Volume 12, Issue 2 , Pages 195-203, February 2006
Consolidation with High-Dose Combination Alkylating Agents with Bone Marrow Transplantation Significantly Improves Disease-Free Survival in Hormone-Insensitive Metastatic Breast Cancer in Complete Remission Compared with Intensive Standard-Dose Chemotherapy Alone
Article Outline
Abstract
We conducted this study to determine event-free and overall survival among women with hormone-insensitive or hormone-resistant metastatic breast cancer receiving consolidation with high-dose chemotherapy (HDC) and hematopoietic support versus no further chemotherapy after intensive induction chemotherapy. Eligible patients received induction doxorubicin, 5-fluorouracil, and methotrexate (AFM) for 2 to 4 cycles. Women in complete remission were randomized to immediate HDC with cyclophosphamide, cisplatin, and carmustine followed by autologous hematopoietic support or to no further therapy. Patients on the observation arm of therapy were offered salvage HDC at the time of relapse. Partial responders to AFM were offered immediate HDC. A total of 425 patients were enrolled onto the study. The median event-free survival for women randomized to induction therapy alone was 3.8 months, compared with 9.7 months for women who completed HDC (P < .006). Of the patients randomized to observation, 5 (10%) of 51 remain event free, compared with 13 (26%) of 49 patients who underwent immediate HDC (P = .03). Of women converted to a complete response by salvage HDC after a partial response to AFM, overall survival was similar to that in women randomized to immediate HDC. Follow-up is now in excess of 5 years. The 5-year event-free survival is 15% (95% confidence interval, 12%-18%), and the 5-year overall survival is 20% (95% confidence interval, 17%-25%). Immediate HDC after a complete response to AFM produced some durable long-term responses in hormone-insensitive/-resistant metastatic breast cancer. Salvage HDC converted 30% of partial responders to complete responders with similar survivals. The addition of novel targeted therapies to intensive-dose chemotherapy regimens may further improve survival in metastatic breast cancer.
Key words: Hormone-insensitive metastatic breast cancer , High-dose chemotherapy , Intensive induction chemotherapy , Bone marrow transplantation
Introduction
Breast cancer is the most common malignancy in women and is the second leading cause of cancer-associated mortality [1]. Despite advances in treatment, the prognosis for women with metastatic breast cancer remains poor, with a median survival of 12 to 18 months [2, 3, 4]. The survival is shorter for the subgroup of hormone receptor–negative patients and for patients whose hormonal therapy has failed; these patients have an 8- to 12-month median survival [3]. It is unusual for a woman with hormone-insensitive metastatic breast cancer to live for 5 years, especially progression free. Large series and meta-analyses have demonstrated <10% 5-year survival for all patients and <5% 5-year survival for hormone receptor–negative patients [2, 3, 4]. Furthermore, long-term survival in breast cancer, as in other cancers, has as a necessary, but not sufficient, condition the achievement of complete remission (CR), which is evident in both primary and metastatic disease.
Breast cancer is generally responsive to chemotherapy, with objective response rates between 50% and 90% in chemotherapy-naive metastatic breast cancer [5, 6, 7, 8]. However, standard chemotherapy, even with contemporary regimens, usually results in CRs in <20% of treated patients [5, 6, 7, 8]. High-dose combination chemotherapy with hematopoietic support produces overall response rates up to 95%, with CR rates between 40% and 60% [9, 10, 11, 12, 13]. The improved survival in women with metastatic breast cancer treated with high-dose chemotherapy (HDC) has been attributed by some to selection of patients with fewer sites of metastatic disease and improved performance status [14]. Few randomized trials have investigated HDC versus standard chemotherapy in patients with metastatic breast cancer, and those that have been reported are small or have had overall poor treatment results. We performed a prospective, randomized study comparing consolidation with HDC with hematopoietic support versus no further chemotherapy in women with hormone-insensitive or hormone-resistant metastatic breast cancer in CR after intensive doxorubicin-based induction chemotherapy.
Methods
Patients
A total of 425 patients were enrolled between May 1988 and May 1995. All patients had biopsy-positive measurable metastatic breast cancer (387 patients) or inflammatory breast cancer (39 patients) and had not received chemotherapy for metastatic disease. Patients were estrogen receptor (ER) and progesterone receptor (PR) negative or had experienced treatment failure of at least 1 round of hormonal therapy if the tumor was ER or PR positive before enrollment.
All patients underwent an extensive staging evaluation, including a computed tomographic scan of the head, chest, abdomen, and pelvis; bone scan; multiple gated acquisition; pulmonary function tests; bilateral bone marrow aspirates and biopsies; creatinine clearance; and routine blood work. Patients were eligible if they had a Karnofsky performance status of at least 80%; forced vital capacity, forced expiratory volume in 1 second, and carbon monoxide diffusion in the lung ≥60% of predicted; left ventricular ejection fraction ≥45% (lower limit of normal at our institution); aspartate aminotransferase and bilirubin ≤1.5 times normal; and creatinine clearance ≥60 mL/min. Patients were ineligible if they had an untreated central nervous system metastasis; positive bone marrow aspirate or biopsy on routine histology; >3 bone metastases; or positive β-human chorionic gonadotropin, human immunodeficiency virus antibody, or hepatitis B surface antigen.
Induction Chemotherapy
Eligible patients received induction doxorubicin, 5-fluorouracil, and intermediate-dose methotrexate (AFM) as previously described [15]. The 5-fluorouracil was given at a dose of 750 mg/m2 as a continuous infusion, days 1 to 5; doxorubicin 25 mg/m2 as an intravenous bolus, days 3, 4, and 5; and methotrexate 250 mg/m2 with folinic acid rescue on day 15. The patients received the methotrexate only if their mucositis and dermatologic toxicity were grade <3 according to the common toxicity grading criteria. The incidence of grade 3 or 4 mucositis was high, so during the study, a cohort of patients (n = 60) was begun on 5-fluorouracil 500 mg/m2. Patients who received 5-fluorouracil 750 mg/m2 achieved a higher CR rate than those who received 500 mg/m2 (30% versus 22%; P = .045; χ2), so the dose was returned to 750 mg/m2.
The patients received 2 to 4 (median, 4) cycles of AFM to the point of maximum response or a maximum dose of doxorubicin 500 mg/m2 for patients who had received prior adjuvant doxorubicin. The design of the trial called for randomization at the point of CR, without additional cycles of AFM, notwithstanding the cumulative doxorubicin exposure at the time of maximum response.
Evaluation
The patients underwent a repeat staging evaluation, including a physical examination and computed tomographic scan of the chest, abdomen, and pelvis, after the second and each subsequent cycle of AFM chemotherapy. The response to induction AFM was determined by using standard criteria, with the sum total of the perpendicular products of measurable disease used as the determinant of response. The responses were scored at a group meeting, which included an independent radiologist. Eight patients with a minimal or indeterminant site of disease initially evaluated as partial response were converted to a CR by either surgical resection or radiation therapy and were then randomized per protocol.
To validate the accuracy of the data, an independent audit of the data from randomized patients was undertaken. Patient charts and radiographs were reviewed to verify patient demographics, sites of disease, chemotherapy treatments, treatment responses, and times to relapse and death. Two cases were identified in which the information extracted during this independent review differed from the initial evaluations. These differences were evaluated and resolved. This analysis used the audited and reconciled database.
Randomization and Treatment Methods
Patients evaluated as having a CR after AFM induction therapy were randomized either to immediate HDC and hematopoietic support or to AFM induction alone (observation). Patients randomized to observation who subsequently relapsed were offered treatment with the same HDC and hematopoietic support as salvage therapy at the time of relapse (immediate versus salvage transplantation) and were followed up for response and survival.
Patients who were evaluated as achieving a partial response after AFM induction therapy were treated with immediate consolidation with HDC and hematopoietic support. The patients whose disease did not respond or progressed on AFM induction were not considered appropriate for HDC on this trial.
Bone Marrow Harvest
After AFM induction chemotherapy and hematopoietic recovery to a leukocyte count ≥3000/μL, patients randomized to HDC underwent a bone marrow harvest, as previously described [16]. Briefly, the bone marrow was obtained from the posterior iliac crests by using multiple aspirations, with a minimum goal of 1 × 108 nucleated cells per kilogram. The patients randomized to AFM induction alone (observation) also underwent the bone marrow harvest immediately after randomization.
Leukapheresis
After the bone marrow harvest, patients underwent cytokine priming to mobilize peripheral blood progenitor cells. The use of cytokine priming evolved during the study, and at different times, patients received granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, or interleukin 3. The patients were cytokine-primed on several growth factor studies [17]. Each cytokine-primed patient underwent 1 to 3 leukaphereses, until collection of a minimum of 1 × 1010 mononuclear cells. CD34 enumeration was not generally used during the time frame of this study as a guide for the number or duration of leukaphereses.
High-Dose Chemotherapy
The patients received high-dose cyclophosphamide, cisplatin, and carmustine, the STAMP 1 regimen developed by Eder et al. [18]. The cyclophosphamide was administered intravenously over 1 hour at 1875 mg/m2/d, days −6, −5, and −4. The cisplatin was administered as a continuous infusion at 55 mg/m2/d on days −6, −5, and −4. The carmustine was administered as a 2-hour infusion at 600 mg/m2 on day −3. The doses of chemotherapy were adjusted to the mean of the actual weight and ideal body weight by using the New York Life Insurance Company Table for patients with an actual weight ≥20% above their ideal body weight. Patients who weighed <20% above their ideal body weight received chemotherapy doses based on their actual weight.
Bone Marrow and Peripheral Blood Progenitor Cell Infusions
The bone marrow was thawed rapidly in a 37°C water bath at the bedside and infused over 15 to 30 minutes through the central venous access catheter. The bone marrow was infused on day +1. The peripheral blood progenitor cells were thawed in a similar fashion at the bedside. Equal aliquots of peripheral blood progenitor cells were infused on days −1, 0, and +1.
Consolidative Radiation Therapy or Surgery
After completion of HDC, patients were intended to receive consolidation radiation therapy to pretreatment sites of bulk disease in excess of 3 cm where possible. A small number of patients underwent surgical consolidation, and they included patients with a residual single lung (n = 1) or liver (n = 2) metastasis or those with modified radical mastectomy for women with inflammatory breast carcinoma (n = 7). Of the other 32 patients with inflammatory breast cancer, 20 did not proceed to HDC (9 had progressive disease, and 11 refused or had excessive pre-HDC toxicity), and 12 had mastectomy before HDC.
The radiation therapy was delivered in an attempt to sterilize the residual metastatic focus and is described in detail elsewhere [19]. Radiation therapy was predominantly administered to soft tissue disease, such as the chest wall or lymph nodes. Visceral disease, such as lung or liver metastases, was rarely consolidated with radiation therapy.
Statistical Methods
The primary end point for this study was event-free survival among randomized patients in an intent-to-treat analysis. In addition, the overall survival for all patients enrolled and after immediate or salvage transplantation, as well as for the patients in partial remission after AFM induction, was determined by using the Kaplan-Meier product-limit method [20]. The crossover design for high-dose consolidation confounds the interpretation of overall survival between the 2 randomized groups and essentially compares immediate versus salvage transplantation, because both groups were prescribed to receive the same HDC. The log-rank test was used to compare the overall or event-free survivals [21]. Event-free survival was calculated from the first cycle of AFM chemotherapy to disease progression (relapse) or death due to any reason, whichever occurred first. Patients who were alive and disease free were censored at the date of the last follow-up visit. Overall survival was calculated from the time of the first cycle of AFM chemotherapy to death, and patients who were alive were censored at the date of last follow-up. The event-free and overall survival durations were calculated from the date of randomization for the analysis of the complete responders.
Results
Patient Characteristics
A total of 425 patients were enrolled on the AFM randomized study. The study is mature for a study of metastatic breast cancer, with a median follow-up of 10.6 years for all patients and 11.4 years for randomized patients. The patient characteristics for the entire study and its major subgroups are listed in Table 1. The average age of the patients was 43 years, with a range of 24 to 64 years. Ninety percent of the patients were white, 9% were black, and 1% were Asian, Hispanic, or Native American. The pretreatment disease characteristics were indicative of a poor prognosis for the treatment group. Most patients had hormone receptor–negative tumors, and the remainder had experienced disease progression during at least 1 hormonal intervention. There were 268 (63%) patients with both ER- and PR-negative tumors. In addition, 69% had measurable visceral metastatic disease, and 35% had hepatic metastases. Most patients (271/414; 66%) had experienced disease progression after receiving adjuvant chemotherapy. The study included 45 (11%) patients whose initial presentation of breast cancer was with metastatic disease and 39 (9%) whose initial presentation was with stage IIIB inflammatory breast cancer.
Table 1. Patient Characteristics
| Variable | Data |
|---|---|
| Age, y, mean (range) | 43 (24-64) |
| Race | |
| White | 384(90.4%) |
| Black | 36(8.4%) |
| Hispanic, Asian, or Native American | 5(1.2%) |
| ER | |
| Positive | 114(27%) |
| Negative | 311(73%) |
| PR | |
| Positive | 124(29%) |
| Negative | 301(71%) |
| Prior adjuvant chemotherapy | |
| Yes | 271(65%) |
| No | 143(35%) |
| Adjuvant doxorubicin | |
| Yes | 53(13%) |
| No | 366(87%) |
| Time from diagnosis to first metastatic disease, mo, median (range) | 16(0-147) |
| Visceral metastases | |
| Yes | 283(69%) |
| No | 128(31%) |
| Liver metastases | |
| Yes | 147(35%) |
| No | 278(65%) |
Response to AFM Induction Chemotherapy
The AFM induction chemotherapy was an active, albeit toxic, standard-dose regimen, with an overall response rate of 75%: there were 113 (27%) complete responders and 202 (48%) partial responders. Of the remaining 110 patients, 39 (9%) patients had no response, 44 (10%) patients had progression of disease on AFM chemotherapy, and 27 (6%) were not evaluable for response to AFM chemotherapy; most of these patients were not considered evaluable because they withdrew from the protocol during induction chemotherapy. The factors predicting a response to AFM chemotherapy are presented elsewhere [22].
Table 2 lists the percentage of responders to AFM chemotherapy with different sites of metastatic involvement. In addition, Table 2 lists the pathologic responses for the patients with inflammatory breast cancer who had a clinical CR to AFM and subsequently underwent mastectomy. Patients with lung or liver metastases were less likely to respond to AFM chemotherapy than were patients with soft tissue disease.
Table 2. Response to AFM According to Site of Disease
| Metastatic Site⁎ | n | Response to AFM (CR + PR/total) |
|---|---|---|
| Lymph nodes and chest wall | 308 | 102+142/308(79%) |
| Lung/pleura | 180 | 32+97/180(72%) |
| Liver | 147 | 20+82/147(69%) |
| Inflammatory | 39 | 12+18/39(77%) |
| Pathologic complete response | 39 | 1/39(2%) |
| Total | 425 | 113+202/425(74%) |
⁎ Note that patients can have more than one site of metastasis. |
Complete Responders
One hundred thirteen (27%) of the 425 patients had a CR to AFM chemotherapy (the median number of cycles of AFM was 4 for both the immediate treatment group and the delayed treatment group). One hundred of the 113 patients were randomized. Thirteen patients who achieved a CR were not randomized: 6 patients with stage IIIB breast cancer achieved a clinical CR but had residual disease at surgical evaluation and therefore were considered medically appropriate for immediate high-dose consolidation, 1 developed rapidly progressive disease, 2 refused randomization, and 4 were refused insurance coverage for HDC.
Of the 100 randomized patients, 49 were randomized to immediate transplantation and 51 to observation. The disease characteristics of the 113 complete responders are listed in Table 3. These characteristics were balanced between the randomized arms. The primary end point of the AFM randomized study was the determination of the difference in event-free survival as a result of consolidation with HDC and hematopoietic support. The median event-free survival for the women who were randomized to induction therapy alone was 3.8 months and was significantly shorter compared with 9.7 months for women randomized to immediate consolidation with HDC and transplantation (log-rank test; P = .006). The Kaplan-Meier curve for event-free survival for the randomized complete responders is shown in Figure 1.
Table 3. Disease Characteristics of the Complete Responders
| Complete Responders to AFM (n = 113) | ||
|---|---|---|
| Variable | Yes | No |
| ER or PR positive | 48(42%) | 65(58%) |
| Adjuvant chemotherapy | 54(48%) | 59(52%) |
| Liver metastases | 20(18%) | 93(82%) |
| Lung metastases | 32(28%) | 81(72%) |
| Multiple (>2) sites of metastasis | 53(47%) | 60(53%) |
| Surgery to CR | 6(5%) | 107(95%) |
| Radiotherapy to CR | 2(2%) | 111(98%) |
| Metastatic disease at presentation | 18(16%) | 95(84%) |
| Inflammatory disease at presentation | 12(11%) | 101(89%) |
Figure 1.
Event-free survival (EFS): randomized patients. TX indicates therapy.
Of the 51 patients in CR randomized to induction therapy alone (AFM alone), 5 patients have not experienced disease progression, with times from randomization of 11, 8, 6, 6, and 5 years. Three patients who have not experienced disease recurrence 11, 8, and 6 years after AFM had metastatic disease isolated to the supraclavicular lymph nodes and have never received radiotherapy. The other patient who was progression free at 6 years presented with a large primary tumor and had supraclavicular adenopathy at the time of presentation. The final patient had biopsy-positive liver metastases and remains event free 5 years after randomization to observation. Of the 49 patients in CR randomized to immediate high-dose consolidation (AFM followed by cyclophosphamide, cisplatin and BCNU [CPB] plus autologous bone marrow transplantation [ABMT]), 13 patients have not experienced disease progression, with a time from randomization of 5 to 12 years.
Overall Survival
Because of the poor prognosis of women with metastatic breast cancer whose disease progresses after doxorubicin-based chemotherapy, patients were offered salvage treatment with HDC with hematopoietic support at the time of disease progression for women who were randomized to AFM alone. This protocol design allows the comparison of survivals of immediate consolidation versus salvage high-dose consolidation for patients in CR. Forty-three of the women whose disease progressed after the AFM alone were treated with salvage HDC with hematopoietic support by using the same high-dose CPB and ABMT regimen that was prescribed for the patients who had immediate consolidation. Twenty-five (58%) of these women were converted by HDC into CR. The other 3 women who had progressive disease after AFM alone refused HDC.
As shown in Figure 2, the overall survival of the women in CR randomized to immediate high-dose consolidation was similar to the overall survival of women randomized to observation, most of whom had HDC as salvage treatment after disease progression. Although patients who had salvage treatment trended toward a longer median overall survival (3.3 versus 2.1 years), the log-rank comparison was not statistically different (P = .20). There were no differences in the median overall survival of the 43 women who underwent delayed HDC versus that of the 49 women who had immediate HDC (P = .69).
Figure 2.
Overall survival (OS): randomized patients. TX indicates therapy.
Partial Responders
One-hundred ninety-three (96%) of the 202 partial responders to AFM induction chemotherapy proceeded with HDC with hematopoietic support. HDC was able to convert 58 patients (30%) to CR from the best response of partial remission achieved from standard-dose therapy. In Figure 3, patients with the best response to induction therapy of partial response had an inferior overall survival compared with patients who achieved a CR after induction therapy. However, the partial responders to AFM induction chemotherapy who were converted to complete responders with HDC had a long-term overall survival similar to that of women who were complete responders to induction chemotherapy and received consolidation with HDC, as shown in Figure 4. In contrast, the patients who were not converted into CR had a 5-year overall survival of <5%.
Figure 3.
Overall survival (OS) by response to AFM. PR indicates partial response.
Figure 4.
Overall survival (OS) by response. TX indicates therapy; PR, partial response.
Overall and Event-Free Survival of All 425 Patients
We have follow-up in excess of 5 years on all 425 women who were enrolled on the trial. The median event-free survival is 10.3 months, and the median overall survival is 21 months. More importantly, the 5-year event-free survival is 15% (95% confidence interval, 12%-18%), and the overall survival is 20% (95% confidence interval, 17%-25%).
Treatment-Associated Mortality
The AFM randomized protocol took 7 years to complete. In the first 2 years of the study, the patients received only bone marrow support (n = 68); subsequent patients received both bone marrow and peripheral blood progenitor cells as support (n = 218). The treatment-associated mortality for the 286 women who received HDC was 8.6% (n = 25). The causes of the treatment-associated mortality are listed in Table 4. The 3 most common causes of treatment-associated mortality were interstitial pneumonitis, infection, and multiorgan failure, which included veno-occlusive disease.
Table 4. Treatment-Associated Mortality
| Cause | n | % Treatment-Associated Deaths |
|---|---|---|
| Infection | 7 | 28% |
| Fungal (n = 3) | ||
| Viral (n = 2) | ||
| Bacterial (n = 2) | ||
| Lung toxicity | 9 | 36% |
| TTP/HUS | 3 | 12% |
| Multiorgan failure/VOD | 2 | 8% |
| Hemorrhage | 4 | 10% |
| Total | 25 | 100% |
Discussion
We hypothesized in the conduct of this trial that long-term, disease-free, and overall survival in breast cancer without continuous treatment depends on the ability of the treatment to produce a CR and that standard-dose chemotherapy and HDC would complement each other toward the achievement of that goal. We performed a large prospective, randomized study of HDC with hematopoietic support among women with poor-prognosis hormone-insensitive/-resistant measurable metastatic breast cancer. Our study was designed to answer 3 questions: (1) Does consolidation with HDC improve event-free survival for women with poor-prognosis metastatic breast cancer who achieve a CR with intensive doxorubicin-based chemotherapy (event-free survival as a primary end point is important to assess patients who do not need HDC or further therapy to maintain CR)? (2) Among women with poor-prognosis breast cancer who relapse from CR after intensive doxorubicin therapy, will salvage therapy with HDC produce long-term remissions compared with immediate high-dose consolidation? and (3) Among women who achieve a partial response with intensive doxorubicin therapy, will HDC convert patients into durable CRs?
Evaluation of the study results was undertaken with recognition of the unique constraints of the timing of the study and the study design. Advances in the science of blood and marrow transplantation occurred over the several years the study was open. An equal number of patients in the immediate-treatment and delayed-treatment arms received peripheral blood progenitor cells or bone marrow alone. Patients enrolled in the study met strict criteria for inclusion. A possible selection bias should not influence the results of the study because all patients who underwent randomization were subject to the same rigorous screening for inclusion in the study. The study design did not include a nontransplantation, or “conventional,” treatment arm.
The trial produced some noteworthy results. Intensive induction therapy with AFM produced frequent CRs (27%). HDC with hematopoietic support significantly prolonged the event-free survival in women who were complete responders compared with induction chemotherapy alone, and disease-free survival longer than 7 years was possible in 27% of the patients treated with this approach. HDC at the time of disease progression for patients who were randomized to observation produced long-term survival equivalent to that of patients who underwent immediate transplantation. Finally, partial responders who were converted to complete responders with HDC had a long-term survival equivalent to that of patients who were complete responders to induction therapy. The importance of CR in event-free survival and overall survival has been previously reported [23, 24].
The prognosis for women with metastatic breast cancer remains unsatisfactory. Clinical trials of the best available standard chemotherapy all have produced <10% 5-year survival, particularly if one focuses on patients similar to the women treated on the AFM randomized protocol, ie, those with hormone-insensitive or hormone-resistant disease and with multiple sites of disease [25, 26].
Randomized clinical trials investigating the role of HDC versus standard chemotherapy for women with metastatic breast cancer present a variety of outcomes but few long-term follow-up data. Stadtmauer et al. [27] found no advantage for untreated metastatic breast cancer patients consolidated with high-dose cyclophosphamide, thiotepa, and carboplatin versus continuation of standard chemotherapy with long-term cyclophosphamide, methotrexate and 5-fluorouracil (CMF) (24 months) after induction therapy with cyclophosphamide doxorubicin and 5-fluorouracil (CAF) or CMF. Significant results from this trial included a low CR rate to induction therapy (11%), few complete responses after HDC (13%), few patients converted from partial response to CR with HDC (6%), a short median follow-up (3 years), and a high dropout rate after induction therapy and randomization (46%).
Berry et al. [28] compared data from patients who received standard-dose chemotherapy on Cancer and Leukemia Group B trials with data from the Autologous Blood and Marrow Transplant Registry to assess overall survival. After controlling for known prognostic factors in the data sets, they found a higher probability of 5-year survival (23% versus 15%) in women who received HDC compared with women who received standard-dose chemotherapy (P = .03).
A retrospective analysis of data from the European Group for Blood and Marrow Transplantation for patients with metastatic breast cancer who underwent HDC from 1990 to 1999 demonstrated significant results. In this data set, patients who underwent transplantation in CR had a 29% 5-year progression-free survival, with a 5-year progression-free survival of 18% for all patients evaluated; the 5-year overall survival for the entire cohort was 27%. The mortality rate for patients treated in the metastatic setting was 3% [29].
Several recent studies have reported improvements in event-free survival and overall survival with double or tandem transplantation. Sayer et al. [23] treated 22 patients with doxorubicin and paclitaxel as induction followed by 2 cycles of high-dose doxorubicin, paclitaxel, cyclophosphamide, and thiotepa with peripheral blood progenitor cell support. They reported an initial response rate of 38.1% CR and 47.6% partial response, with overall survival of 19.0% at a median follow-up of 36 months. There were no toxic deaths on study. Somolo et al. [24] treated 29 patients with metastatic breast cancer by using tandem cycles of cisplatinum and melphalan with peripheral blood progenitor cell support. The CR rate for women with stage IV breast cancer increased from 28% after 1 cycle to 55% after both cycles. The projected 5-year progression free rate for these patients is 35%, and the projected overall survival rate is 61%. In a report of 3 sequential trials that used tandem transplantation, Elias et al. [30] reported response rates of 53% to 76%. The median event-free survival for the 3 trials ranged from 39 to 98 months. The actuarial 5-year overall survival rates for these patients from the time of induction chemotherapy were 29%, 28%, and 50% for the 3 trials reported.
With the median follow-up for all patients now at 10.6 years, the AFM randomized trial provides evidence for clinically meaningful long-term survival in excess of 20% for patients with hormone-insensitive metastatic breast cancer after HDC. These findings, however, are with significant toxicity. The AFM induction therapy produced significant mucositis and neutropenia, and >30% of the patients experienced temporary pulmonary toxicity that necessitated corticosteroids. The HDC was associated with an 8.6% treatment-related mortality, although improvements in supportive care measures offer the opportunity for decreased mortality rates.
In combination with new treatment strategies, including improved induction chemotherapy regimens, biological and immunologic therapy, and encouraging data from the tandem-transplantation studies, HDC may continue to provide a platform for further research toward improvement in the survival of breast cancer patients.
Acknowledgments
This work was supported by National Cancer Institute Program Project grant no. PO1-47741.
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PII: S1083-8791(05)00684-1
doi:10.1016/j.bbmt.2005.10.009
© 2006 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 12, Issue 2 , Pages 195-203, February 2006
