|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 1999 American Society for Clinical Oncology
Further Evaluation of Intensified and Increased Total Dose of Cyclophosphamide for the Treatment of Primary Breast Cancer: Findings From National Surgical Adjuvant Breast and Bowel Project B-25From the National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA. Address reprint requests to Bernard Fisher, MD, Scientific Director, National Surgical Adjuvant Breast and Bowel Project, Allegheny University of the Health Sciences, 4 Allegheny Center, Suite 602, Pittsburgh, PA 15212-5234, email bernard.fisher{at}nsabp.org, or to Stewart Anderson, PhD, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto St, Pittsburgh, PA 15261, email sja@pitt.edu. ABSTRACT PURPOSE: In 1989, the National Surgical Adjuvant Breast and Bowel Project initiated the B-22 trial to determine whether intensifying or intensifying and increasing the total dose of cyclophosphamide in a doxorubicin-cyclophosphamide combination would benefit women with primary breast cancer and positive axillary nodes. B-25 was initiated to determine whether further intensifying and increasing the cyclophosphamide dose would yield more favorable results. PATIENTS AND METHODS: Patients (n = 2,548) were randomly assigned to three groups. The dose and intensity of doxorubicin were similar in all groups. Group 1 received four courses, ie, double the dose and intensity of cyclophosphamide given in the B-22 standard therapy group; group 2 received the same dose of cyclophosphamide as in group 1, administered in two courses (intensified); group 3 received double the dose of cyclophosphamide (intensified and increased) given in group 1. All patients received recombinant human granulocyte colony-stimulating factor. Life-table estimates were used to determine disease-free survival (DFS) and overall survival. RESULTS: No significant difference was observed in DFS (P = .20), distant DFS (P = .31), or survival (P = .76) among the three groups. At 5 years, the DFS in groups 1 and 2 (61% v 64%, respectively; P = .29) was similar to but slightly lower than that in group 3 (61% v 66%, respectively; P = 08). Survival in group 1 was concordant with that in groups 2 (78% v 77%, respectively; P = .71) and 3 (78% v 79%, respectively; P = .86). Grade 4 toxicity was 20%, 34%, and 49% in groups 1, 2, and 3, respectively. Severe infection and septic episodes increased in group 3. The decrease in the amount and intensity of cyclophosphamide and delays in therapy were greatest in courses 3 and 4 in group 3. The incidence of acute myeloid leukemia increased in all groups. CONCLUSION: Because intensifying and increasing cyclophosphamide two or four times that given in standard clinical practice did not substantively improve outcome, such therapy should be reserved for the clinical trial setting. DURING THE MID-1980s, findings from studies conducted to evaluate postoperative systemic adjuvant chemotherapy in patients with primary operable breast cancer revealed a modest benefit in disease-free survival (DFS) and overall survival. It was thought, however, that the results would have been better had more drug been administered.1 That thesis was proposed as a result of (1) a greater remission rate among patients with advanced disease and (2) a retrospective assessment of relapse-free survival in women with early-stage disease, which revealed that higher dose-intensity, ie, amount of drug administered per unit of time, and greater cumulative dose improved patient outcome.2-6 In order to test the hypothesis that increased dose and intensity of chemotherapy would result in improved DFS and survival, the National Surgical Adjuvant Breast and Bowel Project (NSABP) formulated, in the late 1980s, a strategy for evaluating the worth of administering, in the adjuvant setting, different intensities and cumulative doses of a single agent in a multiple-agent regimen. It was recognized that in order to appropriately evaluate this hypothesis, it would be necessary for drug to be given at increasing levels of dose-intensity and total dose. Consequently, the NSABP initiated two trials, B-22 and B-25, to be conducted sequentially. The aim of these studies was to determine whether higher but fewer doses (dose intensification) of cyclophosphamide in a doxorubicin-cyclophosphamide combination would more effectively prolong DFS and overall survival than would the same cumulative dose of cyclophosphamide given over a more prolonged period of time and whether increasing both the dose-intensity and the cumulative dose of cyclophosphamide, ie, administering a higher dose, would result in greater prolongation of DFS and overall survival than would giving cyclophosphamide at a lower dose and intensity over the same period of time, as is done with standard doxorubicin-cyclophosphamide therapy for breast cancer. These trials were designed to ensure (1) strict control over treatment delays and dose reductions, (2) enough properly selected patients who would be randomly assigned to the treatment groups that would receive the same therapy but at different dose intensities and in different cumulative doses, (3) a dose-intensity difference that would be sufficient to provide a reasonable chance of detecting differences in treatment failure and survival rates, (4) therapy that demonstrated a beneficial effect when administered at a standard dose and intensity, and (5) acceptable patient morbidity and mortality. A recent report of findings from the B-22 study through 5 years of follow-up failed to demonstrate a significant improvement in either DFS or overall survival when the same total dose of cyclophosphamide administered in four courses of standard doxorubicin-cyclophosphamide therapy was intensified, ie, given in two courses, or was intensified and increased, ie, doubled in each of four courses. Although these findings failed to support the thesis that intensifying or increasing the total dose of cyclophosphamide would result in a benefit, it was thought that the increased doses of cyclophosphamide administered in B-22 might not be high enough to demonstrate an advantage that might only be evident from increased and/or more intensified therapy. For that reason, the B-25 trial was designed as a sequel to B-22. This report presents the B-25 findings through 5 years of follow-up and relates them to the results obtained from B-22. PATIENTS AND METHODS
Study Design
Patient accrual in the B-25 study began on April 1, 1992, and was terminated on February 28, 1994. During that time, 2,548 patients were randomized among three treatment groups. The relationship of those three groups to the three groups in the B-22 study is depicted in Table 1. Treatment in all three of the groups in B-25 began within 2 to 5 weeks after surgery. Women enrolled in group 1 received doxorubicin (Adriamycin; Pharmacia-Upjohn, Kalamazoo, MI) 60 mg/m2 intravenously and cyclophosphamide (Neostar; Pharmacia-Upjohn) 1,200 mg/m2 intravenously every 21 days for four cycles (courses). Women in group 2 received doxorubicin therapy identical to that in group 1 and two courses of cyclophosphamide, ie, one dose of 2,400 mg/m2 on day 1 of course 1 and another dose of 2,400 mg/m2 on day 1 of course 2. In group 2, no cyclophosphamide was given during cycles 3 and 4. The total dose of cyclophosphamide administered to women in group 2 was identical to that in group 1, but the dose of drug was given in two instead of in four courses. In group 3, doxorubicin was administered in the same manner as in groups 1 and 2. However, the increased dose of cyclophosphamide (2,400 mg/m2) given for two cycles in group 2 was given for four cycles in group 3. All patients who were
Study Information
Patient Characteristics
Toxicity Information
No dose reductions of either doxorubicin or cyclophosphamide were permitted in B-25 as a result of toxicity, except when a septic episode occurred. If a patient had one septic episode, the dose of G-CSF was doubled, but full doses of doxorubicin and cyclophosphamide were maintained. If she had a second septic episode, the G-CSF dosage was maintained at double the original dose, doses of doxorubicin-cyclophosphamide were maintained at the full dose, and ciprofloxacin was administered. If a patient experienced a third septic episode despite having received G-CSF and an antibiotic, the initially stipulated dose of doxorubicin-cyclophosphamide was reduced by 25%. When patients experienced hematologic, gastrointestinal, hepatic, or renal toxicities, administration of chemotherapy was delayed until the full dose could be tolerated. The protocol specifically mandated the course of action to be taken in the event that specific side effects, such as hepatic dysfunction, renal and cardiac toxicities, sepsis, or hemorrhagic cystitis, occurred. The protocol stipulated that cyclophosphamide be discontinued in the presence of grade 2 gross hemorrhagic cystitis. For each group, the ratios of drug doses received to assigned doses were calculated and expressed as percentages. This was performed for each course as well as for the total amount of therapy received across all courses. Findings are presented in Table 7 for the group of patients who had the poorest tolerance for cyclophosphamide. Patients in the 10th percentile demonstrated the least ability to tolerate the dosage as stipulated at randomization. Delays in drug administration are presented as days between courses of therapy for the 90th, 75th, and 50th percentiles of patients. Women in the 90th percentile experienced the longest delays.
Statistical Considerations RESULTS
DFS and Overall Survival
Findings among the three groups relative to survival were concordant. Analyses revealed no significant difference in survival across all groups or across any of the pairwise comparisons. The 5-year survival for women in group 1 was 78%; for those in group 2, 77%; and for those in group 3, 79% (Fig 1). A comparison between group 1 and group 2 demonstrated relative odds of 0.98 (P = .81; 95% CI, 0.80 to 1.19) over the entire period of observation. A comparison between group 1 and group 3 showed relative odds of 1.04 (P = .72; 95% CI, 0.85 to 1.26).
When patients within a treatment group were evaluated according to their nodal status, there was little evidence, in any group with positive nodes (one to three, four to nine, or
When survival was examined according to treatment and nodal status, there was a significant interaction (P = .04). Women in group 1 who had one to three positive nodes had a nearly significantly better 5-year survival (87%) than women in group 2 (82%; P = .08) and those in group 3 (82%; P = .06). A test for heterogeneity among all three groups in patients with one to three positive nodes was not significant (P = .11). However, women with four to nine positive nodes in group 3 had a significantly better 5-year survival (79%) than did women with the same number of nodes in group 1 (68%; P = .01), and the test for heterogeneity among all groups was significant (P = .03) (Fig 2). In patients with
When women in each treatment group were evaluated according to their age and nodal status, the findings relating to their outcome were less consistent than those observed when they were examined relative to treatment and nodal status regardless of age. Whereas no significant qualitative interactions among age, nodal status, and the therapy in group 1 versus the therapy in group 2 were observed for DFS (P = .27), DDFS (P = .13), and overall survival (P = .14), there were highly significant interactions between age, nodal status, and the therapy in group 1 versus that in group 3 DFS (P = .002), DDFS (P = .002), and overall survival (P = .0003). These three-way interactions between group 1 and group 3 were not as significant when age and nodal status were analyzed as continuous variables (DFS, P = .01; DDFS, P = .04; and survival, P = .06). The observed interactions were due mainly to the apparent benefit in DFS and overall survival from intensified and increased cyclophosphamide in women whose age at entry onto the study was less than 50 years and who had four to nine positive nodes (Figs 3 and 4). Similar benefits were not observed for women younger than 50 years of age with one to three or
When annual event rates were compared among the three groups, either overall or according to patient age (
Sites of Treatment Failure
Toxicity
An increase in the frequency of toxicities greater than or equal to grade 4 was observed across age groups (younger than 50, 50 to 59, or
Relatively few patients in group 1 required blood transfusions, the greatest number of which (9%) were administered after the fourth course of therapy (Table 11). In group 2, the most transfusions were given after course 2 (13%); the numbers after courses 3 and 4 were 7% and 4%, respectively. In contrast, in group 3, nearly one half of the patients required transfusions—41% after course 3 and 45% after course 4.
Compliance With Therapy Except in the third and fourth courses of group 3, more than 90% of the dose and intensity of cyclophosphamide specified at randomization (Table 7) was administered to patients in the three groups. Only in the 10th percentile of patients was the total amount of drug and dose-intensity found to be appreciably less than the protocol-designated dose (73.1%). Most of the reduction in amount of drug and intensity in the 10th percentile of women was observed in the later courses of therapy, ie, they received 77% and 0% in courses 3 and 4, respectively. Most of the dose reductions were made in response to septic episodes. When compared with the protocol-stipulated dose and intensity for cyclophosphamide, the dose and intensity of doxorubicin received by treatment group and by course within treatment group were highly concordant with that reported for cyclophosphamide (data not shown), except that the doxorubicin was administered in courses 3 and 4 in group 2 whereas cyclophosphamide was not.
When evaluated according to course of therapy, the rate of delay in administration of therapy was less than 10% among all courses in the three groups, except for the increased incidence of delay in course 4 (16%) in group 3 (Table 12). The duration of the interval between courses of therapy was similar among the three groups. The greatest delays (28 days) occurred between the second and third and the third and fourth courses. As stipulated in the protocol, the median interval between all courses was 21 days.
DISCUSSION
The results of the B-25 trial confirm and augment the findings from the B-22 study, which demonstrated that intensifying and either maintaining or increasing the total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen failed to improve patient outcome. The only manifestation of an improved outcome was observed in the women in group 3 of B-25, who received twice the intensity and total dose of the drug as women in group 1 of that study. The small but questionably meaningful increase (5%) in DFS at 5 years of follow-up was of borderline significance (P = .08); no benefit in overall survival was evident. Furthermore, when examined overall or according to age or ER status, annual event and mortality rates, for the most part, failed to show a significant advantage from dose manipulation, except in women
Another indication of the failure to achieve a meaningful clinical benefit from the administration of an intensified and increased total dose of cyclophosphamide was the observation that, at 5 years of follow-up, the DFS and overall survival of women who received that regimen (66% and 79%, respectively) were highly concordant with those of women in the standard therapy group of B-22, who received the dose and intensity of drug generally administered in clinical practice (62% and 78%, respectively). Those and other cross-protocol comparisons were carried out because, in B-22, the outcome of patients who received the intensified and increased dose of cyclophosphamide was virtually identical to that of women in the standard therapy group of B-25. The DFS at 5 years was 63% and 61%, respectively, and the overall survival was 78% and 78%, respectively (Fig 5). The similarity of the findings among all treatment groups is further demonstrated by the fact that the individual DFS and overall survival outcomes of patients in the six groups comprising B-22 and B-25 were concordant, despite the manipulation of dose-intensity and total dose of therapy (Fig 6 ). Thus, the findings from the two studies are consistent, in that doubling or quadrupling the intensity and total dose of cyclophosphamide failed to demonstrate that manipulating the drug dosage resulted in a clearly significant clinical benefit. Additional follow-up time is necessary to assess the significance of the slight advantages that have been observed. Characteristics of patients in B-25 were similar to those of patients in B-22, with the exception that patients in B-25 were somewhat younger; 59% and 52% of the women were
One intriguing aspect of the B-22 study relates to the biologic significance of the findings, which demonstrated that the outcome in any category of node-positive patients did not improve when either the intensity or the total dose of cyclophosphamide was increased. Certainly, in light of the findings from both B-22 and B-25, which show a lack of benefit, those that relate to the effect of treatment on patients within various node-positive categories are not surprising. They do, however, seem antithetical to the view that nodal status correlates with the extent of residual tumor burden after surgery and, consequently, with patient outcome. That thesis contends that less residual tumor should be present in patients with negative nodes than in patients with one to three positive nodes and that the extent of occult tumor becomes progressively greater as the number of positive nodes increases. Consequently, it has been proposed that high-dose chemotherapy would more likely improve the outcome of patients with fewer positive nodes, which should be associated with a smaller residual tumor burden, and that those patients should, thus, demonstrate a better response to treatment.17-19 However, the findings from B-25, which showed that intensifying and increasing the total dose of cyclophosphamide even further did not improve the outcome of patients with fewer positive nodes, served to confirm the results from B-22, which also failed to support that thesis. The findings from B-25 also demonstrated that the outcome of women with 10 or more positive nodes was little altered by either the degree of intensification or amount of total dose administered.
In both studies, despite the various manipulations of drug dose and intensity, a similarity in DFS was observed in women in each of the three nodal categories evaluated. This phenomenon is illustrated in Fig 7 , in which the outcomes of patients in each of the six treatment groups comprising both trials have been plotted. When survival was taken into consideration, the outcomes of women with one to three or 10 or more positive nodes in the six treatment groups were highly concordant, despite the variable intensity and total dose of drug administered. However, for women with four to nine positive nodes, the findings with regard to DFS and survival were somewhat discordant, in that fewer events and deaths occurred among those who received the greatest intensified and total dose of drug in B-25. Because of a lack of improvement in DFS and in overall survival in women with either one to three or 10 or more positive nodes, it is difficult to assess the clinical significance of the survival findings in the subgroup of patients with four to nine positive nodes. To attach meaningful significance to this discrepancy is difficult in that we are unable to evoke a biologic explanation for it. Thus, the findings from both the B-22 and B-25 studies provide little evidence to support the concept that increasing the intensity and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide combination results in a better outcome, at least in part, by more effectively eradicating the smaller number of residual tumor cells putatively associated with fewer positive nodes.
The findings that relate to the incidence of local and regional treatment failure in both the B-22 and B-25 studies are of particular interest for several reasons. First, the distributions of such events among the treatment groups in both studies at similar follow-up times were almost identical, despite the variation in intensity and total dose of cyclophosphamide administered. Thus, it would seem that the standard dose and intensity of doxorubicin and cyclophosphamide generally used in clinical practice yields a degree of local and regional control that is not enhanced by higher doses of the same therapy. Second, in both studies, the incidence of both local and regional treatment failures was surprisingly low. In the B-22 trial, only 6% of first treatment failures occurred at local sites such as the chest wall and/or scar, and 4% occurred at regional nodal sites. In B-25, this incidence was similar (5% and 4%, respectively). These findings are significant in view of a recent revival of interest in the use of postoperative radiation therapy to diminish the frequency of treatment failures at those sites and, ultimately, to improve survival outcome. Two recent studies support that claim.20,21 In both, the incidence of local-regional treatment failures in women who received chemotherapy but no radiation therapy after surgery was much greater than that observed in our studies. As expected, the high rates of local-regional recurrence were markedly decreased by radiation therapy. Although the follow-up time in both studies was longer than that in our trials, because the majority of local-regional treatment failures are observed within the first 5 or 6 years of follow-up, it is highly unlikely that the lower incidence of such failures observed in our studies will approximate those noted by the other investigators. The basis for the recommendation that radiation therapy be used to reduce local-regional treatment failures is related to the incidence of such recurrences in those studies and to the conclusion that chemotherapy was ineffective in reducing that incidence. Our findings, however, demonstrate not only a lower incidence of such treatment failures but also show that effective chemotherapy can prevent local-regional disease. Consequently, unlike other investigators,22 we do not subscribe to the universal use of postoperative local-regional radiation therapy to treat node-positive and node-negative patients who receive postoperative chemotherapy. Although toxicity data from both B-22 and B-25 have been meticulously gathered and documented, the significance of such information might be considered irrelevant in view of the limited benefit achieved from the dose manipulations of cyclophosphamide that gave rise to the toxicities observed. However, knowledge of the extent of the toxicities that occurred might be important for several reasons. First, such information might serve as an indication of whether enough of the protocol-stipulated dose of drug was administered, despite the toxicity encountered, to provide an adequate test of the concepts being evaluated; second, it might be of value in determining whether the severity of the toxicities that occurred was within boundaries that would allow for further escalation of the intensity and total dose, should that be considered worth doing; and third, it might indicate whether the severity of the toxicities observed would preclude the use of therapy that has demonstrated a minimal benefit. No added benefit was observed from intensifying cyclophosphamide without increasing the total dose of the drug in either the B-22 or B-25 trial. This was not, however, because patients received an amount of drug that was less than that mandated by the protocol, nor was it due to the fact that a greater proportion of women experienced either a delay in receiving therapy or an increase in the number of days between therapy. Thus, it would seem that an appropriate test of cyclophosphamide intensification was carried out in both studies. Consequently, because there is little or no justification for using intensified doxorubicin-cyclophosphamide therapy in the clinical setting, the toxicities observed, while greater than those that occur after the administration of standard therapy, are not of consequence within the context of this report. Some might view the relatively small benefit observed as providing justification for the use of an intensified and increased total dose of cyclophosphamide in clinical practice. However, before such a recommendation can be made, the toxicities that occur as a result of the regimen must be taken into consideration. Particularly noteworthy in that regard is the observation that patients 50 years of age and older were not as likely to tolerate high-dose chemotherapy; in B-25, 26% of them discontinued protocol therapy whereas only 11% of those who received standard therapy, as in B-22, did so. Moreover, when examined according to age group, toxicities of grade 4 or higher occurred in 47% to 55% of women who received high-dose chemotherapy, as compared with 6% to 8% of women on standard therapy in B-22. That increase was apparent after each of the four courses of therapy and was approximately 20% versus less than 10% after standard therapy. There was a markedly greater increase in the number of septic episodes after high-dose chemotherapy (44% v 3%). Those events were largely responsible for the finding that for women in the lowest 10th percentile of the B-25 study, only 77% of the protocol-required dose of drug was received in course 3 and 0% in course 4. This increase occurred despite the administration of G-CSF in all patients in the B-25 study. Moreover, the fact that almost 50% of women who received high-dose chemotherapy required blood transfusions after courses 3 and 4 further demonstrates the severity of toxicity associated with that regimen. Of major significance was the finding that four deaths occurred because of toxicity in patients who received the increased drug dose, whereas only one death was reported in the group of women on standard therapy. Finally, there is evidence that high-dose chemotherapy may be mutagenic.23 Six cases of acute myeloid leukemia and two of myelodysplastic syndrome occurred in patients receiving therapy in which the dose was intensified and increased; after standard therapy, three cases of acute myeloid leukemia and one case of myelodysplastic syndrome were reported. In B-25, five cases of each type of blood dyscrasia occurred when the dose was intensified but the total dose was not increased, whereas in B-22, at a similar follow-up time, only one of each was observed when the dose was intensified but not increased. In view of the extent of the toxicities that occurred and the failure to observe a meaningful benefit when the dose and intensity of cyclophosphamide were increased, we have concluded that attempting to improve patient outcome by administering the drug at an increased dose, as used in B-25, is not advisable. A few comments about how our findings compare with those of others who have evaluated drug intensification and increased total dose of therapy are appropriate. During the last decade, despite the extensive use of high-dose chemotherapy in conjunction with autologous bone marrow or stem-cell rescue, the paucity of data from appropriate randomized clinical trials has prevented definition of the role of such therapy in breast cancer patients who have a large number of positive nodes. Similarly, there is little or no information from trials that have been specifically conducted to evaluate the worth of intensifying and increasing the total dose of the same drug or regimen to a level short of that requiring the need for autologous stem-cell administration. Results that have recently been reported from two randomized phase II trials24,25 have failed to demonstrate a benefit from the use of "high-dose" adjuvant chemotherapy in women with positive nodes. In both studies, patients received several courses of standard "multimodality treatment" before being randomized to receive either more of the same therapy at the same dose or a regimen that contained other chemotherapeutic agents as well as autologous stem-cell transplantation. Thus, each of the studies compared two different regimens of therapy, not increased dose(s) of a similar drug or regimen, an aim that was different from that of our studies. The trial most often considered supportive of the hypothesis that increased dose and dose-intensity of a particular drug or combination of drugs could lead to improvement of DFS and overall survival was the one conducted by the Cancer and Leukemia Group B (CALGB), which compared the outcome of patients who received three different dose levels of cyclophosphamide, doxorubicin, and fluorouracil. Recently updated findings from that study26 show that in no group was the dose intensification and total dose greater than that which might be considered to be the standard dose for the chemotherapy used.27 Consequently, the major finding from that trial demonstrated that dose reduction resulted in a poorer outcome than that achieved from using doses of a therapy known to be efficacious. One recent study in patients with metastatic breast cancer seems to have some relevance to our findings.28 Results from that trial demonstrated an increase in response rate and time to disease progression when the dose of epirubicin administered was increased from one that was most likely ineffective (40 mg/m2) to one that was more effective (90 mg/m2); no further increase was found, however, by increasing the dose from 90 to 135 mg/m2. The conclusion from that study may be viewed in part as being similar to the one reached in the CALGB trial, in that when a suboptimal dose of a therapy was increased to a level of clinical effectiveness, a benefit was observed. It demonstrates, however, that unlike what was observed in the CALGB study but similar to what was demonstrated in our trials, no further benefit may occur when an additional increase in drug dose is administered. Thus, to our knowledge, the B-22 and B-25 studies are the only prospective randomized trials that provide information obtained in the adjuvant setting about the consequences of increasing the total dose and intensity of a drug beyond that demonstrated to be clinically effective. Our observation of an equivocally limited clinical benefit from intensifying and increasing the total dose four-fold beyond that demonstrated to be clinically effective strongly supports the concept that an effective dose of drug exists beyond which no further benefit is likely to be achieved. In that regard, our findings indicate the propriety of continuing to administer cyclophosphamide at a dose of 600 mg/m2 per course in the doxorubicin-cyclophosphamide regimen used in clinical practice. Our findings also fail to support several concepts that relate to the use of high-dose chemotherapy and seem to contradict the findings obtained from in vitro studies that demonstrate a steep dose-response curve for all alkylating agents (including cyclophosphamide), which maintain that small increases in drug dose lead to a disproportionate increase in tumor cell kill.27,29,30 In addition, our findings also fail to provide support for the thesis that higher doses of chemotherapy overcome drug resistance and, thus, confer a benefit.27,29,30 It remains possible, however, that higher doses of multiple alkylators, possibly with stem-cell support, may overcome drug resistance."31 When the B-22 trial was formulated, we realized that the findings, especially if they proved to be negative, would provoke criticism and that our decision to manipulate the dose of only one of the two agents in the regimen, ie, cyclophosphamide and not doxorubicin, was likely to be challenged. The rationale for making those choices has already been presented.9 Most important, when we designed the study, we recognized that there needed to be sufficient points on the dose-escalation curve to test the hypothesis that increased dose and intensity of a drug is beneficial. It was for that reason that we decided to conduct the B-25 study sequentially, thus ensuring that the number of points on the curve be adequate to test the hypothesis while at the same time ensuring that the eligibility criteria and all other aspects of the study would be similar to those of the B-22 trial. We believe that sufficient levels of dose and intensity have been evaluated in the B-22 and B-25 trials to warrant the conclusion that further increasing the dose of cyclophosphamide above that used in standard therapy without stem-cell support is unlikely to be feasible. When our findings are considered together with the results reported from studies that have been conducted by other investigators, including those from randomized trials evaluating the worth of high-dose chemotherapy with stem-cell replacement in the adjuvant setting, the case for the use of such therapy seems weak.32-34 Until evidence is obtained from additional studies testing a variety of new concepts35,36 for more effectively administering therapeutic agents, we recommend that the use of such therapy be limited to the clinical trial setting.
ACKNOWLEDGMENTS Supported by Public Health Service grants no. U10-CA-12027, U10-CA-69651, U10-CA-37377, and U10-CA-69974 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD. The authors thank Richard Mudge, Judy Jones, Gordon Bass, and Darlene Kiniry for assistance in data management and programming, Tanya Spewock for editorial assistance, and Mary Hof for preparation of the manuscript. REFERENCES
1.
DeVita VT: Dose-response is alive and well. J Clin Oncol4:1157-1159, 1986 2. Hryniuk W, Bush H: The importance of dose-intensity in chemotherapy of metastatic breast cancer. J Clin Oncol2:1281-1288, 1984[Medline]
3.
Hryniuk W: More is better. J Clin Oncol6:1365-1367, 1988
4.
Tannock IF, Boyd NF, DeBoer G, et al: A randomized trial of two dose levels of cyclophosphamide, methotrexate, and fluorouracil chemotherapy for patients with metastatic breast cancer. J Clin Oncol6:1377-1387, 1988 5. Hryniuk W, Levine MN, Levin L: Analysis of dose intensity for chemotherapy in early (stage II) and advanced breast cancer. NCI Monogr1:87-94, 1986
6.
Hryniuk W, Levine MN: Analysis of dose-intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol4:1162-1170, 1986
7.
Fisher B, Fisher ER, Redmond C: Ten-year results from the NSABP clinical trial evaluating the use of L-phenylalanine mustard (L-PAM) in the management of primary breast cancer. J Clin Oncol4:929-941, 1986 8. Fisher B, Redmond C, Brown A, et al: Treatment of primary breast cancer with chemotherapy and tamoxifen. N Engl J Med305:1-6, 1981[Abstract]
9.
Fisher B, Anderson S, Wickerham DL, et al: Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-22. J Clin Oncol15:1858-1869, 1997 10. Cutler SJ, Ederer F: Maximum utilization of the life table method in analyzing survival. J Chronic Dis8:699-712, 1958[Medline] 11. Lewis JA, Machin D: Intention to treat: Who should use ITT? Br J Cancer68:647-650, 1993[Medline] 12. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep50:163-170, 1966[Medline] 13. Hankey BF, Myers MH: Evaluating differences in survival between two groups of patients. J Chronic Dis24:523-531, 1971[Medline] 14. Peto R, Peto J: Asymptotically efficient rank invariant test procedures. J R Stat Soc B135:185-206, 1972 15. Gail M, Simon R: Testing for qualitative interactions between treatment effects and patient subsets. Biometrics41:361-372, 1985[Medline] 16. Cox DR: Regression models and life-tables. J R Stat Soc B30:248-275, 1972 17. Hryniuk WM: Average relative dose intensity and the impact on design of clinical trials. Semin Oncol14:65-74, 1987[Medline] 18. Steward WP: High dose chemotherapy with haemopoietic support for breast cancer. Eur J Cancer 31A:S21-S24, 1995 (suppl 7) 19. Triozzi PL, Rhoades C, Thornton DE: High-dose chemotherapy for breast cancer. Cancer Treat Rev21:185-198, 1995[Medline]
20.
Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med337:949-955, 1997
21.
Ragaz J, Jackson SM, Le N, et al: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med337:956-962, 1997
22.
Hellman S: Stopping metastases at their source. N Engl J Med337:996-997, 1997 23. DeCillis A, Anderson S, Bryant J, et al: Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) on NSABP B-25: An update. Proc Am Soc Clin Oncol 16:130a, 1997 (abstr 459) 24. Rodenhuis S, Richel DJ, van der Wall E, et al: Randomised trial of high-dose chemotherapy and haemopoietic progenitor-cell support in operable breast cancer with extensive axillary lymph-node involvement. Lancet352:515-521, 1998[Medline] 25. Hortobagyi GN, Buzdar AU, Champlin R, et al: Lack of efficacy of adjuvant high-dose (HD) tandem combination chemotherapy (CT) for high-risk primary breast cancer (HRPBC): A randomized trial. Proc Am Soc Clin Oncol 17:123a, 1998 (abstr 471)
26.
Budman DR, Berry DA, Cirrincione CT, et al: Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer. J Natl Cancer Inst90:1205-1211, 1998
27.
Henderson IC, Hayes DF, Gelman R: Dose-response in the treatment of breast cancer: A critical review. J Clin Oncol6:1501-1515, 1988
28.
Bastholt L, Dalmark M, Gjedde SB, et al: Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer: A randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group. J Clin Oncol14:1146-1155, 1996 29. Frei E III, Teicher BA, Cucchi CA, et al: Resistance to alkylating agents: Basic studies and therapeutic implications, in Wooley PV III, Tew KD (eds): Mechanisms of Drug Resistance to Neoplastic Cells. Bristol-Myers Cancer Symposium. San Diego, CA, Academic Press, 1988, pp 69-86 30. Frei E III, Antman K, Teicher B, et al: Bone marrow autotransplantation for solid tumors: Prospects. J Clin Oncol7:515-526, 1989[Abstract]
31.
Zujewski J, Nelson A, Abrams J: Much ado about not... enough data: High-dose chemotherapy with autologous stem cell rescue for breast cancer. J Natl Cancer Inst90:200-209, 1998 32. Peters W, Rosner G, Vredenburgh J, et al: A prospective, randomized comparison of two doses of combination alkylating agents (AA) as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes (LN): Preliminary results of CALGB 9082/SWOG 9114/NCIC MA-13. Proc Am Soc Clin Oncol 18:1a, 1999 (abstr 2) 33. The Scandinavian Breast Cancer Study Group 9401: Results from a randomized adjuvant breast cancer study with high dose chemotherapy with CTCb supported by autologous bone marrow stem cells versus dose escalated and tailored FEC therapy. Proc Am Soc Clin Oncol 18:2a, 1999 (abstr 3) 34. Bezwoda WR: Randomised, controlled trial of high dose chemotherapy (HD-CNVp) versus standard dose (CAF) chemotherapy for high risk, surgically treated, primary breast cancer. Proc Am Soc Clin Oncol 18:2a, 1999 (abstr 4) 35. Norton L: Evolving concepts in the systemic drug therapy of breast cancer. Semin Oncol 24:S10-3–S10-10, 1997 (suppl 10) 36. Frei E III, Elias A, Wheeler C, et al: The relationship between high-dose treatment and combination chemotherapy: The concept of summation dose intensity. Clin Cancer Res4:2027-2037, 1998[Abstract] Submitted January 4, 1999; accepted July 9, 1999.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
10), age (
49 years or 
2 test (log-rank statistic).
= 5-year DFS ± 1 SE).
