Introduction
Improvements in cancer screening and therapy have led to earlier detection and a reduction in the mortality of breast cancer over the past 2 decades. Despite this progress, one in eight American women who live to age 85 will develop breast cancer. Furthermore, breast cancer remains a leading cause of death in women between the ages of 15 and 54.[1-3] In an attempt to improve the outcome of therapy for breast cancer, researchers and clinicians have examined the use of higher doses of effective anticancer agents. Substantial in vitro and animal data support the concept that increasing drug dose is an effective method of increasing tumor cell kill.[4] These models, however, frequently indicate a plateau, above which increases in drug dosage do not result in further antitumor activity. In patients, it is not known whether this plateau has been reached when the maximal tolerated dose has been given.
For many effective anticancer agents, myelotoxicity is the major toxicity that limits further drug administration. Recent improvements in supportive care, the development of hematopoietic growth factors, and the use of bone marrow and stem cell support now allow for the safer administration of higher doses of chemotherapeutic agents. The question remains, however, whether increasing the dose intensity of chemotherapy will result in improved clinical outcome.
The Dose-Intensity Concept
Several retrospective analyses in breast cancer have suggested that dose might correlate with clinical outcome. In 1981, Bonadonna and Valagussa[5] reported that women with node-positive breast cancer who received > 85% of a planned dose of CMF (cyclophosphamide [Cytoxan, Neosar], methotrexate(Drug information on methotrexate), fluorouracil(Drug information on fluorouracil) [5-FU]) achieved a better clinical outcome than those who received less. On the other hand, those who received < 65% of the intended dose fared no better than women in the untreated control group. Based on information from this trial as well as other retrospective studies, Hryniuk et al devised the concept of "dose intensity," a measure of the amount of drug administered per unit time. Retrospective evaluations of dose intensity vs outcome in both the adjuvant and metastatic disease settings supported the hypothesis that higher doses of chemotherapy impart a better outcome in breast cancer. These results led to a series of prospective, randomized clinical trials that addressed the issue of dose in breast cancer.[6,7]
Dose Escalation in the Subtransplant Range
Several methods are used to increase the dose of drug delivered. Biganzoli and Piccart summarized a number of variables in breast cancer treatment, including dose intensity, dose density, cumulative dose delivered, and duration of therapy, that may contribute to treatment results.[8] They postulated the existence of at least five models using these variables that could permit the delivery of higher chemotherapy doses in both early and advanced stages of breast cancer. Many of these have been tested in the randomized clinical trials discussed in this article. In general, these trials have sought to evaluate the effect of dose increases of anthracyclines (such as doxorubicin(Drug information on doxorubicin) or epirubicin(Drug information on epirubicin) [Ellence]), alkylating agents (such as cyclophosphamide(Drug information on cyclophosphamide)), and more recently, the taxanes.
Dose Escalation in Advanced Breast Cancer
Low-Dose vs Standard-Dose CMF: In one of the first trials to evaluate the effect of drug dose on response, Tannock et al prospectively compared two doses of CMF in patients with previously untreated metastatic breast cancer.[9] Low-dose CMF (cyclophosphamide, 300 mg/m2; methotrexate, 20 mg/m2; and 5-FU, 300 mg/m2 IV, on day 1 of 21-day cycles) was compared to standard-dose CMF (600, 40, and 600 mg/m2, respectively). Response rates were 26% for the standard-dose arm and 11% for the low-dose arm, demonstrating that low-dose CMF was inferior to standard dosing. Median survival was 15.6 months in the standard-dose arm and 12.8 months in the low-dose arm—a difference that was not significant. The European Organization for Research and Treatment of Cancer compared a standard CMF regimen that incorporated higher oral doses of cyclophosphamide and a higher 5-FU dose with a modified lower-dose IV schedule. Results showed improvements in both response and survival with the higher-dose intensity standard CMF regimen.[10]
High-Dose Epirubicin: In the past decade, eight large randomized trials have examined the effects of epirubicin dose on outcome for women with advanced, metastatic breast cancer.[11-18] These trials evaluated epirubicin alone or in combination with cyclophosphamide, 5-FU, or both (FEC). The increased dose intensity of epirubicin in these trials ranged from approximately 1.5- to 3.5-fold, and the planned and delivered dose intensities were generally similar.
In all of these studies, increased dose intensity was associated with improved response rate. In some trials, this was associated with a prolongation in median time to progression. However, none of these trials noted any significant survival benefit. One consistent finding supported the concept of a dose threshold; ie, that clinical outcome as measured by response rate is compromised by a low epirubicin dose intensity. However, there is little evidence for a substantial benefit of epirubicin dose escalation beyond the standard dose.
High-Dose Paclitaxel(Drug information on paclitaxel): More recently, paclitaxel (Taxol) has emerged as an effective agent for the treatment of breast cancer. Nabholtz et al compared the doses of paclitaxel, 175 mg/m2 vs 135 mg/m2, both given as a 3-hour infusion every 21 days to 471 patients with metastatic breast cancer.[19] Results showed a trend toward a better overall response rate (29% vs 22%) and complete response rate (5% vs 2%), as well as a significant improvement in median time to disease progression (4.2 vs 3 months, P = .027) for the higher dose. However, median survival and response duration were not affected by dose.
Examining even higher doses of paclitaxel, a Cancer and Leukemia Group B (CALGB) trial randomized 475 women with stage IV breast cancer to paclitaxel doses of 175, 210, or 250 mg/m2, all infused over 3 hours.[20] Response rates were similar for the three dosing schedules (21%, 28%, and 22%, respectively), as were median survival rates (9.8, 11.8, and 11.9, months, respectively). A correlation of borderline significance (P = .03) between paclitaxel dose and time to treatment failure (3.8, 4.1, and 4.8 months for 175, 210, and 250 mg/m2, respectively) was observed. Neurosensory and hematologic toxicities were found to increase with the dose of paclitaxel. Thus, based on these trials, there is no obvious benefit for the routine dose escalation of paclitaxel beyond the dose of 175 mg/m2 over 3 hours.
Dose Escalation in Adjuvant Therapy for Early-Stage Breast Cancer
It may be argued that improved outcome with increased dose intensity will most likely be seen in the adjuvant setting, where the target is micrometastatic disease. One of the most important trials to examine the role of anthracycline and alkylating agent dose intensity was CALGB 8541.[21] Women with node-positive breast cancer were randomly assigned to receive cyclophosphamide, doxorubicin, and 5-FU at one of the following three levels of dose intensity: high dose (600 mg/m2 cyclophosphamide, 60 mg/m2 doxorubicin, and 600 mg/m2 5-FU, every 4 weeks for four cycles); moderate dose (400 mg/m2 cyclophosphamide, 40 mg/m2 doxorubicin, and 400 mg/m2 5-FU, every 4 weeks for six cycles); or low dose (300 mg/m2 cyclophosphamide, 30 mg/m2 doxorubicin, and 300 mg/m2 5-FU, every 4 weeks for four cycles). On day 8 of each cycle, 5-FU was repeated. Cumulative doses of the three drugs were identical in the high- and moderate-dose groups and 50% lower in the low-dose group. Thus, the high- and moderate-dose arms featured the same cumulative dose with different dose intensities, whereas the low-dose arm had both reduced cumulative doses and reduced dose intensities.
In the first report of this study, the low-dose arm showed poorer results in all clinical outcomes at 3 years when compared with the moderate- or high-dose arms. However, no major differences were noted between outcome in the moderate- and high-dose arms. Disease-free survival at 3 years was 74%, 70%, and 63%, while overall survival was 92%, 90%, and 84% for the high-, moderate-, and low-dose arms, respectively. Updated results after a median follow-up of 9 years continue to show benefit for the moderate- and high-dose arms compared with the low-dose group, with no substantial difference in outcome between the first two arms.[22] Disease-free survival at 5 years was 66%, 61%, and 56%, while overall survival was 79%, 77%, and 72% for the high-, moderate-, and low-dose arms, respectively.
A provocative finding from this trial was the retrospective observation that high expression levels of the HER2/neu gene were associated with superior patient outcome on the high-dose arm.[23] Analyses of tumors derived from 397 patients enrolled in CALGB 8541 demonstrated that patients assigned to the high-dose, but not the low- or moderate-dose, had significantly longer disease-free survival and overall survival if their tumors had high levels of expression of the HER2/neu protein. However, a second analysis that included a further 595 patients was not as compelling,[24] and thus, the issue of HER2/neu overexpression as a predictor of chemotherapy dose response remains an open question.
A similarly designed trial was reported by the French Adjuvant Study Group.[25] Over 500 women with high-risk, node-positive breast cancer were randomized to receive six cycles of FEC 50 (fluorouracil, 500 mg/m2; epirubicin, 50 mg/m2; and cyclophosphamide, 500 mg/m2, on day 1 every 3 weeks) or the same regimen with epirubicin, 100 mg/m2 (FEC 100). As expected, toxicity was less in the FEC 50 group, but clinical outcome was also inferior. Disease-free survival at 5 years was 54.8% for FEC 50 and 66.3% for FEC 100 (P = .03), while 5-year overall survival was 65.3% for FEC 50 and 77.4% for FEC 100 (P = .007). Taken together, the results of these two trials are consistent with a dose threshold hypothesis; that is, an adequate dose of chemotherapy is necessary to maximize efficacy. However, neither trial addresses the role of routine dose escalation of these agents beyond standard doses.
High-Dose Cyclophosphamide: Dose escalation of cyclophosphamide with fixed-dose doxorubicin has now been tested in two sequential National Surgical Adjuvant Breast and Bowel Project (NSABP) trials as adjuvant treatment in women with node-positive breast cancer.[26,27] In both trials, doxorubicin at 60 mg/m2 was given every 3 weeks for a total of four cycles, while the cyclophosphamide dose varied. In NSABP B-22, patients in the standard-dose arm received 600 mg/m2 of cyclophosphamide in each cycle, whereas patients in the high-dose arm received 1,200 mg/m2 of cyclophosphamide in each of the four cycles.[26] An intermediate arm administered 1,200 mg/m2 of cyclophosphamide during the first two cycles only, thus providing the same total cyclophosphamide dose as in the standard-dose arm, but at a higher dose intensity since it was administered over half the time. Colony-stimulating factors were not used. Over 2,300 patients were randomized in this trial.
Results showed no significant differences in disease-free or overall survival through 5 years. The 5-year disease-free survival rates were 62%, 60%, and 64% for the standard-, intermediate-, and high-dose arms, respectively, while overall survival rates were 78%, 77%, and 77%. Not surprisingly, toxicities worsened with treatment intensity. Of particular concern was the observation of hematologic malignancies in two patients in the standard-dose group, one patient in the intermediate-dose group, and three patients in the high-dose group. Thus, in this trial, the administration of cyclophosphamide at a twofold higher dose intensity offered no benefit and was associated with excess toxicity.
Before the results of NSABP B-22 were reported, NSABP B-25 explored the value of even greater cyclophosphamide dose escalation, again with fixed-dose doxorubicin.[27] In this study, 2,548 node-positive patients were randomized to receive four cycles of variable doses of cyclophosphamide with doxorubicin at 60 mg/m2/cycle. The three cyclophosphamide levels were 1,200 mg/m2/cycle for four cycles; 2,400 mg/m2/cycle for two cycles; and 2,400 mg/m2/cycle for four cycles. Granulocyte colony-stimulating factor (G-CSF [Neupogen]) was routinely administered beginning on day 2.
This trial did not show any statistically significant benefit of cyclophosphamide doses increased fourfold over the standard dose. At 5 years, the disease-free survival of women in the three groups, respectively, was 60%, 61%, and 66%—a difference that did not achieve statistical significance. Survival was identical across the three groups at 77%, 76%, and 78%. Of note, 14 patients enrolled in this trial have developed acute myelogenous leukemia and 7 other patients were found to have myelodysplastic syndrome—a 0.8% incidence of these myeloproliferative disorders.
Based on the combined results of NSABP B-22 and B-25 to date, dose escalation of cyclophosphamide beyond standard dose in this type of outpatient regimen is not a useful clinical strategy and is clearly associated with greater toxicity.
High-Dose Doxorubicin: Doxorubicin is an active agent in breast cancer, and studies of its use as a single agent in metastatic breast cancer suggest a dose-response relationship. Based on these observations, the CALGB instituted a trial investigating escalating doses of doxorubicin in the adjuvant setting.[28] This Intergroup trial, CALGB 9344, randomized 3,120 women with node-positive breast cancer in a 3 × 2 factorial trial design to a standard dose of cyclophosphamide (600 mg/m2) plus doxorubicin (60, 75, or 90 mg/m2) given every 3 weeks for a total of four cycles, followed or not by paclitaxel at 175 mg/m2 every 3 weeks for four cycles. Use of G-CSF prophylaxis was allowed for the intermediate dose of doxorubicin and was required for the highest dose. Disease-free survival at 18 months was 86% in doxorubicin/cyclophosphamide recipients not given paclitaxel and 90% in those who were given paclitaxel; overall survival was 95% and 97% in the two groups, respectively. No effect was noted with changes in the doxorubicin dose. Thus, initial results of this trial would argue that a 50% increase in doxorubicin dose is not beneficial in the adjuvant treatment of node-positive breast cancer. Results from this series of trials are summarized in Table 1.
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