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. 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
Several retrospective analyses in breast cancer have suggested
that dose might correlate with clinical outcome. In 1981, Bonadonna and
Valagussa reported that women with node-positive breast cancer who received
> 85% of a planned dose of CMF (cyclophosphamide [Cytoxan, Neosar],
methotrexate, 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]
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. 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 or epirubicin [Ellence]), alkylating agents (such as
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. 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 arma 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.
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
High-Dose 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.
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.
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
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. 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
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
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. 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. 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, 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. 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. 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. 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 syndromea 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. 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
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