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Journal of Clinical Oncology, Vol 18, Issue 24 (December), 2000: 4028-4037
© 2000 American Society for Clinical Oncology

Received Dose and Dose-Intensity of Chemotherapy and Outcome in Nonmetastatic Extremity Osteosarcoma

By Ian J. Lewis, Simon Weeden, David Machin, Dan Stark, Alan W. Craft, for the European Osteosarcoma Intergroup

From the St James’s University Hospital, Leeds; Cancer Division, Medical Research Council Clinical Trials Unit, London; and Department of Child Health, University of Newcastle upon Tyne, Newcastle upon Tyne; and United Kingdom Children’s Cancer Study Group, University of Leicester, Leicester, United Kingdom.

Address reprint requests to Simon Weeden, MSc, Cancer Division, Medical Research Council Clinical Trials Unit, 222 Euston Rd, London NW1 2DA, United Kingdom; email sw{at}ctu.mrc.ac.uk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To examine the relationship between received dose, received dose-intensity (RDI), and survival in patients with osteosarcoma.

PATIENTS AND METHODS: Between 1983 and 1993, the European Osteosarcoma Intergroup (EOI) conducted two randomized trials involving patients with high-grade, nonmetastatic, biopsy-proven osteosarcoma of the extremity. These trials shared a common treatment arm of doxorubicin (DOX) 75 mg/m2 and cisplatin (CDDP) 100 mg/m2 planned for six cycles at 3-week intervals. Definitive surgery was scheduled at week 9, after three cycles. Survival time was calculated from 122 days, the scheduled end of chemotherapy.

RESULTS: A total of 287 patients randomized to DOX/CDDP received at least one cycle of chemotherapy, and 232 (81%) received all six cycles. On average, 79% of the intended dose of DOX and 80% of the intended dose of CDDP was given. Mean time to completion of chemotherapy was 1.27 times that specified by the protocol. Mean RDI was 0.64 for DOX (SD = 0.19) and 0.65 for CDDP (SD = 0.18). Progression-free survival was lower for those who received one to five cycles compared with those who completed all six cycles (hazards ratio, 1.69; 95% confidence interval, 1.03 to 2.78). Survival and progression-free survival were lowest for patients with RDI less than 0.6, although these differences were not statistically significant at the 5% level. There was no clear evidence of preoperative dose or dose-intensity influencing histologic response.

CONCLUSION: This analysis did not establish a clear survival benefit for increasing received dose or dose-intensity in the context of this two-drug regimen. The hypothesis that increasing dose-intensity may improve survival in osteosarcoma requires prospective evaluation.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BEFORE THE introduction of adjuvant chemotherapy, the 5-year survival rate for patients with operable osteosarcoma, using amputation alone, was less than 20%.1 Early European studies of adjuvant chemotherapy using cautious dosing strategies demonstrated little improvement over historical data.2,3 However, the introduction of adjuvant and neoadjuvant chemotherapy in the context of more intensive multiagent schedules has led to 5-year survival in excess of 50%.4-7

Pharmacologic principles, animal studies,8 and mathematic modelling9 have suggested an important theoretic role for the amount and intensity of chemotherapy delivery. A number of studies in various adult and childhood malignancies have supported these hypotheses and indicated that dose-intensity of chemotherapy may be important in determining survival. Retrospective studies in breast cancer,10,11 Hodgkin’s lymphoma,12 non-Hodgkin’s lymphoma,13,14 and neuroblastoma15 have shown a positive association between planned dose-intensity and survival. More recently, the absence of convincing prospective data supporting the role of dose-intensity has been highlighted and the hypothesis challenged.16

Several retrospective studies have addressed the potential role of dose-intensity in osteosarcoma. Smith et al17 looked at 16 studies and found that doxorubicin (DOX) intensity was an important determinant for outcome as defined by tumour necrosis, with probable additional dose-related roles for cisplatin (CDDP), high-dose methotrexate (HDMTX), and ifosfamide. Delepine et al18 analyzed 30 studies in which HDMTX had been incorporated into the schedule. They reported a strong association between dose-intensity of HDMTX and disease-free survival. They also concluded that no other drug dose or dose-intensity had as important an influence on outcome. Bacci et al19 have suggested that DOX dose was the most important drug component in determining outcome. A more recent article from the same group20 concluded that MTX serum peak level significantly influenced percentage tumor necrosis.

The majority of these retrospective studies have reported on comparisons between intended, as opposed to received, dose schedules from different trials. The purpose of this article is to review the information available on received as opposed to intended dose-intensity from two completed randomized trials of the European Osteosarcoma Intergroup (EOI) in patients with nonmetastatic limb osteosarcoma.21,22 These trials have used a common 18-week regimen consisting of DOX and CDDP and have produced long-term results comparable to those achieved by longer and more complex multiagent regimens when given in a multi-institutional setting.

The EOI consists of the Bone Sarcoma Working Party of the United Kingdom Medical Research Council, the United Kingdom Children’s Cancer Study Group, the Société Internationale d’Oncologie Paedriatrique, and the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Between July 1983 and February 1993, the EOI conducted two randomized trials for patients with osteosarcoma. The first trial (EOI BO02/80831) compared DOX 75 mg/m2 and CDDP 100 mg/m2 to be given every 3 weeks for six cycles with essentially the same schedule of DOX/CDDP but preceded 10 days earlier by HDMTX 8 g/m2 administered as a 6-hour infusion every 4.5 weeks for four cycles. The second trial (EOI BO03/80861) compared DOX/CDDP given every 3 weeks for six cycles with a multidrug schedule based on the Rosen T10 regimen.23 Patients in both trials included those with biopsy-proven high-grade nonmetastatic operable osteosarcoma of the extremity, age <= 40 years, who had not had definitive surgery for their disease. More precise details of the eligibility criteria, therapeutic regimens, and clinical outcome are given in the corresponding publications.21,22 For the purposes of this study, patients were included if they received at least one cycle of chemotherapy.

Treatment Regimen
The regimen common to both trials combined DOX 75 mg/m2 (25 mg/m2/d for 3 days) with CDDP 100 mg/m2 given as a 24-hour infusion together with a recommended hydration schedule. Cycles were scheduled to commence every 3 weeks. Surgery was recommended at week 9 after three cycles of chemotherapy (Fig 1), and this was followed by three further cycles of chemotherapy.



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  		Fig 1. The DOX/CDDP regimen and timing of surgery

 
Advised Dose Reduction and Delay
The doses of DOX and CDDP were to be reduced in subsequent cycles by 15% for World Health Organization grade 3 hematologic toxicity (nadir WBC count of 1.0 to 2.0 x 109/L and/or platelets 25 to 50 x 109/L) and by 30% for grade 4 toxicity (nadir WBC count of <= 1.0 x 109/L and/or platelets <= 25 x 109/L), including serious infection or bleeding. In addition, DOX was to be reduced by 20% for grade 3 or 4 mucositis.

Chemotherapy was to be delayed until hematologic recovery (WBC count >= 3.0 x 109/L, granulocytes >= 1.5 x 109/L, platelets >= 100 x 109/L), with repeat blood counts at weekly intervals and doses dictated by nadir hematologic values. If, at the scheduled time of next treatment, only the total WBC count was available and was less than 3.0 x 109/L or the granulocyte count was less than 1.0 x 109/L, treatment was delayed for 1 week. Chemotherapy was to be discontinued if recovery was not complete after 3 weeks’ delay. Timing of surgery could be brought forward if there was a clinical opinion of tumor progression despite chemotherapy. The date of surgery was to be delayed until hematologic recovery after the third cycle of chemotherapy.

Histologic Response
Histologic response was obtained from the resected specimen, because this is an important outcome when evaluating the effectiveness of chemotherapy regimens in osteosarcoma. Good histologic response was defined as less than 10% viable tumor remaining.

Data Collection
For each patient in each trial, the data collected prospectively included surface area (SA) at diagnosis and postsurgery and for each cycle of chemotherapy the absolute amount of DOX and CDDP the patient received. The date that each cycle commenced was also recorded.

Definition of Received Dose-Intensity (RDI)
Standardizing time: the anticipated duration of chemotherapy, T. The scheduled time for each cycle, TC, was specified in the protocol as indicated in Fig 1. Thus T1 = 21, T2 = 21, and T3 = 3, and there was an additional TR = 18 days for hematologic recovery before surgery. After surgery, TS = 14 days for surgery and postsurgical recovery before cycle 4 was to commence. Postoperatively, T4 = 21, T5 = 21, and T6 = 3 days.

For a patient who completed all three preoperative cycles and had surgery, the anticipated time to complete the three preoperative cycles and then the delay to surgery was TPreop = T1 + T2 + T3 + TR = 21 + 21 + 3 + 18 = 63 days. If the patient then completed all postoperative cycles, TPost = TS + T4 + T5 + T6 = 14 + 21 +21 + 3 = 59 days. The anticipated time to complete six cycles of chemotherapy was T = TPreop + TPost = 122 days. If the patient completed fewer than six cycles, then T was calculated from the day of commencement of chemotherapy and included the 3 days of the (final) chemotherapy cycle. For example, a patient who stopped chemotherapy after cycle 4 had T = TPreop + TS + 3 = 80 days.

The actual time to complete chemotherapy, t. This was the time taken from commencement of cycle 1 to completion of chemotherapy. The date of completion of chemotherapy was day 3 of the last cycle given.

The actual time to complete preoperative chemotherapy, tPreop, was calculated as the time taken from commencement of cycle 1 to the date surgery was performed. If no surgery was performed, then the time to day 3 of the last chemotherapy cycle was used, ie, tPreop = t.

The standardized time, {Gamma}. The standardized ratio {Gamma} = t/T compared observed and anticipated times. For example, in a patient for whom the actual time to complete six cycles of chemotherapy was t = 159 days as compared with T = 122 as scheduled, then {Gamma} = 159/122 = 1.3.

Received dose: the anticipated total dose, D. DC was defined as the dose in milligrams, as specified by the protocol and taking account of SA, that the patient should receive in cycle C (maximum of six). The anticipated total dose was therefore D = {Sigma}DC.

For example, for a patient with SA = 1.5 m2 at entry, the dose of DOX received in each preoperative cycle was anticipated to be D1 = D2 = D3 = 1.5 x 25 x 3 = 112.5 mg, giving an anticipated preoperative dose DPreop = 337.5 mg. If the SA was reduced after surgery to SA = 1.4 m2, then for each postoperative cycle D4 = D5 = D6 = 1.4 x 25 x 3 = 105.0 mg, and the anticipated postoperative dose was DPost = 315.0 mg. No allowance was made for protocol dose reductions for toxicity in these calculations. The anticipated total dose D = DPreop + DPost = 337.5 + 315.0 = 652.5 mg of DOX.

The actual dose received, d. This was the sum of the doses received at each cycle, thus d = {Sigma}dC. For patients who did not receive all cycles, dC = 0 for missing cycles, but DC remained for that patient calculated as if the cycle had been received. For example, if the patient described above with SA = 1.5 m2 preoperatively, SA = 1.4 m2 postoperatively, and D = 652.5 received the first five cycles precisely as anticipated but omitted the sixth, then d = 112.5 + 112.5 + 112.5 + 105.0 + 105.0 + 0 = 547.5 mg.

The actual dose received preoperatively, dPreop, was the sum of the doses received at each preoperative cycle. If no surgery was performed, then dPreop = d.

The standardized received dose, {Delta}. The standardized ratio {Delta} = d/D compared observed and anticipated doses. In the example above, {Delta} = 547.5/652.5 = 0.84.

RDI. The RDI was defined by RDI = {Delta}/{Gamma}. If a patient received chemotherapy according to the protocol without any dose reduction or delay, then {Delta} = 1, {Gamma} = 1, and RDI = 1 (or 100%). For a patient receiving six cycles, this equated to 600 mg/m2 of CDDP and 450 mg/m2 of DOX over 122 days.

Combining the two chemotherapy components of the regimen. These calculations were undertaken for DOX and CDDP separately to obtain {Delta}DOX and {Delta}CDDP. The doses of DOX and CDDP were combined additively to give the combined standardized dose as {Delta} = ({Delta}DOX + {Delta}CDDP)/2.

Preoperative dose-intensity. Pre-operative dose-intensity was defined by RDIPreop = {Delta}Preop/{Gamma} Preop, where {Delta}Preop = dPreop/DPreop and {Gamma}Preop = tPreop/TPreop as defined above. Although dose-intensity over the whole treatment period formed the basis of this analysis, the relationship between dose, dose-intensity, and histologic response was examined using preoperative assessments and quantified using the {chi}2 test for trend.24

Statistical Methods
Because RDI can only be calculated after completion of treatment, it is not appropriate to compare survival or progression-free survival (PFS) of different {Delta} and RDI groups using calculations from the date of commencement of the first cycle of chemotherapy. Therefore, survival and PFS were calculated from the scheduled end of six cycles of chemotherapy as defined by the protocol at 122 days. Such an analysis therefore precludes all patients who died (or experienced disease progression, in the case of PFS) before 122 days had elapsed from the commencement of treatment. This contrasts with the publications of the trials themselves, for which it is appropriate to measure time from the date of randomization, and all eligible patients are included in the calculations. Survival curves were estimated for each dose or RDI group using the Kaplan-Meier method and compared using the log-rank statistic.25 The dose and RDI groups were defined by splitting the data at points corresponding to the respective tertiles but rounded to meaningful category divisions.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
Of 198 nonmetastatic patients randomized to receive neoadjuvant treatment in the trial EOI BO02/80831, there were 88 eligible patients who commenced the first cycle of DOX/CDDP, and, of 407 patients randomized in trial EOI BO03/80861, there were 199 eligible patients who commenced treatment with the same regimen. The admission and surgical characteristics of the 287 patients who commenced the first course of chemotherapy are listed in Table 1. Thus 60% of patients were male, 80% were >= 12 years of age, and the most common sites were the femur and tibia.


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  		Table 1. Baseline Characteristics of Patients Receiving at Least One Cycle of DOX/CDDP Chemotherapy
 
Treatment Received
The total number of cycles received was 1,582 (Table 2), and the majority of patients (75% in EOI BO02/80831% and 83% in EOI BO03/80861) received all six cycles. There were 31 patients (11%) who received preoperative but not postoperative chemotherapy. The main reasons for 55 patients not receiving all six cycles of chemotherapy were excessive toxicity (22 patients) and occurrence of disease progression while on treatment (19 patients). There were also seven protocol violations, four treatment refusals, two patients who had postoperative complications, and one patient who was lost to follow-up.


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  		Table 2. Number of Cycles Completed by Patients in Each Trial
 
Dose Received
The distributions of {Delta} for DOX, CDDP, and combined are listed in Table 3. The mean standardized doses were {Delta}DOX = 0.79 (SD = 0.20), {Delta}CDDP = 0.80 (SD = 0.20), and combined {Delta} = 0.80 (SD = 0.20). Although both protocols recommended reduction of both drugs in equal proportions, there was some evidence of a differential, with DOX being reduced slightly more than CDDP; however, one patient who had six cycles received as little as {Delta}CDDP = 0.33 but {Delta}DOX = 0.77.


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  		Table 3. Distribution of {Delta} and RDI for DOX, CDDP, and Both Combined
 
Figure 2 shows a scatterplot of {Delta}DOX against {Delta}CDDP. It suggests that, for the majority of patients, the standardized doses of both drugs were very similar. Thus {Delta}DOX and {Delta}CDDP were combined into overall {Delta} for the remainder of this analysis.



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  		Fig 2. Scatterplot of {Delta}DOX against {Delta}CDDP. Numbers indicate the number of cycles received; · = treatment completed.

 
The distribution of {Delta} is shown in Fig 3. The top panel contains all patients; in the bottom panel they are split by number of cycles received. Those who received fewer cycles have lower values of {Delta}. This is because the corresponding value of d = 0 for the missing cycles, but D remains as defined by the protocol. Values of {Delta} for those given all six cycles range from 0.44 to 1.10 of that anticipated; approximately 90% of these patients received more than {Delta} = 0.7.



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  		Fig 3. Distribution of {Delta} for patients receiving 1 to 6 cycles of chemotherapy.

 
The relationship between {Delta}, split into tertiles, and baseline characteristics is presented in Table 4. Patients with osteosarcoma of the fibula seem to receive a low dose, although numbers are small, but the other baseline variables are well balanced across the three dose groups.


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  		Table 4. Baseline Characteristics of Patients Receiving at Least One Cycle of DOX/CDDP Chemotherapy, by Combined {Delta}
 
Dose Delay
The distribution of standardized time to complete chemotherapy, {Gamma}, was centered above unity (Fig 4, top panel), and only three patients who had six cycles received them in less than the time planned (two were 2 days short of schedule and one was 1 day short). The mean standardized time taken to complete chemotherapy was 1.27 (SD = 0.23). In those patients completing the full six cycles, {Gamma} ranged up to 2.3, so chemotherapy can take more than twice the scheduled time to complete. However, 90% of the patients had completed therapy by 1.45 times the scheduled time.



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  		Fig 4. Distribution of {Gamma} for patients receiving 1 to 6 cycles of chemotherapy.

 
Figures 3 and 4 show that the majority of data points are below {Delta} = 1 and above {Gamma} = 1. The patients for whom {Gamma} < 1 were mostly those who did not complete all cycles. Thus the majority of patients received less chemotherapy given over a longer period than that planned in the protocol.

RDI
Table 3 shows the distribution of RDI, calculated from {Delta} and {Gamma} for both DOX and CDDP. Mean RDIDOX = 0.64 (SD = 0.19) and mean RDICDDP = 0.65 (SD = 0.18). The distributions of RDI for both drugs are very similar and were combined into a single mean RDI. This distribution is shown in Fig 5 and has a mean of 0.65 (SD = 0.18).



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  		Fig 5. Distribution of RDI for patients receiving 1 to 6 cycles of chemotherapy.

 
The relationship between RDI, split into tertiles, and baseline characteristics is presented in Table 5. There is a greater proportion of male patients in the highest dose-intensity group, but the other baseline variables are well balanced across the three RDI groups.


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  		Table 5. Baseline Characteristics of Patients Receiving at Least One Cycle of DOX/CDDP Chemotherapy, by Combined RDI
 
Survival
There were no patients from EOI BO02/80831 who died before the scheduled end of therapy at 122 days, and only one patient died in the EOI BO03/80861 trial before the scheduled end of therapy (death at 76 days). Survival from 122 days after start of treatment by {Delta}, categorized into tertiles, is shown in Fig 6 and Table 6. Patients in the lowest dose group ({Delta} < 0.75) had poorer survival than the middle dose group of 0.75 <= {Delta} < 0.90 (hazards ratio [HR] = 1.61; 95% confidence interval [CI], 1.02 to 2.56), but there is no overall trend for survival increasing with increasing dose (log-rank test for trend = 2.47, P = .12 on 1 df). Survival by RDI is shown in Fig 7 and Table 7 and the same pattern is repeated. The HR for patients with 0.60 <= RDI < 0.75 compared with those with RDI less than 0.6 falls just short of significance at the 5% level (HR = 1.53; 95% CI, 0.99 to 2.37). There is no evidence to suggest overall that survival increases with increasing RDI (log-rank test for trend = 1.24, P = .27 on 1 df).



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  		Fig 6. Survival from day 122 by {Delta} (all cycles). See Table 6 for additional data.

 

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  		Table 6. Panel for Fig 6
 


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  		Fig 7. Survival from day 122 by RDI (all cycles). See Table 7 for additional data.

 

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  		Table 7. Panel for Fig 7
 
PFS
Thirteen patients are excluded from the PFS analysis, because they experienced disease progression before day 122. Figure 8 and Table 8 show that patients who received fewer than six cycles are at greater risk of progression or death than those who received all six cycles (HR = 1.69; 95% CI, 1.03 to 2.78). No significant differences in PFS were found for increasing values of {Delta} (log-rank test for trend = 0.55, P = .46 on 1 df) or RDI (log-rank test for trend = 0.54, P = .46 on 1 df).



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  		Fig 8. PFS from day 122 by number of cycles received. See Table 8 for additional data.

 

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  		Table 8. Panel for Fig 8
 
Preoperative Dose-Intensity
The distributions of preoperative {Delta} and RDI by drug are listed in Table 9. Again, the distributions for the two drugs are very similar and were combined for the purposes of analysis. Mean preoperative {Delta} = 0.89 (SD = 0.21) and mean preoperative RDI = 0.75 (SD = 0.22). The higher levels of dose and RDI were given before surgery, although there is little difference in variability between the preoperative and overall assessments.


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  		Table 9. Distribution of Preoperative {Delta} and RDI for DOX, CDDP, and Both Combined
 
Histologic response was available for 166 patients. Of these, 55 (33%) had >= 90% necrosis and were thus adjudged to have responded well to chemotherapy. Table 10 lists the number of good histologic responders by preoperative {Delta} and RDI, split into tertiles. The proportion of good responders did not increase significantly with greater levels of dose ({chi}2 test for trend = 0.05, P = .83 on 1 df), nor does it increase with increasing RDI ({chi}2 test for trend = 2.48, P = .12 on 1 df).


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  		Table 10. Histologic Response by Preoperative {Delta} and RDI (divided into tertiles)
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The first randomized trial of the EOI compared the two-drug DOX/CDDP regime with a 3-day schedule that incorporated the addition of HDMTX.21 The results showed that in patients with nonmetastatic limb primaries, the schedule containing two drugs had significantly superior disease-free survival at 5 years (55% v 41%). In retrospect, this may have been due to the trial design reducing both the total dose and the dose-intensity of DOX and CDDP within the HDMTX arm.

There have been several retrospective studies of intended dose-intensity in osteosarcoma that seem to indicate that this might be an important variable determining outcome. Some have suggested that DOX dose-intensity is the most important variable,17 some have suggested that HDMTX dose-intensity is most significant,18 whereas others have reported evidence for both drugs.19,20

Most previous studies have been retrospective analyses of planned protocol dose and assumed equal efficacy of different drugs within the schedule. The present study set out to examine the role of received, as opposed to intended, dose and dose-intensity in determining outcome. Calculating RDI is relatively straightforward within the simple two-drug regimen. We assumed equal efficacy for both CDDP and DOX, and the analysis suggests little difference in standardized dose or dose-intensity between the two drugs.

This study does not show any significant influence of either dose or dose-intensity on outcome as determined by PFS or survival. There does seem to be a trend toward reduced survival in the group of patients who received the lowest total dose and dose-intensity, but this did not reach significance and there is no trend for improved outcome in those patients who received the highest total dose or dose-intensity. There was evidence of reduced PFS in the small group of patients who received fewer than the planned six courses. This analysis excludes patients with early progression and suggests a possible role for length of chemotherapy exposure.

There is only one other study that has looked at the influence of received dose-intensity in osteosarcoma.19 It suggested that in a more complex regime incorporating up to five drugs, dose-intensity was an important determinant of treatment outcome at the relatively short follow-up time of 2 years. The present study also indicates a dose-intensive effect on survival at 2 years; however, this seems to be lost over time. It would be of interest to know whether this loss of effect was also observed by Bacci et al.19

What then might be the reasons for a relative lack of received total dose or dose-intensive effect when there is a strong theoretic basis for expecting an effect? It has long been recognized that, experimentally, most cytotoxic drugs in sensitive tumors exhibit a sigmoidal dose-response curve that consists of lag, linear, and plateau phases.8 During the linear phase, increasing dose or dose-intensity can be shown to increase cell kill, and these important observations have formed the basis of many current clinical trials. Problems arise in the clinical setting because the true nature of dose response curves are unknown, and, in particular, plateau doses are undetermined. A strong dose-intense relationship for DOX as determined by tumor necrosis percentage has been suggested.17 Interestingly, the range of intended DOX intensity of 15 to 19 mg/m2/wk resulted in a maximum reported 75% to 88% of patients achieving greater than 90% tumor necrosis, with neoadjuvant regimes lasting 8 to 16 weeks. In the European Osteosarcoma Group two-drug regime, this level of tumor necrosis has not been seen despite intended dose-intensity being greater than this, ie, 25 mg/m2/wk. Even in the group receiving less than 60% of intended dose-intensity, the range of DOX dose-intensity was close to 15 mg/m2/wk. There are several possible reasons for this. First, 15 to 19 mg/m2/wk is close to the dose-intensive/response plateau for DOX; also, perhaps a significantly greater dose or dose-intensity may be needed to have an impact on outcome.

There are a number of other parameters that may affect the impact of chemotherapy on any particular tumor, including drug scheduling, resistance mechanisms, and pharmacodynamic influences. The way that individual patients tolerate chemotherapeutic agents may be influenced by endogenous drug metabolism and handling, performance and physical status, and tumor burden. In this study, some patients received close to the maximum recommended dose-intensity. It can be hypothesized that some of these patients may have endogenous drug handling mechanisms that produce less toxicity with particular agents, but it is not known whether this may also reduce tumor cell–killing effects. There is a possible analogy with acute lymphoblastic leukemia therapy where endogenous mercaptopurine metabolism can allow some patients to handle apparently standard doses of 6-mercaptopurine without toxicity whereas others require significant reductions in dose.26 There is evidence that those tolerating full dose without toxicity may have a worse outcome, and it is hypothesized that these patients will benefit from further mercaptopurine dose escalation. Similar mechanisms may apply in other tumors, including osteosarcoma.

There is some limited evidence in this study of an effect of length of received drug exposure in that those receiving fewer than the full recommended six courses had a worse outcome. Even though this analysis excluded patients who relapsed during the 121-day planned treatment duration, the observation is compromised in that some patients only received one or two courses of therapy. Hryniuk27 acknowledged that when calculating RDI, it may not be justifiable to include patients who have only received one or two cycles. There may, however, be justification for implying that there is a minimum number of courses or length of exposure of conventional therapy below which patients are at greater risk of treatment failure but above which there is no benefit to increasing the number of cycles. The EOI BO03/80861 trial22 compared the six-course, 18-week, two-drug CDDP/DOX regimen with a 47-week multicourse, multidrug schedule and showed no benefit for increased length of exposure to a multiple drug combination.

Overall, our analysis is consistent with much recent evidence casting doubt on the benefits of dose-intensifying treatments for many cancers.16 These authors suggest that apart from acute myeloid leukemia and lymphoma, there is little evidence from randomized trials to support routine introduction of dose intensification. They do, however, recognize that many controlled studies had concluded that so-called low-dose therapy is inferior to standard-dose therapy, and they recommend that every attempt should be made to use standard therapy according to protocol guidelines. These authors have largely focussed on the treatment of common adult cancers and not at all on those occurring in children or young adults. There have been no published data of randomized trials in osteosarcoma testing the hypothesis of a planned increase in dose-intensity in a prospective manner. It has been shown that it is feasible to deliver the DOX/CDDP regimen in a dose-intensified manner at 2-week intervals using granulocyte colony-stimulating factor support28 and giving a planned dose-intensity of 1.5 when compared with the standard DOX/CDDP regime but with the same planned total dose. These two regimes are now being compared by EOI in a randomized controlled trial and should demonstrate whether a moderate increase in planned dose-intensity improves survival in patients with osteosarcoma.


   NOTES
 
The European Osteosarcoma Intergroup consists of the Bone Sarcoma Working Party of the United Kingdom Medical Research Council, the United Kingdom Children’s Cancer Study Group, the Société Internationale d’Oncologie Paedriatrique, and the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Carter SK: The dilemma of adjuvant chemotherapy for osteogenic sarcoma. Cancer Clin Trials 3: 29-36, 1980[Medline]

2. Medical Research Council (MRC): A trial of chemotherapy in patients with osteosarcoma: A report to the Medical Research Council by their Working Party on Bone Sarcoma. Br J Cancer 53: 513-518, 1986[Medline]

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4. Rosen G, Nirenberg A: Chemotherapy for osteogenic sarcoma: An investigative method, not a recipe. Cancer Treat Rep 66: 1687-1697, 1982

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Submitted December 6, 1999; accepted July 14, 2000.


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