Induction, mobilization of peripheral blood stem cells (PBSC), high- dose chemotherapy and PBSC infusion in patients with untreated stage IV breast cancer: ...
Bone Marrow Transplantation, (1997) 19, 661–670 1997 Stockton Press All rights reserved 0268–3369/97 $12.00
Induction, mobilization of peripheral blood stem cells (PBSC), highdose chemotherapy and PBSC infusion in patients with untreated stage IV breast cancer: outcomes by intent to treat analyses CH Weaver, WH West, LS Schwartzberg, T Alberico, R Leff, FA Greco, J Hainsworth, R Birch, B McAneny, M Magee, E Raefsky, L Kalman and CD Buckner Clinical Research Division of Response Oncology, Inc., Memphis, TN, USA
Summary: We investigated the outcomes of patients with breast cancer undergoing induction chemotherapy, mobilization of peripheral blood stem cells (PBSC) and highdose chemotherapy (HDC) with PBSC infusion. One hundred and fourteen patients with untreated stage IV breast cancer, with a median age of 46 years (range 24– 62), were entered on a phase II trial consisting of: (1) doxorubicin, 5-flurouracil, methotrexate (AFM) × 4 courses at 2 week intervals; (2) cyclophosphamide (4 g/m2), etoposide (600 mg/m2), cisplatin (105 mg/m2) (CEP), filgrastim (6 mg/kg/day) and PBSC collection; (3) cyclophosphamide (6 g/m2), thiotepa (500 mg/m2), carboplatin (800 mg/m2) (CTCb) followed by PBSC infusion. All patients received AFM, 107 (94%) received CEP, 93 (82%) received CTCb and PBSC as per protocol and 99 (87%) ultimately received HDC and PBSC. There was one infectious death after AFM and all other deaths were associated with progressive disease. Fiftytwo patients (46%) are alive, 21 (18%) without progression, at a median 31 months (range 22–47). The probabilities of survival and progression-free survival at 3.5 years were 0.40 and 0.17, respectively. All 62 patients with visceral disease and/or a prior history of doxorubicin adjuvant therapy have relapsed or progressed. We conclude that the sequential administration of AFM, CEP and CTCb followed by PBSC resulted in long-term PFS only in patients who were NED, had bone-only disease or had lymph node or soft tissue disease with or without bone disease. Other strategies, aimed at improving responses to initial therapy, improving HDC regimens and/or developing immunomodulatory therapies, will be necessary to improve PFS for patients who fail doxorubicin adjuvant or who have visceral disease. Keywords: high-dose chemotherapy for breast cancer
Phase II clinical trials of high-dose chemotherapy (HDC) with autologous stem cell support have resulted in high Correspondence: Dr CD Buckner, Response Oncology, Inc., 600 Broadway, Suite 230, Seattle, WA 98122, USA Received 10 September 1996; accepted 12 December 1996
complete remission (CR) rates (40–50%) with median overall survivals of 18–24 months and progression-free survivals (PFS) of 12–25% in patients with breast cancer responsive to conventional induction chemotherapy.1–6 A recent randomized phase III trial demonstrated the superiority of two cycles of HDC with peripheral blood stem cell (PBSC) support compared to conventional-dose treatment in patients with newly diagnosed metastatic breast cancer.7 Although HDC with PBSC support may be superior to conventional-dose chemotherapy, the majority of patients will relapse and die of progressive disease or of attempts at salvage treatment.5 In order to design future clinical trials it is important to determine the characteristics of patients who are not likely to benefit from current HDC regimens and to determine the applicability of HDC to the general population of patients presenting with newly diagnosed metastatic breast cancer. A phase II study was designed to enroll patients with stage IV breast cancer at diagnosis and to evaluate outcomes following the sequential administration of induction chemotherapy, chemotherapy and growth factor mobilization of PBSC and HDC followed by PBSC infusion. Outcomes were analyzed and reported on an intent to treat basis with a minimum follow-up of 24 months from enrollment. Patients and methods Between March 1992 and January 1994, 120 patients with untreated stage IV breast cancer were enrolled in a phase II trial of chemotherapy induction, chemotherapy and filgrastim mobilization of PBSC, HDC and infusion of PBSC. Patients were eligible if they had newly diagnosed and untreated breast cancer (except for adjuvant therapy), were 65 years of age or less, had an ECOG performance of 0– 1 and evidence of adequate hepatic, renal and cardiac function. Pre-menopausal women could be entered on the study without a previous trial of hormonal therapy. All patients signed a protocol-specific informed consent approved by the institutional review board of the hospital where the therapy was administered. On review, six patients were excluded; two had received prior chemotherapy for metastatic disease, two had stage III disease, one had incomplete data and one refused further therapy and was lost to follow-up after one course of AFM induction therapy. Thus, data from 114 patients were available for analysis.
High-dose therapy, intent to treat analysis CH Weaver et al
662
Treatment centers
Toxicity grading
Patients were treated in one of 24 participating medical centers in the United States under the care of 159 community oncologists.8 Chemotherapy for all three phases of treatment was administered and PBSC harvested in an outpatient facility. At the completion of PBSC infusion patients were admitted to hospitals meeting the criteria of ASCO/ASH guidelines for stem cell transplantation.9
All patients were evaluated daily until resolution of signs and symptoms and graded for toxicity using standard criteria.11
Induction chemotherapy (AFM) All patients were scheduled to receive four courses of induction chemotherapy at 14 day intervals consisting of: doxorubicin, 50 mg/m2, by continuous i.v. infusion over 24 h; methotrexate, 60 mg/m2, i.v. bolus on day 1; leucovorin 10 mg/m2 orally q 6 h × 6 doses and 5-flurouracil 600 mg/m2 i.v. bolus on day 2. Mobilization chemotherapy (CEP) Patients who completed AFM were scheduled to receive cyclophosphamide 4 g/m2 on day 1 and etoposide 200 mg/m2, cisplatin 35 mg/m2 on days 1–3 (CEP) followed by filgrastim 6 mg/kg/day beginning on day 4 and continued until PBSC harvests were complete.10 Collection, cryopreservation and infusion of PBSC Peripheral blood stem cells were collected and cryopreserved as previously described.8,10 Attempts were made to collect >2.5 × 106 CD34+ cells/kg from each patient.8 Cryopreserved PBSC were thawed and infused 72 h after the last dose of chemotherapy.10 The day of PBSC infusion was designated day 0. High-dose chemotherapy Cyclophosphamide 2 g/m2/day, thiotepa 167 mg/m2/day and carboplatin 267 mg/m2/day were administered in 1 h infusions for 3 consecutive days. All patients received filgrastim 6 mg/kg/s.c./day from the day of PBSC infusion (day 0) until the ANC was .0.5 × 109/l for 3 consecutive days.5 Treatment after high-dose chemotherapy and PBSC infusion Hormonal: Twenty-four patients who were estrogen receptor and/or progresterone receptor positive were given tamoxifen 10 mg, orally, twice a day or megace 40 mg, orally, four times a day following recovery from HDC for a minimum of 2 years or until disease progression. Radiation therapy: Local radiation therapy, 2.0–5.0 Gy, was given after PBSC infusion and prior to disease progression to sites of previous disease involvement to 21 of 99 patients receiving HDC and PBSC. Chemotherapy: One patient was treated with 5-flurouracil beginning immediately after hematological recovery following CTCb to the present time.
Evaluation of response Patients were staged prior to AFM induction, following AFM induction and 60 days following PBSC infusion. Staging included computed tomography (CT) scans of the chest, abdomen and brain, an isotopic bone scan and a bone marrow aspirate and biopsy. Complete response was defined as complete clinical resolution of all evidence of disease. Partial response (PR) was defined as 50% or greater reduction in the sum of the products of all measurable lesions and at least 50% improvement in tumor markers. Partial response* (PR*) was defined as complete clinical resolution of all evidence of non-skeletal disease with a bone scan showing improvement, with evidence of sclerosis of lytic lesions on X-ray or CT and bone pain that had completely resolved. 1 For statistical purposes patients with PR and PR* were included together as PR. Patients were classified as no evident disease (NED) if disease could not be detected after surgery at the time of diagnosis of metastatic disease. Statistics Data were collected using a custom designed distributed data system, reviewed at a central clinical center (Response Oncology, Inc., Memphis, TN, USA) and analyzed using the SAS system (SAS Institute, Cary, NC, USA). Actuarial probabilities were computed according to the methods of Kaplan and Meier12 and compared using the log rank test.13 The endpoints for survival were duration from enrollment until death censored by the date of last contact, and for relapse or progression from enrollment until relapse or progression censored by death or end of follow-up. The date of last follow-up was 1 May 1996. Multivariate analyses were performed using a proportional hazards regression model.14 All proportions were compared using an adjusted x2 test. The clinical factors evaluated, on an intent to treat basis for all 114 patients, for potential prognostic significance are shown in Table 4. For the 68 patients with measurable disease who completed all three phases of therapy, response to AFM (PR + PR* and/or CR vs all others) was added to the model along with the factors listed in Table 4.
Results Patient characteristics Tables 1 and 2 show the characteristics of the 114 patients enrolled on this trial. Twenty-nine patients were not evaluable for response; 10 were NED following surgery (three with supraclavicular node, one with axillary node, two with chest wall, three with lung and one with ovarian involvement) and 19 had bone-only disease. As a generality
High-dose therapy, intent to treat analysis CH Weaver et al
Table 1
Patient characteristics at diagnosis (n = 114) Number of patients (%)
Estorgen receptor status Positive Negative Unspecified
58 (51) 44 (39) 12 (11)
Progesterone receptor status Positive Negative Unspecified
60 (53) 41 (36) 13 (11)
Number of positive lymph nodes 0 1–4 5–9 >10 Unspecified
34 (30) 31 (27) 17 (15) 15 (13) 17 (15)
Stage of disease I IIA IIB IIIA IIIB IV Unspecified
22 (19) 14 (12) 37 (33) 8 (7) 3 (3) 28 (25) 2 (1)
ER = estrogen receptor; PR = progesterone receptor.
Table 2
Protocol compliance (Table 3) One hundred and fourteen patients received two to five courses of AFM. One hundred and six patients (93%) received CEP and 93 (82%) received CTCb on protocol. One patient had PBSC mobilized with filgrastim alone. In five patients the physician administered paclitaxel before or after CEP and prior to CTCb. In one instance the physician treated the patient with busulfan, melphalan and thiotepa and PBSC on another protocol.15,16 Thus, 98 (86%) received CTCb with PBSC support and 99 patients (87%) received HDC followed by PBSC infusion. Induction with doxorubicin, 5-flurouracil and methotrexate (AFM) Compliance with AFM: Four patients received two to three courses of AFM. One patient developed cardiac symptoms Table 3
Patient characteristics at enrollment (n = 114) Number of patients (%)
ECOG performance status 0 1 Prior adjuvant therapy Doxorubicin in adjuvant therapy Prior hormonal therapy Refractory to hormonal therapy
94 (82) 20 (18) 67 (59) 23 (20) 34 (30) 33 (29)
Menopausal status Pre Peri Post Unspecified
41 (36) 16 (14) 52 (46) 5 (4)
Number of disease sites 1 2 >3
61 (54) 33 (29) 20 (18)
Lung and/or liver metastasis No evidence of disease after surgery
39 (34) 10 (9)
Sites of disease Non-bone Bone and other Bone only
58 (51) 37 (32) 19 (17)
Duration of disease De novo state IV 2 years
28 34 52
23.6 20.5 NR
0.004
15.0 11.4 17.2
0.34
Lung and/or liver involvement
No Yes
75 39
NR 18.6
0.0001
18.6 11.1
0.0001
Bone involvement
No Yes
58 56
28.2 36.6
0.12
13.7 14.7
0.44
Lung involvement
No Yes
94 20
33.0 19.7
0.01
15.0 11.2
0.001
Liver involvement
No Yes
91 23
33.5 18.6
0.005
15.7 11.1
0.001
Number of nodes at diagnosis
0 1–3 4–9 >10 Stage IV
33 24 16 8 28
36.6 31.4 NR 35.8 23.6
0.51
14.4 20.4 12.3 12.4 15.0
0.25
Evident disease
No Yes
10 104
NR 31.1
0.08
NR 13.4
0.0047
Number of lesions in: Dominant organ Number of sites
0.01
0.03
ER = estrogen receptor; PR = progesterone receptor; NR = not reached.
Outcomes for 93 patients completing the protocol One of 93 patients died in the first 100 days of PBSC infusion; from complications of progressive disease on day 16. The probabilities of survival and PFS at 3.5 years for the
1 0.9 0.8
n = 114
0.7
Probability
liver involvement were 2.5 times more likely to relapse or progress and patients who had received prior adjuvant therapy with doxorubicin were 2.0 times more likely to relapse or progress than patients without these risk factors (Table 5). All 39 patients with lung and/or liver involvement and all 23 patients who had failed doxorubicin adjuvant therapy have progressed (Figures 2 and 3).
0.6 0.5 0.4 0.3
None/no doxorubicin
0.2 0.1
Doxorubicin 0
Table 5 Multivariate correlates of mortality or progression intent to treat analysis (n = 114) Parameter
P value
RR
95% CI
Lung and/or liver metastasis Prior doxorubicin adjuvant
0.0001 0.0056
2.5 2.0
(1.6–3.9) (1.2–3.3)
0
5
10
15
20
25
30
35
40
45
50
Months Figure 2 The probability of progression-free survival for 23 patients with (&) and 91 patients without (J) a history of prior adjuvant doxorubicin therapy.
High-dose therapy, intent to treat analysis CH Weaver et al
0.21, respectively. No patient with persistent evaluable disease after CTCb is surviving without progression.
1 0.9 0.8
n = 114
Outcome for all patients receiving high-dose chemotherapy
Probability
0.7 0.6 0.5 0.4
No lung/liver involvement
0.3 0.2 0.1
The outcomes for the 99 patients who ultimately received HDC and PBSC infusion are shown in Figure 4. Ninetythree patients received CTCb as per protocol, five received CTCb off protocol and one received busulfan, melphalan and thiotepa prior to PBSC infusion (Table 3).
Lung/liver involvement
Outcome for patients not completing the protocol
0 0
5
10
15
20
25
30
35
40
45
50
Months Figure 3 The probability of progression-free survival for 39 patients with lung and/or liver metastasis (&) and 75 patients without (J).
93 patients completing all three phases of the protocol were 0.42 and 0.19, respectively. Sixty-eight patients with measurable disease received CTCb and PBSC infusions as per protocol. Table 6 summarizes the responses observed in relation to the initial response to AFM. Seven of 27 patients (26%) with lung and/or liver metastasis achieved CR and eight (30%) PR (PR* = 3) following CEP and CTCb. Five of 13 patients (39%) with a history of prior doxorubicin adjuvant achieved CR and 3/13 (23%) achieved PR*. The 35 patients without either risk factor had a CR rate of 60% and a PR rate of 23%. Multivariate analysis involving the 68 patients with measurable disease, including response as a covariable, demonstrated that patients with a history of prior doxorubicin adjuvant therapy had a 2.4-fold and patients with lung and/or liver involvement had 2.5-fold probability of relapse or progression (P = 0.009 and 0.001, respectively). Patients who responded to AFM had a better PFS (9/43) than patients who did not respond (1/25, P = 0.06). In the multivariate analysis, response to AFM (PR + PR* and/or CR vs all others) was not a statistically significant predictor of outcome (P = 0.10). Four of the 15 patients (27%) who were not in CR after AFM but achieved CR after CEP and CTCb are surviving without disease progression. The probabilities of survival and PFS, at 3.5 years, for the patients with measurable disease who were in CR after CEP and CTCb were 0.37 and
Three of 15 patients (20%) not receiving HDC are alive, one disease-free (7%), 33–45 months after diagnosis. The patient who did not proceed to CTCb because of thrombocytopenia after CEP is in CR at 33 months (Table 3). Five of six patients receiving HDC off protocol are alive 26–34 months after diagnosis; one progression-free, while four are alive after disease progression. Characteristics of patients surviving without progression (Table 7) Twenty-one patients survive without disease progression; 20/99 (20%) who received HDC with PBSC infusion and 1/15 (7%) who did not. Discussion The current study was designed to determine the outcome of patients with stage IV breast cancer committed at diagnosis to receive induction chemotherapy, mobilization chemotherapy and HDC with PBSC infusion. This strategy 1
n = 99
0.9 0.8 0.7
Probability
666
0.6
NED
0.5 0.4 0.3
CR 0.2
Table 6 Response in patients with measurable disease completing the protocol (n = 68) Response Progressive disease Stable disease Partial response Complete response
AFM (%) 3 (4) 22 (32) 26 (38) 17 (26)
CEP + CTCb 7 (10) 12 (18) 17 (25) 32 (47)
AFM = doxorubicin, 5-flurouracil, methotrexate; CEP = cyclophosphamide, etoposide, cisplatin; CTCb = cyclophosphamide, thiotepa, carboplatin.
PR Bone only
0.1
