For the Anglo-Celtic Cooperative Oncology Group
Affiliations of authors: South West Wales Cancer Institute and University of Wales, Swansea (RCFL); Academic Department of Oncology, University of Hull, Hull, England (ML); Cancer Research UK Cancer Research Unit, University of Bradford, Bradford, England (CT); Weston Park Hospital and University of Sheffield, Sheffield, England (RC); University Hospital of Ghent, Ghent, Belgium (SVB); Addenbrookes Hospital, Cambridge, England (CW); University College, London, England (JL); Waikito Hospital, Waikito, New Zealand (IK); Velindre NHS Trust and Welsh School of Pharmacy, Cardiff, Wales (PBL); St. James's University Hospital, Leeds, England (TP); Northern Institute for Cancer Research, Newcastle upon Tyne, England (MV); Western General Hospital and Edinburgh University, Edinburgh, Scotland (DC); Scottish Cancer Therapy Network, Edinburgh (LF); Quantics Consulting Limited, Edinburgh (AY); St. Vincent's University Hospital, Dublin, Ireland (JC)
Correspondence to: R. C. F. Leonard, MD, South West Wales Cancer Institute, Singleton Hospital, Swansea, Wales, U.K. SA2 8QA (e-mail: r.c.f.leonard{at}swan.ac.uk)
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ABSTRACT |
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INTRODUCTION |
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Breast cancer is a partially chemotherapy-sensitive neoplasm (4), and contemporary chemotherapy regimens frequently produce tumor regression in patients with overt metastases. Tumor regression, which is usually partial and almost always temporary, translates into improvements in quality of life and provide a degree of prolonged survival. Although cure is rare, survival is increased by more than 1 or 2 years (5). The impact of these same treatments is considerably greater when they are used as postoperative adjuvant therapy in patients with early-stage disease (6), a phenomenon that is consistent with the preclinical results of Skipper and Schabel (7), who reported that all cancer cells grow and regress according to exponential kinetics and that there was invariably an inverse relationship between a tumor's size and its response to chemotherapy.
Adjuvant chemotherapy is now a widely accepted component of standard treatment for patients with lymph nodepositive breast cancer or for patients with higher-risk, lymph nodenegative breast cancer. There is general agreement that the anthracycline-containing combination chemotherapies are superior to older regimens that included only alkylating agents and antimetabolites, such as CMF (cyclophosphamide, methotrexate, and 5-fluorouracil). One such adjuvant therapy regimen, A-CMF (doxorubicin followed by CMF), has produced particularly promising results in breast cancer patients with multiple positive lymph nodes (8). However, the benefit of adjuvant chemotherapy, although of societal importance in reducing the death rates from this common cancer (9), has not met the expected benefit calculated by the exponential model (10). The absolute annualized survival benefits amount to a reduction in mortality of about 10% for lymph nodepositive breast cancer (11).
There are several possible explanations for this modest effect on absolute annualized survival. Drug-resistant cancer cells may lead to treatment failure. Such cells may be present before drug treatment or may develop by mutation in response to the evolutionary pressure of chemotherapy (10). In addition, resistance might be relative rather than absolute. Doseresponse relationships are fundamental to human pharmacology; in laboratory systems, cells can be killed by higher doses of chemotherapy drugs but can be resistant to lower doses of the same drug (12). Logarithmic degrees of dose escalation were usually required to effect cure in these models, and regimens that deliver modestly increased doses produce only inconsistent results (13,14).
Bone marrow autografting allows patients to receive much higher doses of chemotherapy agents (especially the alkylating agents) whose doses are otherwise limited by myelosuppression (15). In early studies (16,18,19), high-dose chemotherapy with autologous bone marrow cell support produced high rates of temporary response in patients with metastatic breast cancer who had already received extensive prior chemotherapy. Such prior treatments would have limited the tolerance of these patients to further chemotherapy and increased the likelihood that the cancers would be relatively resistant to further chemotherapy. Prolonged myelosuppression, however, frequently caused treatment-related death (16). This problem was addressed by the introduction of hematopoietic growth factors and peripheral blood progenitor cells that dramatically reduced the toxicity of this treatment, facilitating its use in patients at an earlier stage of the disease, especially in patients receiving adjuvant therapy (17).
The strategy that evolved and has been studied in most subsequent trials was the induction/intensification strategy, in which patients receive conventional chemotherapy, followed by high-dose therapy as a late-intensification regimen. Nonrandomized studies indicated that there was a substantial benefit from high-dose therapy in patients with metastatic breast cancer and in early disease in patients who had multiple positive lymph nodes (18,19), so even in the absence of appropriate evidence from randomized trials, high-dose therapy was soon established as a widely used standard therapy for breast cancer (20). Because of the urgent need for confirmation of these results in randomized trials, the Anglo-Celtic Group was founded in 1994 for the express purpose of conducting a prospective, nonblinded, randomized trial that compared a single cycle of high-dose chemotherapy with conventional chemotherapy in patients with high-risk breast cancer.
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PATIENTS AND METHODS |
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After providing written informed consent and before starting any chemotherapy, 605 patients were randomly assigned to one of the two treatment arms (307 to the high-dose arm and 298 to the conventional-dose arm) by the trial management office. Treatment was allocated by use of a computer-based randomization program that balanced two patient factors: 1) hospital of treatment and 2) number of positive lymph nodes (49 or 10 or more). Patients were randomly assigned to their treatment by telephone from the trial management office. The conventional-dose regimen consisted of four cycles of doxorubicin (75 mg/m2) given at 3-week intervals followed by eight cycles of intravenous CMF given at 3-week intervals (in doses of 600, 50, and 600 mg/m2, respectively). The high-dose regimen also consisted of four cycles of doxorubicin (75 mg/m2) at 3-week intervals, followed by a stem-cell mobilization cycle of cyclophosphamide (4000 mg/m2) and filgrastim (300 µg/day) until adequate CD34 cell counts were obtained. This treatment was followed by leukapheresis to harvest peripheral blood progenitor cells; a minimum of 1 x 106 CD34-positive cells was required. If this criterion was not met, bone marrow was harvested. After a 7- to 10-day rest period, patients received high-dose therapy with cyclophosphamide (6000 mg/m2) and thiotepa (800 mg/m2). Cyclophosphamide (with mesna at 900 mg/m2 in 1 L of normal saline over 24 hours) and thiotepa (in 1 L of normal saline over 24 hours) were administered concurrently over 24 hours on days 0, 1, 2, and 3, with 1 L of normal saline containing mesna (300 mg/m2) given over 12 hours on day 4. At the largest recruiting center with the most experienced nurses, nine patients in the high-dose arm were managed during the recovery phase as outpatients. No early deaths occurred in this group. All other patients in the high-dose arm were admitted to the hospital within the next 2 or 3 days after infusion for protocol-guided management of the recovery phase for marrow function. After recovering from the toxic effects of chemotherapy, patients were given adjuvant radiotherapy according to institutional guidelines. The protocol mandated that, after the completion of chemotherapy, tamoxifen (20 mg/day taken orally for 5 years) be taken by all patients with known estrogen receptorpositive tumors and to all patients with unknown estrogen receptor status. The patients who were estrogen receptornegative were given tamoxifen at the discretion of the treating physician. At the time of the trial, overview data were lacking on whether tamoxifen was beneficial for estrogen receptornegative disease.
Radiation therapy to the chest wall was given to all patients after completion of all chemotherapy. Field size and dose were set out in the protocol. Variations in axillary fields were allowed according to the extent of axillary surgery and the presence of an extra-nodal extension of axillary lymph node metastases.
Of the 605 patients randomly assigned to treatment (Fig. 1), 307 were assigned to high-dose therapy, 296 of these patients received their allocated treatment, two of these patients were lost to follow up, and 15 discontinued treatment; all patients in the high-dose arm, except the two patients lost to follow-up, were included in the intent-to-treat analysis. In the conventional-dose arm, 298 patients were randomly assigned to treatment, 290 of these patients received their allocated treatment, no patient was lost to follow-up, and four of these patients discontinued treatment; all patients in the conventional-dose arm were included in the intent-to-treat analysis.
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The 5-year relapse-free survival rate was expected to be about 50% in the conventional-dose arm from the results of Bonadonna et al. (8). With 300 patients assigned to each arm, their study was designed to have 80% power to detect an absolute difference (by a two-sided test) of 12% in relapse-free survival at 5 years with an alpha level of 5%.
Patient characteristics were compared between the two arms of the trial to check for balance. For continuous variables, the median, maximum, and minimum values were reported for each arm, and the Wilcoxon test was used to compare the results among arms. For categorical variables, Fisher's exact test was used to compare proportions, except that the chi-squared test was used when there were more than two classes.
Relapse-free survival was defined as the shorter of the time to first relapse or the time to death from breast cancer. Patients who were alive and disease-free had their relapse-free survival censored at the date they were last seen alive. Patients who died from causes other than breast cancer had their relapse-free survival censored at the date of death. Overall survival was defined as the time to death from any cause. Patients who were alive had overall survival censored at the date last seen alive. A further end pointevent-free survivalwas also defined as the shorter of either the time to first recurrence or the time to death from any cause. Toxicity was monitored by the Monitoring Committee. If treatment-related mortality had reached unacceptable levels (5%), the trial would have been stopped. A sequential decision rule was used. Analysis was to be performed on an intent-to-treat basis. No interim analyses were planned.
Survival curves for end points were estimated by the KaplanMeier method, and the curves were compared between treatment arms with the log-rank test, stratified by lymph node status. Five-year survival was estimated, and 95% confidence intervals (CIs) were calculated. The Cox proportional hazards model was also used to compare relapse-free survival between the treatment arms, adjusting for age, menopausal status, estrogen receptor status, and lymph node status. The hazards functions for the subgroups were compared graphically and were judged to have met the proportionality assumptions required for this analysis. All statistical tests were two-sided.
Study Organization and Support
The Anglo-Celtic Cooperative Oncology Group is a voluntary, investigator-led initiative, set up specifically to conduct this study (and future studies) in the United Kingdom and Ireland. The Group expanded in 1997 to include investigators from Belgium and New Zealand. Data management was provided through the Scottish Cancer Treatment Network. Amgen (U.K.) provided an unrestricted grant to facilitate the conduct of the trial and offered filgrastim to participating centers at reduced cost.
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RESULTS |
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There was no statistically significant difference in relapse-free survival between the arms of the trial. At the time of this analysis, 253 relapses had been reported (four of which were deaths from cancer in which initial time of relapse was not reported), 124 of the 253 patients were in the high-dose arm and 129 patients were in the conventional-dose arm. Figure 2 shows the life-table estimates of the relapse-free survival probabilities for these two groups. Two patients, both on the high-dose arm of the study, were lost to follow-up immediately after random assignment, so the number of patients in the high-dose arm for this analysis was 305. The difference between the groups at this stage was not statistically significant (P = .73, log-rank test adjusted for lymph node status). The 5-year relapse-free survival rate estimated for the high-dose arm was 57% (95% CI = 51% to 63%) and that for the conventional-dose arm was 54% (95% CI = 48% to 61%). The Cox proportional hazards model was also applied to the relapse-free survival analysis to adjust for age, menopausal status, estrogen receptor status, and lymph node status. The adjusted difference between the treatment arms was not statistically significant (P = .64). Several subgroup analyses (which were not specified in the original protocol) were conducted. No obvious benefit for high-dose therapy over conventional-dose chemotherapy was observed in patients with four to nine involved axillary lymph nodes or 10 or more involved axillary lymph nodes in patients who were age 50 years or younger or in patients who were pre- or postmenopausal.
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The life-table estimates of the overall survival probabilities for the two arms of the trial are shown in Fig. 3. At the time of this analysis, 211 deaths had been reported: 111 in the high-dose arm and 100 in the conventional-dose arm. The difference between the groups at this stage was not statistically significant(P = .38, log-rank test adjusted for lymph node status), and no statistically significant difference between the arms was observed for any subgroup. The 5-year overall survival rate estimated for the high-dose arm was 62% (95% CI = 56% to 68%) and that for the conventional-dose arm was 64% (95% CI = 57% to 70%).
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There were five treatment-related deaths in the high-dose arm. These five patients were randomly assigned between April 1995 and September 1998 and died between October 1996 and March 1999. The causes of death were sepsis, suspected pulmonary fibrosis, toxic shock syndrome, organ failure caused by systemic Aspergillus infection, and gram-negative bacterial sepsis. Because of the frequency of treatment-related deaths, it was also appropriate to examine event-free survival, where an event was defined as a relapse of cancer or a treatment-related death. These results are shown for the two treatment arms in Fig. 4. Again, the difference between the arms was not statistically significant (P = .89, adjusted for lymph node status). The 5-year event-free survival rate estimated for the high-dose arm was 55% (95% CI = 49% to 61%) and that for the conventional-dose arm was 54% (95% CI = 48% to 61%).
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Toxicity caused by chemotherapy was largely predictable and successfully managed at all centers. A detailed analysis of toxicities from the induction phase of chemotherapy with doxorubicin found that the main hematologic toxicity was, predictably, neutropenia, which was grade 4 in 89 of the 605 patients and was associated with infection in 13 patients; none of the infections were reported as life threatening. Grade 3 nausea was reported in 51 patients, and severe vomiting was reported in 17 patients. There was no clinical cardiac toxicity, and other toxicities were minor.
Toxicities reported on the treatment summary form and on follow-up forms after completion of treatment are provided in Table 2. In addition, several cases of shingles were reported in patients in the high-dose arm, although data on this complication were not collected systematically, and all cases of shingles responded well to treatment with acyclovir. Menopausal symptoms were also a common complaint among women in both arms of the trial but, again, these data were not collected systematically.
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DISCUSSION |
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It is important to note that the outcome of current conventional adjuvant treatment regimens may be better than that of the conventional adjuvant treatment regimens used in the uncontrolled studies of high-dose treatment of the early 1990s (19). In fact, the A-CMF regimen used in this trial appears to be an effective therapy for breast cancer patients with four or more positive lymph nodes and may not be inferior to the newer taxane-based regimensa possibility that is currently being tested in a randomized trial in the United Kingdom. In indirect comparisons, medium-term, disease-free survival was at least equivalent for patients treated with a block sequential A-CMF regimen and for patients treated with taxane-based regimens (2123).
A similar argument may also explain the relative lack of benefit for patients treated with a single high-dose, late-intensification regimen, as reported in the Swedish trial by Bergh et al. (24). However, the conventional-dose arm in that trial was distinctly unconventional because of its pioneering use of a tailored, toxicity-directed, dose escalation regimen that resulted in higher total doses for several cytotoxic agents than those in the high-dose arm.
Although the results of randomized trials of high-dose chemotherapy in patients with metastatic breast cancer and in the adjuvant setting for high-risk, early-stage breast cancer have not fulfilled the expectations generated by the results of earlier nonrandomized trials, none of these randomized trials (2433) reported improved overall survival in the high-dose arm. The accumulation of these data, coinciding with the disclosure that the results of two other allegedly positive studies were unreliable (34,35), resulted in an appropriate decline in the use of high-dose therapy as an off-study treatment for breast cancer. Regrettably, however, valid ongoing studies were also prematurely terminated. A consensus emerged that the promising results reported from single-arm studies of high-dose chemotherapy were artifacts of case selection biases (36).
Could it be that an inadequate reduction of tumor burden was achieved by the anthracycline induction phase of high-dose chemotherapy, an outcome that was ameliorated by prolonged CMF exposure in the conventional-dose arm? Three large studies of autograft-supported, high-dose, adjuvant chemotherapy given as a late-intensification regimen versus more conventional approaches have been published (24,25,30). The Bergh et al. study (24) was discussed above. The Dutch national study (25) compared FEC therapy (5-fluorouracil, epirubicin, and cyclophosphamide) followed by high-dose chemotherapy with FEC therapy alone in breast cancer patients with four or more involved lymph nodes. There was a statistically nonsignificant trend for improved relapse-free survival in the high-dose arm. For patients with 10 or more involved lymph nodes, those in the high-dose arm had statistically significantly longer relapse-free survival (P = .05) than those in the FEC alone arm (25). A smaller ECOG trial showed no benefit for a single high-dose intensification regimen (30). Two other small negative studies had limited power to detect differences between treatment regimens (27,28).
In a study by Peters et al. (29), a decreased rate of cancer relapse was associated with high-dose therapy compared with conventional-dose therapy, but a relatively high rate of treatment-related death in the high-dose arm undermined any survival benefit. In a French trial (PEGASE 01) (30), high-dose therapy, compared with conventional-dose control therapy (four cycles of FE100C), was associated with superior disease-free survival but not with superior overall survival. A small Japanese (37) study was also negative. Gianni et al. (31) reported that an alternative approach to a therapeutic intensification regimen was not superior to A-CMF. In the alternative approach, higher-than-standard doses of single agents were administered in sequence, followed by a single autograft-supported cycle of high-dose sequential chemotherapy. Thus, these studies appear to indicate that high-dose chemotherapy has a weak or inconsistent impact, or perhaps no impact at all, in breast cancer. However, we urge that a meta-analysis be conducted of the currently completed trials of adjuvant high-dose chemotherapy to provide additional information.
The results of the high-dose treatment could be dependent on the specific form of high-dose chemotherapy investigated or on the order in which agents were administered. Is the dogma that high-dose chemotherapy should be given after a phase of conventional induction therapy correct? Is single-cycle, high-dose therapy ever going to be adequate to initiate cure by killing cancer cells or does it merely serve to induce chemoresistance? It has been hypothesized that multiple high-dose cycles should be administered as primary treatment in order to overcome resistance (38). It is striking that three recent studies (32,33,39), two of which showed increased disease-free survival (32,33) with the third (39) showing a compelling trend for increased disease-free survival, had at least two cycles of high-dose therapy with limited conventional induction therapy. Other explanations for the failure of high-dose chemotherapy to eradicate disease include graft contamination by tumor cells or the differential effects of high-dose therapy on distinct biologic subgroups of patients (e.g., those defined as positive or negative for HER2)should also be considered.
In conclusion, after surgery for high-risk breast cancer, a single high-dose chemotherapeutic treatment, given after a phase of conventional-dose anthracycline chemotherapy, is not superior to conventional-dose A-CMF sequential chemotherapy. This conclusion is based on a protocol-directed analysis of the outcomes after a median follow-up of 60 months. These results both in isolation and in the context of the individual analyses of similarly powered, single, high-dose, randomized, controlled trials, indicate that the single, high-dose, late-intensification chemotherapy strategy confers extra cost and toxicity without added anticancer benefit. The results of two similarly designed trials (24,28), however, suggest that there may be biologically discrete subgroups of patients who appear to benefit. Results of a meta-analysis of all the available data from the recent studies may allow better targeting of relevant therapy to such subgroups.
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NOTES |
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Dr. Cameron has received financial support to conduct research and honoria from Amgen, Pfizer, and Roche. R. C. F. Leonard is a consultant for Amgen, U.K., and his unit received an educational grant from Amgen, U.K., in 2001.
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Manuscript received December 23, 2003; revised May 4, 2004; accepted May 13, 2004.
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