapy.


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  		Table 2. Patient characteristics
 
Chemotherapy Dose Delivery
In the NSCLC trial, a comparison of the control (without filgrastim) with the standard (with filgrastim) cohort shows that the proportion of cycles that were delayed was lower with filgrastim (12%) than without filgrastim (38%), and the proportion of cycles that had a reduction in chemotherapy dose was also lower—3% in the standard cohort versus 12% in the control cohort (Table 3Go). In the control group, most delays and reductions (35% of total cycles) were for neutropenia and related complications. With filgrastim (standard), there were proportionally fewer, with only 3% of cycles delayed or reduced for neutropenia-related events. The shorter cycle length of 14 days (dense cohort) did not result in a higher proportion of cycles that were delayed or reduced. However, thrombocytopenia emerged as the most common reason for interrupted or reduced chemotherapy. The shorter cycle length allowed for greater dose intensities of etoposide and cisplatin, by 57% and 55%, respectively, of an intended 50%, in the dense cohort relative to the control cohort (Fig. 1Go).


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  		Table 3. Dose reductions and delays
 


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  		Figure 1. Planned versus delivered DIs in the NSCLC trial for etoposide (A) and cisplatin (B).

 
In the NHL trial, the proportions of cycles delayed or reduced in the conventional chemotherapy cohorts (control and standard) were lower, making it difficult to discern trends (Table 3Go). Most dose reductions and delays in these cohorts were for nonhematologic toxicities and nonmedical reasons (dosing error, scheduling issues, etc.). The only notable trend in this trial was a higher incidence of dose-limiting thrombocytopenia seen in the intensified cohort, in which cyclophosphamide was delivered at a dose of 2,000 mg/m2, doxorubicin was administered at a dose of 65 mg/m2, and the cycle length was 14 days. Through escalating the chemotherapy dose and shortening the cycle length, a 268% intensification of cyclophosphamide was achieved, with a mean delivered DI of 241 mg/m2/week in the control cohort and a mean delivered DI of 889 mg/m2/week, of an intended 1,000 mg/m2/week, in the intensified cohort (Fig. 2Go).



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  		Figure 2. Planned versus delivered DIs in the NHL trial for cyclophosphamide (A) and doxorubicin (B). One patient in the standard cohort was excluded from the DI analysis due to miscalculation of chemotherapy dose (50% of the per-protocol dosage) in every cycle.

 
Filgrastim Dosing
In the standard cohorts of the two trials, the mean durations per cycle of filgrastim administration were 11.7 days (NSCLC) and 12.4 days (NHL), which closely approximate the durations seen in other studies [16, 17]. For the dense cycles in the NSCLC trial, the mean duration was less (10.5 days) due to the constraints of cycle length and the 3 days of chemotherapy administration (necessitating start of filgrastim at day 4). The mean filgrastim dosing duration was greatest (13.0 days) in the intensified cohort of the NHL trial, in which patients were given escalated chemotherapy in addition to a 14-day cycle length.

Neutropenia
Results from both trials illustrate the effects of filgrastim on the incidence and duration of neutropenia within a standard dose and schedule of chemotherapy. Comparing the conventional every-21-day regimens with and without filgrastim (standard versus control), the incidences of both grade 3 and 4 neutropenia were between 62% and 77% lower in both trials in the standard cohort versus the control cohort (Fig. 3Go and Fig. 4Go). Similarly, the mean duration of grade 3 and 4 neutropenia was between 81% and 94% lower with filgrastim.



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  		Figure 3. A) Incidence of grade 3 or higher neutropenia across cycles for the NSCLC trial. Error bars indicate 95% CI. B) Duration of grade 3 or higher neutropenia. Error bars indicate standard deviation.

 


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  		Figure 4. A) Incidence of grade 3 or higher neutropenia across cycles for the NHL trial. Error bars indicate 95% CI. B) Duration of grade 3 or higher neutropenia. Error bars indicate standard deviation.

 
Patients experienced brief ANC nadirs and rapid ANC recoveries with filgrastim. Table 4Go shows, for the conventional every-21-day cycles of each trial, the median cycle day on which the ANC nadir occurred and the proportion of patients whose ANC had recovered to 2 x 109/l or more by day 14. In the NSCLC trial, the nadir occurred sooner in the standard (with filgrastim) cohort, at a median of day 11, versus a median of day 18 in the control (without filgrastim) cohort. A similar phenomenon occurred in the NHL trial. In the NSCLC trial, the proportions of cycles with an ANC of 2 x 109/l or more at day 14 were 99% versus 19% for the standard and control cohorts, respectively; in the NHL trial, the proportions were 100% and 0% of cycles, respectively.


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  		Table 4. ANC nadir and day 14 recovery
 
Neutrophil variables are also provided for the patients who received the every-14-day chemotherapy cycles with filgrastim. In the NSCLC trial, the incidence and duration of neutropenia in the every-14-day cycles were similar to those seen in the every-21-day cycles with filgrastim (Fig. 3Go). Despite the higher incidence and duration of neutropenia seen in the NHL trial with the 14-day cycle (Fig. 4Go), in virtually all cycles of both trials, the ANC had recovered by day 14 (Table 4Go).

Figure 5Go provides median ANC profiles for cycle 1 of the NSCLC and NHL trials, showing the conventional 21-day cycles without and with filgrastim, and the superimposed 14-day cycles; both illustrate successful ANC recovery during the delivery of dose-dense chemotherapy.



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  		Figure 5. Median ANC profile on log scale for cycle 1 from the NSCLC trial (A) and NHL trial (B). Error bars indicate interquartile ranges.

 
Substantial intensification was achieved in the intensified cohort of the NHL trial with the sequential escalation of chemotherapy in addition to the shorter cycle length, with cyclophosphamide dosage increased from 750 to 2,000 mg/m2 and doxorubicin from 50 to 65 mg/m2. In this cohort, grade 4 neutropenia was universal, and the duration of grade 4 neutropenia was longer than that seen in the control (Fig. 4Go). Nevertheless, by day 14, patients’ ANCs had recovered to ≥2 x 109/l, and thus, they were eligible for their next cycle of chemotherapy (Table 4Go).

In the cohorts receiving filgrastim, the highest incidence and the longest mean durations of neutropenia were seen in cycle 1 (Fig. 6Go), after which, both the incidence and mean duration of neutropenia decreased successively to 0 in later cycles. The shorter cycle length of 14 days had little impact on these variables; both the incidence and the mean duration of neutropenia in the dense cohort showed successive decreases through the six cycles. For the control cohort (no filgrastim), the incidence and mean duration both remained high throughout all cycles.



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  		Figure 6. Incidence (A) and duration (B) of grade 3 or higher neutropenia by cycle for the NSCLC trial.

 
Toxicity
The shorter cycle length of 14 days did not appear to result in higher incidences of severe nonhematologic toxicities in either the NSCLC or NHL trials (Table 5Go). However, in the intensified cohort of the NHL trial, there was some evidence that fever, fatigue, nausea, and vomiting occurred in a greater proportion of these patients.


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  		Table 5. Severe or greater clinical adverse events that occurred at an incidence ≥5% of the population
 
In the NSCLC trial, the rate of grade 4 thrombocytopenia was not higher in the 14-day cycle than in the 21-day cycle (Table 6Go). However, as indicated above, more patients in the dense cohort received a dose reduction or delay (Table 3Go) due to the end-of-cycle platelet count, which, per protocol, had to be at least 90 x 109/l in order for the next cycle of chemotherapy to be given. In the NHL trial, the rates of grade 4 thrombocytopenia were 20% in the dense cohort and 86% in the intensified cohort; the proportion of cycles (13%) delayed or reduced for platelet counts was also higher (Table 3Go). Platelet transfusions reflected the rate of grade 4 thrombocytopenia.


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  		Table 6. Summary of supportive care requirements
 
At standard doses of chemotherapy, the incidence and severity of anemia were higher in the NSCLC trial than in the NHL trial (Table 6Go), due presumably to the platinumcontaining regimen employed in the former. The shorter 14-day cycle in the NSCLC study had no measurable impact on anemia requiring red blood cell transfusions (grade 3, <8 g/dl). In the NHL trial, anemia was less prevalent at standard intensities of chemotherapy. However, increasing the density of chemotherapy and escalating the dosage were both associated with a higher incidence of grade 3 anemia (71%) and a higher proportion of patients receiving transfusions (100%).

The mean total days in the hospital in the NHL trial increased as chemotherapy was intensified (Table 6Go), with a mean of 4.7 days in the standard cohort and a mean of 18.6 days in the intensified cohort.

Four patients were removed from the NSCLC trial due to chemotherapy-related toxicities: one patient in the control cohort for respiratory distress, one patient in the standard cohort for acute respiratory reaction, and two patients in the dense cohort for renal toxicity and shortness of breath with facial flushing. Three of the 55 total patients died on study: two in the control cohort (both of sepsis and one additionally with congestive heart failure) and one in the standard cohort (disease progression). In the NHL trial, three patients in one of the four dose-escalation cohorts were removed from study because of toxicities: lung abscess and sepsis, pancytopenia, and hemorrhagic cystitis. Two of the 49 total patients died on study: one in the standard cohort, of sepsis and respiratory failure, and one in a dose-escalation cohort, of cardiopulmonary arrest.

Disease Outcome
Across all NSCLC cohorts, a complete or partial response was seen in 27% of patients (95% CI = 16%–41%). In the NHL trial, the overall response rate was 88% (95% CI = 75%–95%), with 44% (95% CI = 29%–59%) being complete responses. These studies were not designed to measure differences in response rates or survival among cohorts.


   DISCUSSION
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 Additional Reading
 
Results of this phase I dose-intensification study showed that, in NSCLC using etoposide and cisplatin chemotherapy and in NHL using CHOP chemotherapy, dose intensification is possible, by both reducing the length of each cycle and escalating the dose of chemotherapy administered within a cycle. The three-times-weekly blood count monitoring enabled sensitive detection of neutropenia incidence and accurate calculation of its duration. Additionally, the neutropenia that was observed in comparative cohorts (not given filgrastim) demonstrates the challenges inherent in chemotherapy intensification without adjunctive growth factor support.

Neutropenia was most severe in cycle 1 of all cohorts in both studies. In the control cohorts without filgrastim, there was little change in incidence or duration in subsequent chemotherapy cycles. However, in both the NSCLC and NHL trials, cohorts receiving filgrastim demonstrated successive decreases in both incidence and duration of neutropenia. These observed reductions in subsequent cycles cannot be explained by patient attrition, but may be accounted for by a "priming" effect of filgrastim, which has been observed previously [18, 19]. Across all cycles, the incidence of neutropenia with filgrastim administration decreased by approximately 75%, and the mean duration of neutropenia decreased by up to 90%. Recovery of ANC to ≥2 x 109/l by day 14 occurred in 99% of patient cycles with filgrastim, making a 14-day cycle length feasible.

Thrombocytopenia was dose limiting in the 14-day (dense) cohorts. As chemotherapy dosage was escalated in the CHOP regimen for NHL, the incidence of neutropenia rose, but was seldom of a duration that was dose limiting. At higher doses of chemotherapy, thrombocytopenia emerged as a cause for delays and reductions, and nonhematologic toxicities were encountered more often.

The relatively small size of the cohorts in these pilot studies precludes any meaningful comment on clinical outcome. The overall response rates seen in both trials, however, were in the range of what would be expected for these patient populations. In the NHL trial, the high complete response rate seen in the intensified cohort was consistent with the high proportion alive without disease at 6 months (100%). The important finding in these pilot trials, however, was the demonstration that preemptive filgrastim administration permitted a shortening of cycle length in two chemotherapy settings, with neutropenia effectively removed as a trigger for chemotherapy delays and reductions.

Using filgrastim support, other clinical investigators successfully intensified CHOP chemotherapy by reducing cycle length from 21 days to 15 days, and again to 10 days [20]. They concluded that the 15-day schedule was the most acceptable due to emergent nonhematologic toxicities (especially mucositis) and infections encountered in the 10-day cohort. We noted no greater incidences of mucositis in our dose-dense cycles, but we did encounter a higher incidence of mild-to-moderate mucositis when chemotherapy was escalated in the NHL trial (data not shown). Only one patient experienced severe mucositis in our trials.

The Southwest Oncology Group (SWOG) recently reported the long-term results from their trial of dose-intensified CHOP with filgrastim support [11], for which the NHL trial in our report was the phase I dose-finding study. The SWOG study selected the sixth cohort from this trial (cyclophosphamide at a dose of 1,600 mg/m2 and doxorubicin at a dose of 65 mg/m2, with vincristine given at a dose of 1.4 mg/m2 and prednisone given at a dose of 100 mg x 5 in a 14-day cycle, or CHOP-DI) to take into a larger phase II setting of 103 patients with intermediate- or high-grade lymphoma. Although the 2-year progression-free survival rate estimate of 51% in 88 evaluable patients did not reach the desired target of 60%, the 5-year overall survival rate estimate of 60% was significantly better than the 46% rate observed in a previous SWOG trial of a conventional CHOP regimen [21]. Rates of grade 3–4 hematologic toxicities were 92% for granulocytopenia, 57% for anemia, and 42% for thrombocytopenia. Importantly, that trial demonstrated the feasibility of a dose-dense CHOP regimen in a cooperative group setting and provided promising long-term outcome data on which future randomized trials could be based.

A large randomized trial in a similar NHL setting that contained additional promising results in disease outcome using dose-dense chemotherapy approaches was recently published. The German High-grade Non-Hodgkin’s Lymphoma Study Group [22–24] performed a four-treatment comparison that intensified CHOP chemotherapy by the addition of etoposide (CHOEP) and by decreasing cycle length from 21 days (without filgrastim) to 14 days (with filgrastim). In patients greater than 60 years of age, cycle shortening (CHOP-14) had a more favorable impact on complete response (CR) rate, time to treatment failure, and overall survival, than did the inclusion of etoposide [22]. Attempting both (CHOEP-14) compromised the average relative DI. Patients less than 60 years of age were able to tolerate all four regimens relatively equally (average relative DIs >95%) [23]. In this subset of patients, the etoposide-containing regimens were superior in terms of CR rate, time to treatment failure, and overall survival. The highest CR rates were seen in the CHOEP-14 regimen. Across all cohorts, the etoposide caused some chemotherapy dose erosion, while CHOP-14 and CHOP-21 were equally well tolerated.

Additional studies are under way to document the potential benefits of increasing DI on disease outcome. Quality-of-life considerations should not be ignored. A rapid completion of therapy would be perceived as desirable to many patients. Dose-dense therapy combined with higher-than-conventional doses of the component drugs has theoretical promise and has been shown to be technically feasible. However, such intensification must be balanced by the possibility of more severe nonhematologic toxicities and of nonneutropenic dose-limiting myelosuppression (namely, anemia and thrombocytopenia).

The two trials we present demonstrate the capacity for considerable intensification over conventional chemotherapy regimens using both dose densification and dose escalation with filgrastim support. In the absence of filgrastim, only a small proportion of patients’ ANCs had recovered by day 14 in the two settings studied. With adjunctive filgrastim in each cycle, this proportion was virtually 100%. Given these observations, we conclude that dose-dense approaches to chemotherapy are feasible only with adjunctive growth factor support.


   ACKNOWLEDGMENT
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 Additional Reading
 
The authors thank the principal investigators, study coordinators, and patients at each of the participating institutions. Richard Erwin and Melody Wyres monitored and managed the trials.

The trials in this manuscript were presented previously [14, 15, 25]. These studies were supported by Amgen Inc.

Douglas Blayney has received honoraria from, and has received a grant from Amgen. Brian McGuire is a former employee, a current consultant, and a stockholder of Amgen. Scott Cruickshank is a consultant, former employee, and stockholder of Amgen. David Johnson is a stockholder of Amgen.


   REFERENCES
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
Additional Reading
 

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   ADDITIONAL READING
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 Additional Reading
 
    Ozer H, Armitage JO, Bennett CL et al. 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. J Clin Oncol 2000;18:3558–3585.[Free Full Text]

    Milpied N, Deconinck E, Gaillard F et al. Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. N Engl J Med 2004;350:1287–1295.

    Rigas JR. Taxane-platinum combinations in advanced non-small cell lung cancer: a review. The Oncologist 2004;9:16–23.[Abstract/Free Full Text]

Received March 8, 2004; accepted for publication October 6, 2004.




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