A Phase II Study of High-Dose Cyclophosphamide, Thiotepa, and Carboplatin With Autologous Marrow Support in Women With Measurable Advanced Breast Cancer Responding to Standard-Dose Therapy By Karen Antman, Lois Ayash, Anthony Elias, Cathy Wheeler, Myla Hunt, Joseph Paul Eder, Beverly A. Teicher, Jonathan Critchlow, Judy Bibbo, Lowell E. Schnipper, and Emil Frei III Purpose: The study was designed to determine the duration of complete response (CR) for patients with unresectable or metastatic breast cancer treated with high-dose cyclophosphamide, thiotepa, and carboplatin (CTCb) while responding to conventional-dose therapy. Methods: Eligibility criteria included histologically documented metastatic or unresectable breast cancer, at least a partial response (PR) to conventional-dose therapy, no priorpelvic radiotherapy, cumulative doxorubicin of less than 500 mg/m2, and physiologic age between 18 and 55 years. Patients with inadequate renal, hepatic, pulmonary, and/or cardiac function or tumor involvement of marrow or CNS were excluded. Cyclophosphamide 6,000 mg/m 2 , thiotepa 500 mg/m2, and carboplatin 800 mg/m2 were given by continuous infusion over 4 days. After recovery, sites of prior bulk disease were to be radiated or resected if feasible. Results: Of 29 registered patients, one died of toxicity
(3%; hemorrhage). CRs and PRs continued a median of 16 and 5 months after transplant, respectively (26 and 9 months from initiation of chemotherapy for metastatic disease). Of 10 patients transplanted in CR, four have not progressed at 17 to 31 months after transplantation (25 to 43 months after beginning standard-dose therapy). One of four patients with uptake on bone scan as their only sites of residual disease before transplant and one of three who converted from PR to CR with transplant have not progressed at 27 and 29 months, respectively, after transplant. Conclusions: CTCb is an intensification regimen with a low mortality that delivers a significantly increased dose of agents with known activity at conventional doses in breast cancer. Although the duration of PR is short as expected, CRs appear to be durable. J Clin Oncol 10:102-110. C 1992 by American Society of Clinical Oncology.
BREAST
The median duration of response to the first regimen for metastatic disease is only about 8 months, and metastatic breast cancer virtually always progresses with shorter and fewer CRs achieved with subsequent regimens. Theoretical, experimental, and clinical data suggest that breast cancer recurs despite an initial response to chemotherapy because of endogenous or acquired resistance to cytotoxic agents. In the laboratory, resistance to alkylating agents can often be overcome by a five- to 10-fold higher dose. In laboratory models of breast cancer, administration of the highest possible doses of chemotherapy is essential to the design of curative regimens.4 The objective of this clinical program was to develop a high-dose combination regimen with a low mortality rate and significant activity in breast cancer. We initially combined three drugs from different alkylating agent classes, cyclophosphamide, carmustine (BCNU), and cisplatin, at high doses with autologous marrow support.5 In patients with metastatic breast cancer, 14 of 16 (88%) responded.' The mortality overall (22%) and at the phase II dose (15%) was of concern. Clinical and preclinical efforts were next focused on
CANCER currently develops in 10% of American women. Metastatic breast cancer is essentially incurable. The median survival with standard therapy of about 2 years after documentation of metastases 1' 2 has not changed in the 5 decades for which statistics are available. Although patients are frequently responsive to initial chemotherapy regimens, complete responses (CRs) occur in only 4% to 27% of patients.3
From the Departments ofMedicine, Statistics, and CancerPharmacology, Dana-FarberCancerInstitute; Division of Medical Oncology, Department of Medicine and Surgery, Beth Israel Hospital; and HarvardMedical School, Boston, MA. Submitted June 7, 1991; acceptedJuly 31, 1991. Supported in part by United States Public Health Service grant no. PO1CA-38493 and a grant from the Mather's Foundation. L.A., J.P.E., and A.E. are recipients of career development awardsfrom the American Cancer Society. Presented in part at the Health Improvement Institute- and National Institutes of Health-sponsored 1991 Forum on Emerging Treatments for Breast Cancer. Address reprint requests to Karen Antman, MD, Dana-Farber CancerInstitute, 44 Binney St, Boston, MA 02115. 0 1992 by American Society of ClinicalOncology. 0732-183X/9211001-0002$3.00/0
102
Journal of Clinical Oncology, Vol 10, No 1 (January), 1992: pp 102-110
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CTCB WITH MARROW SUPPORT IN BREAST CANCER
developing an effective but less toxic regimen, with the assumption that a regimen with a low mortality rate would be required to allow its use in an adjuvant setting in women with poor prognoses. Thiotepa is an active drug in breast cancer. In preclinical studies using cultured human breast cancer cells or murine mammary cancer growing in vivo, thiotepa and cyclophosphamide (or an activated form, 4 hydroperoxy-cyclophosphamide) showed striking synergy or marked additivity through four orders of magnitude of tumor-cell cytotoxicity.7 In addition, continuous exposure to cyclophosphamide or thiotepa was superior to bolus administration.8 The first clinical trial combined continuous infusion of 6 g/m 2 cyclophosphamide and escalating doses of thiotepa with dose-limiting mucositis. The response rate in advanced, generally refractory breast cancer was 75% (six of eight).' Carboplatin was then added to the cyclophosphamide-thiotepa doublet to increase response and decrease the emergence of drug resistance. Cisplatin and carboplatin are active in untreated breast cancer.' 0 12 However, neurologic and renal toxicity preclude significant dose escalation of cisplatin. Carboplatin has little renal or neurotoxicity, and its dose-limiting toxicity at standard doses (myelosuppression) makes it ideal for escalation with autologous marrow support.13 Cyclophosphamide, thiotepa, and carboplatin (CTCb) proved less toxic than cyclophosphamide, BCNU, and cisplatin.' 4 Two of 27 patients died of multiorgan failure in the phase I study (7.4%) at doses above that chosen for the phase II dose. The enhanced safety and tolerance of CTCb did not appear to compromise its antineoplastic efficacy. The response rates in refractory breast cancer for CTCb and cyclophosphamide, BCNU, and cisplatin were 86% and 83%, respectively.9,14,15 Using high-dose therapy in lymphoma and leukemia as a model, such regimens are most likely to benefit patients with minimal residual disease such as in an adjuvant setting or in patients with small amounts of metastatic disease who have had very good partial responses (PRs) or CRs to standard induction therapy. An intensification regimen associated with a low mortality rate and that achieves the goal of delivery of significantly increased doses of agents known to be active at standard doses would be a prerequisite to this type of trial in breast cancer.14 This study was designed to examine the CR and total response rates and the duration of response after a single course of high-dose CTCb in women with metastatic breast cancer responding to standard-dose therapy.
103 METHODS PatientSelection Women aged 18 to 55 years with metastatic or unresectable breast cancer responding to a standard-dose chemotherapy regimen were assessed by history, physical examination, pathologic review, hepatic and renal chemistries, ECG, chest roentgenogram, pulmonary function testing, computed tomography (CT) of the head, and bilateral posterior iliac crest biopsies. Patients with bone marrow or CNS metastases, significant hepatic, renal, or cardiopulmonary impairment, performance status greater than 1, or prior pelvic radiation were excluded. Patients referred for this trial were given doxorubicin, fluorouracil, and methotrexate; however, patients referred with a response to other regimens were also eligible.
Supportive Care and Bone Marrow Reinfusion The techniques of bone marrow harvest under general anesthesia, cryopreservation, reinfusion, and supportive care have been previously reported."
Therapy Patients received continuous intravenous infusion CTCb over 96 hours (day -7 to -3 through separate ports of multiple lumen indwelling central venous catheters) followed in 72 hours by autologous bone marrow reinfusion (day 0). Cyclophosphamide 1.5 g/m2/d (for a total dose of 6 gm/mz) was given with bladder irrigation to prevent cystitis. Thiotepa 125 mg/m 2 /d (500 mg/m 2 total dose) and carboplatin 200 mg/m 2/d (800 mg/m2 total dose) were administered concurrently. When feasible, sites of prior bulk disease or residual disease after high-dose therapy were resected or radiated.
Response Criteria Lesions were measured before the initiation of chemotherapy. Palpable tumors and those visible on chest roentgenogram were measured weekly. More complicated imaging studies were delayed until reverse isolation was discontinued. CR or PR was defined as the disappearance of all tumor or a 50% to 99% reduction in the product of the bidimensional measurements, respectively, for a minimum of 4 weeks. PR (bone scan-positive) was further identified as the subset of patients with complete resolution of all soft tissue disease, sclerosis of prior lytic bone lesions, but continuing activity by bone scan in areas of prior uptake. Disease progression was defined as a greater than 25% increase in tumor size or the appearance of any new lesions. Patients who died early of toxicity were considered unassessable (UA) for response, although tumor progression was coded if observed. Survival and time to disease progression were calculated from the date of marrow reinfusion.
RESULTS Between May 1988 and September 1989, 29 women were entered on study. Patient characteristics are listed in Table 1. The median follow-up is 28 months from
autotransplant (range, 19 to 33 months). The median time to treatment failure for all 29 patients was 6 months after marrow transplant (or 10 months from start of induction therapy). The median survival is undefined (at
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104
ANTMAN ET AL Table 1. Patient Characteristics
Patients entered Median age, years (range) Prior adjuvant therapy Prior induction regimens for metastatic or inoperable disease 1 2 Receptor-positive Estrogen Progesterone Not done or insufficient material obtained Prior marrow involvement Predominant disease site Lung Lymph nodes Liver Bone Skin Breast
No.
%
29 39 (27-55) 14
100
24 5
83 17
9 5 4 2
31 17 14 7
8 6 5 4 4 2
28 21 17 14 14 7
48
least 20 months from the time of transplant) because 15 of the 29 women remain alive. Toxicity Absolute granulocytopenia, fevers, and thrombocytopenia developed in all patients (Table 2). One patient died early of CNS bleeding before reingraftment despite intensive platelet support. A second patient had poor platelet engraftment at the time of her death on day 108 of progression of massive liver metastases, hepatic insufficiency, and gastrointestinal bleeding. Of the remaining 27 patients with full engraftment, the median Table 2. Toxicity of High-Dose CTCb Toxicity
No.
%
Patients Toxic deaths Hematologic Bleeding Sepsis Fungal infection Infectious pneumonitis Drug-associated interstitial pneumonitis Transient congestive heart failure Renal Creatinine level 1.5-3 mg/dL Creotinine level > 3 mg/dL Gross hematuria Hepatic Bilirubin level 2-5 mg/dL Bilirubin level 5-6 mg/dL Stomatitis transiently precluding oral intake
29 1*
100 3
2 8 3 0 0 6
7 28 10 0 0 21
5 1 3
17 3 10
5 3 8
17 10 28
*A second patient with poor platelet engraftment died of progression of massive liver metastases, hepatic insufficiency, and gastrointestinal bleeding on day 108.
time to recovery of granulocytes to greater than 500/[tL was 21 days (range, 10 to 51 days); to platelet independence greater than 20,000/pIL without transfusion, 23 days (range, 10 to 81 days). The median number of total hospital days was 32 (range, 22 to 113 days). One patient who had received prior melphalan later developed myelodysplasia. Six patients developed transient congestive heart failure lasting 1 to 6 days at a median of 10 days (range, 8 to 13 days) after marrow reinfusion. All six patients had tachycardia, tachypnea, rales, and weight gain, and five had a documented cardiac gallop. On chest x-ray all six patients had interstitial edema or alveolar edema with a pleural effusion. One of the six developed cardiomegaly. Symptoms in all patients resolved with treatment with diuretics with or without vasodilators. This constellation of symptoms was believed to represent transient cyclophosphamide cardiotoxicity. While patients had a substantial obligatory fluid intake from antibiotics and blood products over the course of their 4- to 6-week hospitalization, there was no other immediately apparent explanation for the temporary cardiac decompensation in these patients. There was no evidence of peripheral edema to suggest a capillary leak syndrome. A serum bilirubin level above 5 mg/dL occurred in three patients. None of these patients had ascites, abrupt weight gain, or right upper quadrant tenderness suggestive of venoocclusive disease of the liver. Hepatomegaly developed in only one of the three patients that proved to be late enlargement of her known liver metastases, originally identified by CT. One patient had a conjugated bilirubin level of 3.3 when her total bilirubin level peaked at 6.0 mg/dL and was found to be Coombs' test-positive, suggesting a mixed mechanism for hyperbilirubinemia. Bilirubin in two patients fluctuated with blood transfusions. Slight transaminase elevations followed elevated bilirubin in all three patients. Alkaline phosphatase was elevated slightly in two and substantially in one. Stomatitis was moderate in seven patients and precluded oral intake in eight. No patient required intubation. Response Responses to high-dose therapy and the current status of patients are listed in Table 3. Time to treatment failure is 19 months (Fig 1A) for those who achieved a CR (or an abnormal bone scan as the only residual evidence of disease) versus 5 months for patients with only a PR (26 and 9 months from the initiation of chemotherapy for metastatic disease, respectively). Time
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105
CTCB WITH MARROW SUPPORT IN BREAST CANCER
Table 3. Responses to High-Dose Therapy and the Current Status of Patients by the Response of Breast Cancer to Standard Therapy Before High-Dose Therapy CR* No Measurable Disease (10)t Prognostic variables Prior adjuvant chemotherapy Prior adjuvant doxorubicin Prior chemotherapy for metastatic disease AFM chemotherapy as induction Disease-free interval < 6 months after diagnosis Visceral disease (eg, lung, liver) Bone metastases Results after high-dose therapy with marrow support Toxic death Resection of sites of prior bulk disease Radiotherapy to sites of prior bulk disease No progression Median months to progression from transplant Follow-up for patients without progression Months from induction Months from transplant
PR* CR (3)t
PRt (4)t
5 2 3 4 4 3 0
1 0 0 3 1 2 1
3 2 0 4 0 0 4
5 4 2 5 3 8 2
0 0 0 4 16
1 0 1 1 6
0 0 1 1 21
0 2 3 1 5
33 29
32 27
37 26
25-43 17-31
PR(12)t
Abbreviations: AFM, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), fluorouracil, and methotrexate. *Response to standard-dose therapy.
"tResponseto high-dose therapy (n). SPatients with complete resolution of all soft tissue disease but continuing activity on bone scan in areas of prior uptake.
to treatment failure and survival for the group as a whole are shown in Fig lB. Because of multiple and visceral disease sites, postintensification resection or irradiation of prior bulk or residual disease proved feasible in only five patients. Ten patients entered the study in CR; four have not progressed. Of the 15 patients who were in PR at the time of high-dose therapy, three converted to CR (20%; 90% confidence interval, 6% to 44%) and one has not progressed. Of the four patients who underwent transplantation with a positive bone scan as their only evidence of residual disease, one has not progressed. Of A l.0
1.0
B
0.8
0.8
J• 0.6 o
S0.6
i,
i.
S0.4
0.4 i,,.1t .... I-.. I.
0.2
0.2
......... ............ . . ... ....I .. .. .. ... .. ... •
I
S0.0
0.0 0
10
20 Months
30
40
0
10
20
30
40o
Months
Fig 1. (A) Disease-free survival and survival are shown for the group as a whole. Survival time (-): 15 censored, 14 failed, 29 total. Time to failure (..--): 7 censored, 22 failed, 29 total, 6 median. (B) Time to treatment failure is shown for patients who achieved a CR to either standard- or high-dose therapy (including patients with PRs whose only site of residual disease was a positive bone scan) versus those who never achieved a CR. CR + PR (-): 6 censored, 11 failed, 17 total, 19 median. PR (....): 1 censored, 11 failed, 12 total, 5 median.
those with PRs after marrow transplantation, one patient with biopsy-proven hepatic metastases has had no progression of residual abnormalities on CT of the liver. Of the seven patients who have not progressed, the predominant sites of disease were (one patient each) liver, lung, bone, chest wall, bilateral lymph nodes, skin, and breast. Five were estrogen receptor- and progesterone receptor-negative. One with multiple liver metastases was estrogen receptor- and progesterone receptorpositive, and testing for receptors was not performed on one patient. Two patients had received adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF), and five had had no adjuvant chemotherapy. (Thus, none of those without progression had received adjuvant doxorubicin.) Four responded to the initial induction regimen; one had no response to initial melphalan therapy for metastases but then responded to cyclophosphamide, doxorubicin, and fluorouracil (CAF) chemotherapy. Two received postintensification therapy; one underwent radiation after a needle biopsy-proven CR of a large breast mass and a 3-cm lymph node. A second patient with estrogen receptor-positive disease with a PR of liver metastases after transplantation was placed on tamoxifen. DISCUSSION The principles of dose-response and combination chemotherapy were basic to the design of treatment
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106
ANTMAN ET AL
regimens for malignancies now curable with chemotherapy (eg, leukemias, lymphomas, and testis and breast cancer in the adjuvant setting)."6 " Skipper et al20'23 estimated the spontaneous rate of mutations conferring resistance to a single drug as one in 106 to 10' cancer cells. Therefore, the likelihood of the spontaneous emergence of drug resistance is high in patients with visually apparent tumor, suggesting that combinations of active noncrossresistant agents with different mechanisms of action are essential to decrease the emergence of drug resistance. Agents are then selected with different dose-limiting toxicities, resulting in subadditive toxicity in combination. These strategies can then be used to design high-dose regimens for use with marrow transplant. Clinically, the importance of dose in breast cancer has been extensively debated. 2426 Data from the few randomized trials at doses feasible without growth-factor or stem-cell support are not conclusive. These trials are difficult to interpret because the doses planned in the high-dose arms varied only 10% to about threefold higher than the low-dose arms. Because the serum levels for a given dose of drug commonly vary fivefold, the bioavailability of agents given in these trials must overlap considerably. In addition, the actually delivered dose (which is not always included in the report) is often not significantly different from that delivered on the lowerdose arm. Nevertheless, there are significant differences in about half of the trials, and the trends in the remaining trials are generally in favor of the higher-dose arm (Table 4). Of particular note for patients with untreated metastatic disease, the response rates (11% to 70%) and survivals (13 to 22 months) are reasonably representative of results achievable with conventionaldose therapy in this population. In this phase II study, CTCb was demonstrated to be
an intensification regimen with a low mortality rate, which achieved the goal of delivery of significantly increased doses of agents known to be active at conventional doses in breast cancer. While profound myelosuppression and some mucositis was considered acceptable, agents with organ toxicity such as doxorubicin or BCNU were avoided in the construction of this high-dose regimen.1 4 Nevertheless, a 21% to 28% incidence was observed of transient moderate renal, cardiac, and hepatic toxicity. The use of continuous infusions of the three drugs may decrease peak drug levels associated with toxicity. For example, a divided-dose schedule of cyclophosphamide is less cardiotoxic in primates than the same dose given as a single bolus infusion. 35 The cytotoxicity of cyclophosphamide, unlike most alkylating agents, is enhanced in actively proliferating cancer cells.37 Cyclophosphamide also differs from other alkylating agents in that cytotoxicity was enhanced when a given total dose was divided and administered in multiple doses in vivo but not in tissue culture.8 Because cyclophosphamide induces its own metabolism, the half life is shortened, and the total alkylating capacity (area under the curve) is significantly increased when it is administered as multiple daily doses, particularly at high 3 total doses." This may explain the lack of schedule effect in vitro using the activated 4-hydroxycyclophosphamide. Thus, a multiple dose (ie, continuous infusion schedule) may exploit these unique properties of cyclophosphamide. As predicted by modeling experiments and also observed in studies of marrow transplant in patients with leukemia and lymphoma, the duration of PRs were short. The impact of less than 2 logs of tumor cytotoxicity (ie, a PR) is small if tumor-growth kinetics are assumed to be Gompertzian.'3 CRs (whether achieved after induction or after intensification) appear to be
Table 4. Randomized Studies of Dose in Breast Cancer Response Rate (%) Reference 27
Tannock et al Hoogstraten et al'8 Tormey et al" 30 Malik et al, Hortobagyi et a131 32 Beretta et a1 O'Bryan et al13 33 O'Bryan et al" Forastiere et a134 3 Samal et al
TTF (%)
Survival (months)
Stage/Prior Chemotherapy
No.
Regimen
LD
HD
LD
HD
LD
HD
IV/None IV/None IV/None IV/None IV/Limited IV/Limited IV/Extensive IV/Extensive IV/Extensive
133 283 165 60 103 103 68 37 23
CMF CMFVP CMF ± P FAC x 3 CMF A A P P
11* 40* 57 39 32 32 6 0 0
30* 59* 63 70 50 30 24 21 0
7 10 5* 15
7 8 9* 11
13* 14 14* 22
16* 14 16* 19
3 0
3 0
Abbreviations: TTF, time to treatment failure; CMFVP, CMF plus vincristine and prednisone; CMF ± P, CMF with or without prednisone; FAC, fluorouracil, doxorubicin, and cyclophosphomide; A, doxorubicin; P, cisplotin; HD, high dose; LD, low dose. *Significant difference between LD and HD.
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CTCB WITH MARROW SUPPORT IN BREAST CANCER
107
relatively durable, as did responses in patients with only residual positive bone scans and sclerosis on x-ray. There are too few patients to draw any conclusions regarding prognostic variables. Nevertheless, none of the seven patients without progression after transplantation had received prior adjuvant doxorubicin (and five had had no adjuvant chemotherapy). Visceral versus soft tissue disease did not predict for durability of remission; the predominant sites of disease were different in each of these seven patients. Although patients with large bulky tumors or many sites of disease responded to both standard- and high-dose therapy, they were less likely to achieve CRs or durable responses. Theoretically, the use of an induction regimen reduces tumor bulk, decreases the number of cells resistant to the high-dose regimen, and allows the selection of patients with sensitive tumors for high-dose therapy. Alternatively, several cycles of conventional-dose therapy could induce multidrug or specific resistance or allow the growth of partially resistant clones. Nevertheless, a number of investigators have chosen this strategy. In the 267 women who underwent transplantation after some response to conventional-dose therapy (Table 5), 59% had achieved CRs to either conventional-dose therapy or high-dose therapy with marrow transplant. At the time of data analysis, 28% were in continuous CR.4' From the experience gained so far, several regimens designed for breast cancer yield both a high CR rate and relatively durable remissions in patients responding to standard-dose chemotherapy. Response rates of 30% to
50% in refractory breast cancer (with CRs in 10% to 20% of patients) provide evidence of a dose-response relationship." Intensification early in the course of malignant disease, after a good response to standarddose therapy yields a CR rate higher than the 10% to 20% reported with standard-dose therapy. With follow-up intervals of 18 to 40 months from the time of transplant (24 to 44 months from the beginning of induction therapy), these unmaintained responses appear to be relatively durable (16% to 30% in continuous CR, Table 5). For patients with metastatic disease, attempts to improve further the therapeutic index of high-dose chemotherapy using other active agents, modulation of chemotherapeutic agents to address mechanisms of resistance, or the use of two or more high-dose treatments are currently underway. Based on the currently available data, a number of randomized trials are being planned or are already underway to address the impact of dose or dose rate, as well as to delineate optimal timing for dose-intensive therapy. Certainly, the study of a high-dose regimen with documented activity in metastatic disease as primary or adjuvant therapy for patients with inflammatory, stage III disease, or stage II disease with more than 10 positive lymph nodes is now totally appropriate. Stage II and III patients with no macroscopic metastatic disease and whose primary lesions can be adequately treated with local therapy provide an optimal group in which to test the efficacy of dose or dose rate in a prospective randomized trial. Unlike most
Table 5. Results of High-Dose Therapy With ABMT in Responding Stage IV Breast Cancer Response After Induction CR
Response to ABMT
RR
CR
Reference
Agents
No.
No.
%
No.
%
Livingston etal"' 4 243 Gisselbrecht et al , Vaughan (personal communication, 1990) Vincent et oal" Gisselbrecht (personal communication, 1990) Maraninchi (personal communication, 1990) 5 Spitzer et al, "46 Dunphy et al0", Jones et a149"5 Antman (present report) Williams et a1,52 Bitran and Williams5 3 55 Kennedy et al,s4, Beveridge et 0al" Vaughan (personal communication, 1990) 5 9 Rosti et al," " Leoni et al Mulder et al," Willemse et al" Slease et a16 Total
C/TBI C/TBI CT or P/TBI L CL Mitox CL/Mitox CPE CPB CTCb CT CT CTH C/MC/Vb CE/Tam CB
7 5 7 15 18 5 58 39 29 22 20 12 9 10 11 267
2 1 3 7 6 1 20 17 10 6 8 3 4 10 5 104
29 20 43 47 33 20 34 44 34 27 40 25 44 100 45 39
7 5 5 14 14 2 49 35 29 19 20 12 7 10 11 240
100 100 71 93 78 40 84 90 100 86 100 100 78 100 100 90
No. 3 5 4 12 11 5 31 25 17* 12 9 3 6 10 7 160
Follow-Up After ABMT Continuous CR
%
Toxic Death
No.
%
Duration (months)
43 100 57 80 61 100 53 64 59* 55 45 25 67 100 64 60
0 0 3 3 2 0 2 8 1 2 0 2 0 1 2 26
1 1 1 1 9 3 13 10 6 3 5 3 5 3 6 70
14 20 14 7 50 60 22 26 21 14 25 25 56 30 55 26
42+ 30 40+ 18 1-18 4-18 40 20/9-34 19-35 17 10-20 2-10 1-9+ 21 10/2-21
Abbreviations: B, BCNU; C, cyclophosphamide; Cb, carboplatin; E, etoposide; H, hydroxyurea; L, melphalan; MC, mitomycin; Mitox, mitoxantrone; NA, data not available; P, cisplatin; T, thiotepa; Tom, tamoxifen; TBI, total-body irradiation; Vb, vinblastine; RR, response (PR+ CR) rate. *Includes four patients with resolution of all soft tissue disease but sclerosis of previous lytic lesions and residual positive bone scan.
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108
ANTMAN ET AL
patients with metastatic disease, such patients have not received prior adjuvant chemotherapy, have only microscopic metastatic disease, and their performance status
factors and peripheral-blood progenitor-cell support significantly lower the costs, dose-intensive therapy may prove both effective and cost-effective.6 7
is generally excellent. Concurrent studies of prophylactic antibiotics, colonystimulating factors, and peripheral-blood stem-cell support may substantially decrease the morbidity and the length of admissions for these patients, significantly decreasing the cost of this mode of therapy.63 -66If growth
ACKNOWLEDGMENT We thank the house staffs of the Beth Israel Hospital and the Brigham and Women's Hospital and the nursing staffs of 12W at the Dana-Farber Cancer Institute and 4S of the Beth Israel Hospital.
REFERENCES 1. Clark G, Sledge GW, Osborne CK, et al: Survival from first recurrence: Relative importance of prognostic factors in 1,015 breast cancer patients. J Clin Oncol 5:55-61, 1987 2. Mick R, Begg CB, Antman K, et al: Diverse prognosis in metastatic breast cancer: Who should be offered alternative initial therapies? Breast Cancer Res Treat 13:33-38, 1989 3. Henderson IC: Chemotherapy for advanced disease, in Harris JR, Hellman S, Henderson IC, et al (eds): Breast Diseases. Philadelphia, PA, Lippincott, 1987, pp 428-479 4. Frei E III, Antman K, Teicher B, et al: Bone marrow autotransplantation for solid tumors-Prospects. J Clin Oncol 7:515-526, 1989 5. Peters WP: The rationale for high-dose chemotherapy with autologous bone marrow support in treating breast cancer, in Dicke K, Spitzer G, Zander A, (eds): Autologous Bone Marrow Transplantation. Proceedings of the First International Symposium. Houston, TX, University of Texas, MD Anderson Cancer Center Press, 1985, pp 189-196 6. Eder JP, Antman K, Peters W, et al: High-dose combination alkylating agent chemotherapy with autologous bone marrow support for metastatic breast cancer. J Clin Oncol 4:1592-1597, 1986 7. Teicher B, Holden S, Cucchi C, et al: Combination of N, N', N"-triethylenethiophosphoramide and cyclophosphamide in vitro and in vivo. Cancer Res 48:94-100, 1988 8. Teicher BA, Holden SA, Eder JP, et al: Influence of schedule on alkylating agent cytotoxicity in vitro and in vivo. Cancer Res 49:6994-6998, 1989 9. Eder JP, Antman K, Elias A, et al: Cyclophosphamide and thiotepa with autologous bone marrow transplantation with solid tumors. J Natl Cancer Inst 80:1221-1226, 1988 10. Kolaric K, Roth A: Phase II clinical trial cis-dichlorodrammine platinum for anti tumorogenic activity in previously untreated patients with metastatic breast cancer. Cancer Chemother Pharmacol 11:108-112, 1983 11. Kolaric K, Vukas D: Carboplatin activity in untreated metastatic breast cancer-A phase II trial. Proc Am Soc Clin Oncol 9:26, 1990 (abstr) 12. Sledge GW, Loehrer PJ, Roth BJ, et al: Cisplatin as first-line therapy for metastatic breast cancer. J Clin Oncol 6:1811-1814, 1988 13. Shea TC, Flaherty M, Elias A, et al: A phase I clinical and pharmacological study of high-dose carboplatin and autologous bone marrow support. J Clin Oncol 7:651-661, 1989 14. Eder JP, Elias A, Shea TC, et al: A phase I/II study of cyclophosphamide, thiotepa, and carboplatin with autologous bone
marrow transplantation in solid tumor patients. J Clin Oncol 8:1239-1245, 1990 15. Antman K, Eder J, Elias A, et al: High-dose combination alkylating agent preparative regimen with autologous bone marrow support: The Dana-Farber Cancer Institute/Beth Israel Hospital experience. Cancer Treat Rep 71:119-125, 1987 16. Pinkel D: Ninth annual David Karnofsky lecture: Treatment of acute lymphocytic leukemia. Cancer 43:1128-1137, 1979 17. Frei E III, Freireich EJ: Progress and perspectives in the chemotherapy of acute leukemia. Adv Pharmacol Chemother 2:269-289, 1965 18. Frei E III, Karon M, Levin RH, et al: The effectiveness of combinations of antileukemic agents in inducing and maintaining remission in children with acute leukemia. Blood 26:642-656, 1965 19. Freireich EJ, Henderson ES, Karon M, et al: The Treatment of Acute Leukemia With Respect to Cell Population Kinetics. The Proliferation and Spread of Neoplastic Cells; 21st Annual Symposium on Fundamental Cancer Research. Houston, TX, University of Texas, MD Anderson Hospital and Tumor Institute, University of Texas Press, 1968 20. Skipper HE, Schabel FM, Jary R, et al: Experimental evaluation of potential anticancer agents. Cancer Chemother Rep 35:1-111, 1964 21. Skipper HE: Criteria associated with destruction of leukemia and solid tumor cells in animals. Cancer Res 27:2636-2645, 1967 22. Skipper HE: Combination therapy: Some concepts and results. Cancer Chemother Rep 4:137-145, 1974 23. Skipper HE: Stepwise progress in the treatment of disseminated cancers. Cancer 51:1773-1776, 1983 24. Henderson IC, Hayes DF, Gelman R: Dose-response in the treatment of breast cancer: A critical review. J Clin Oncol 6:1501-1515, 1988 25. Hryniuk WM: More is better. J Clin Oncol 6:1365-1367, 1988 26. Canellos G: The dose dilemma. J Clin Oncol 6:1363-1364, 1988 27. Tannock IF, Boyd NF, Deboer G, et al: A randomized trial of two dose levels of cyclophosphamide, methotrexate, and fluorouracil chemotherapy for patients with metastatic breast cancer. J Clin Oncol 6:1377-1387, 1988 28. Hoogstraten B, George SL, Samal B, et al: Combination chemotherapy and Adriamycin in patients with advanced breast cancer. Cancer 38:13-20, 1976 29. Tormey DC, Gelman R, Band PR, et al: Comparison of induction chemotherapies for metastatic breast cancer: An Eastern Cooperative Oncology Group trial. Cancer 50:1235-1244, 1982 30. Malik R, Blumenschein GR, Legha SS, et al: A randomized
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CTCB WITH MARROW SUPPORT IN BREAST CANCER trial of high dose 5-fluorouracil (F), doxorubicin (A) and cyclophosphamide (C) vs conventional FAC regimen in metastatic breast cancer. Proc Am Soc Clin Oncol 1:79, 1982 (abstr 303) 31. Hortobagyi GN, Bodey SP, Buzdar AU, et al: Evaluation of high-dose versus standard FAC chemotherapy for advanced breast cancer in protected environment units: A prospective randomized study. J Clin Oncol 5:354-364, 1987 32. Beretta G, Gambrosier P, Tabiodon D, et al: Therapeutic response after two dose levels of intravenous CMF in metastatic breast carcinoma. Proc Am Soc Clin Oncol 5:77, 1986 (abstr) 33. O'Bryan RM, Baker LH, Gottlieb JE, et al: Dose response evaluation of Adriamycin in human neoplasia. Cancer 39:19401948, 1977 34. Forastiere AA, Hakes TB, Wittes JT, et al: Cisplatin in the treatment of metastatic breast carcinoma: A prospective randomized trial of two dosage schedules. Am J Clin Oncol 5:243-247, 1982 35. Samal B, Vaitkevicius V, Singhakowinta A, et al: CISdiamiminedichloroplatinum (CDDP) in advanced breast and colorectal carcinomas. Proc Am Soc Clin Oncol 19:347, 1978 (abstr) 36. Storb R, Buckner C, Dillingham L, Thomas ED: Cyclophosphamide regimens in rhesus monkeys with and without marrow infusions. Cancer Res 30:2195-2203, 1970 37. Bruce WR, Meeker BE, Valeriote FA: Comparison of the sensitivity of normal hematopoietic and transplanted lymphoma colony forming cells to chemotherapeutic agents administered in vivo. J Natl Cancer Inst 37:233-245, 1966 38. Wagner T, Ehninger G: Self-induction of cyclophosphamide and ifosfamide metabolism by repeated high-dose treatment. Controversies in Oncology 26:69-75, 1987 39. Norton L, Day R: Potential innovations in scheduling of cancer chemotherapy, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Important Advances in Oncology 1991. Philadelphia, PA, Lippincot, 1991, pp 57-72 40. Antman K, Bearman S, Davidson N, et al: High dose therapy in breast cancer with autologous bone marrow support: Current status, in Gale RP, Champlin RE (eds): New Strategies in Bone Marrow Transplantation (new series in Molecular & Cellular Biology). New York, NY, Liss, 1991, pp 423-436 41. Livingston R, Schulman S, Griffin B, et al: Combination chemotherapy and systemic irradiation consolidation for poor prognosis breast cancer. Cancer 9:1249-1254, 1987 42. Gisselbrecht C, Lepage E, Espie M, et al: Cyclophosphamide, total body irradiation with autologous bone marrow support for metastatic breast cancer. Proc Am Soc Clin Oncol 6:65, 1987 (abstr 255) 43. Gisselbrecht C, LePage E, Extra J, et al: Inflammatory and metastatic breast cancer: Cyclophosphamide and total body irradiation (TBI) with autologous bone marrow transplantation (ABMT), in Dicke K, Spitzer G, Jagannath S, et al (eds): Autologous Bone Marrow Transplantation. Proceedings of the Fourth International Symposium. Houston, TX, University of Texas, MD Anderson Cancer Center Press, 1989, pp 363-367 44. Vincent MD, Trevor J, Powles R, et al: Late intensification with high-dose melphalan and autologous bone marrow support in breast cancer patients responding to conventional chemotherapy. Cancer Chemother Pharmacol 21:255-260, 1988 45. Spitzer G, Buzdar A, Auber M, et al: High dose cyclophosphamide/VP-16/platinum intensification for metastatic breast cancer. Breast Cancer Res Treat 10:89, 1987 (abstr) 46. Spitzer GF, Dunphy I, Ellis J, et al: High-dose intensification
for stage IV hormonally-refractory breast cancer, in Dicke K, Spitzer G, Jagannath S, et al (eds): Autologous Bone Marrow Transplantation. Proceedings of the Fourth International Symposium. Houston, TX, University of Texas, MD Anderson Cancer Center Press, 1989, pp 399-405 47. Dunphy F, Spitzer G, Buzdar A, et al: High-dose therapy with ABMT in metastatic breast cancer; clinical features of prolonged progression-free survival. Proc Am Soc Clin Oncol 8:25, 1989 (abstr 91) 48. Dunphy FR, Spitzer G, Dicke K, et al: Tandem high-dose chemotherapy as intensification in stage IV breast cancer, in Bone Marrow Transplantation: Current Controversies. New York, NY, Liss, 1989, pp 245-251 49. Jones RB, Shpall EJ, Peters WP: AFM-Intensive induction chemotherapy for advanced breast cancer. Breast Cancer Res Treat 10:90, 1987 (abstr) 50. Jones RB, Shpall EJ, Shogan J, et al: AFM induction chemotherapy followed by intensive consolidation with autologous bone marrow support for advanced breast cancer. Proc Am Soc Clin Oncol 7:8, 1988 (abstr 29) 51. Jones RB, Shpall EJ, Ross M, et al: AFM induction chemotherapy, followed by intensive alkylating agent consolidation with autologous bone marrow support (ABMS) for advanced breast cancer, current results. Proc Am Soc Clin Oncol 9:9, 1990 (abstr 30) 52. Williams S, Mick R, Dresser R, et al: High-dose consolidation therapy with autologous stem-cell rescue in stage IV breast cancer. J Clin Oncol 7:1824-1830, 1989 53. Bitran JD, Williams SF: A phase II study of induction chemotherapy followed by intensification with high dose chemotherapy with autologous bone marrow rescue (ABMR) in stage IV breast cancer. Breast Cancer Res Treat 10:88, 1987 (abstr) 54. Kennedy M, Beveridge R, Rowley S, et al: Dose-intense cytoreduction followed by high dose consolidation chemotherapy and rescue with purged autologous bone marrow for metastatic breast cancer. Breast Cancer Res Treat 14:133, 1989 (abstr 3) 55. Kennedy MJ, Beveridge R, Rowley S, et al: High dose consolidation chemotherapy and rescue with purged autologous bone marrow following dose-intense induction for metastatic breast cancer. Proc Am Soc Clin Oncol 8:19, 1989 (abstr 69) 56. Beveridge RA, Abeloff MD, Donehower RC, et al: Sixteen week dose intense chemotherapy for breast cancer. Proc Am Soc Clin Oncol 7:13, 1988 (abstr 47) 57. Rosti G, Galligioni E, Argnani M, et al: Autologous bone marrow transplantation as intensification therapy in breast cancer: An Italian cooperative experience, in Dicke K, Spitzer G, Jagannath S, et al (eds): Autologous Bone Marrow Transplantation. Proceedings of the Fourth International Symposium. Houston, TX, University of Texas, MD Anderson Cancer Center Press, 1989, pp 357-363 58. Rosti G, Tumolo S, Figoli F, et al: High dose chemotherapy and autologous bone marrow transplantation in advanced breast cancer. Breast Cancer Res Treat 10:110, 1987 (abstr) 59. Leoni M, Rosti G, Flamini E, et al: High-dose chemotherapy and ABMT in advanced breast cancer: A pilot study. Bone Marrow Transplant 3:299, 1988 (abstr) 60. Mulder NH, Sleijfer DT, de Vries EG, et al: Intensive induction chemotherapy and intensification with autologous bone marrow reinfusion in patients with stage IIIB and IV breast cancer. Proc Am Soc Clin Oncol 7:8, 1988 (abstr 26)
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61. Willemse PHB, de Vries EGE, Sleijfer DT, et al: Intensive induction chemotherapy and intensification with autologous bone marrow reinfusion in patients with stage IIIB and IV breast cancer. Breast Cancer Res Treat 12:147, 1988 (abstract 163) 62. Slease R, Selby G, Saez R, et al: Autologous bone marrow transplantation for metastatic breast carcinoma in complete or partial remission. Breast Cancer Res Treat 14:147, 1989 (abstr 58) 63. Elias A, Mazanet R, Wheeler C, et al: Peripheral blood progenitor cells: Two protocols using GM-CSF potentiated progenitor cell collection, in Dicke KA, Armitage J (eds): Autologous Bone Marrow Transplantation. Proceedings of the Fifth International Symposium. Omaha, NE, University of Nebraska, 1991, pp 875-880 64. Gianni AM, Bregni M, Siena S, et al: Rapid and complete
hematapoietic reconstitution following combined transplantation of autologous blood and bone marrow cells. A changing role for high dose chemoradiotherapy. Hematol Oncol 7:139-148, 1989 65. Gianni AM, Siena S, Bregni M, et al: Granulocytemacrophage colony stimulating factor to harvest circulating hematopoetic stem cells for autotransplant. Lancet 2:580-585, 1989 66. Mazanet R, Elias A, Hunt M, et al: Peripheral blood progenitor cells (PBPCs) added to bone marrow (BM) for hemopoietic rescue following high dose chemotherapy for solid tumors reduces morbidity and length of hospitalization. Proc Am Soc Clin Oncol 10:324, 1991 (abstr 1142) 67. Hillner BE, Smith TJ, Desch CE: Estimating the costeffectiveness of autologous bone marrow transplantation for metastatic breast cancer. Proc Am Soc Clin Oncol 10:46, 1991 (abstr 60)
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(3%; hemorrhage). CRs and PRs continued a median of 16 and 5 months after transplant, respectively (26 and 9 months from initiation of chemotherapy for metastatic disease). Of 10 patients transplanted in CR, four have not progressed at 17 to 31 months after transplantation (25 to 43 months after beginning standard-dose therapy). One of four patients with uptake on bone scan as their only sites of residual disease before transplant and one of three who converted from PR to CR with transplant have not progressed at 27 and 29 months, respectively, after transplant. Conclusions: CTCb is an intensification regimen with a low mortality that delivers a significantly increased dose of agents with known activity at conventional doses in breast cancer. Although the duration of PR is short as expected, CRs appear to be durable. J Clin Oncol 10:102-110. C 1992 by American Society of Clinical Oncology.
BREAST
The median duration of response to the first regimen for metastatic disease is only about 8 months, and metastatic breast cancer virtually always progresses with shorter and fewer CRs achieved with subsequent regimens. Theoretical, experimental, and clinical data suggest that breast cancer recurs despite an initial response to chemotherapy because of endogenous or acquired resistance to cytotoxic agents. In the laboratory, resistance to alkylating agents can often be overcome by a five- to 10-fold higher dose. In laboratory models of breast cancer, administration of the highest possible doses of chemotherapy is essential to the design of curative regimens.4 The objective of this clinical program was to develop a high-dose combination regimen with a low mortality rate and significant activity in breast cancer. We initially combined three drugs from different alkylating agent classes, cyclophosphamide, carmustine (BCNU), and cisplatin, at high doses with autologous marrow support.5 In patients with metastatic breast cancer, 14 of 16 (88%) responded.' The mortality overall (22%) and at the phase II dose (15%) was of concern. Clinical and preclinical efforts were next focused on
CANCER currently develops in 10% of American women. Metastatic breast cancer is essentially incurable. The median survival with standard therapy of about 2 years after documentation of metastases 1' 2 has not changed in the 5 decades for which statistics are available. Although patients are frequently responsive to initial chemotherapy regimens, complete responses (CRs) occur in only 4% to 27% of patients.3
From the Departments ofMedicine, Statistics, and CancerPharmacology, Dana-FarberCancerInstitute; Division of Medical Oncology, Department of Medicine and Surgery, Beth Israel Hospital; and HarvardMedical School, Boston, MA. Submitted June 7, 1991; acceptedJuly 31, 1991. Supported in part by United States Public Health Service grant no. PO1CA-38493 and a grant from the Mather's Foundation. L.A., J.P.E., and A.E. are recipients of career development awardsfrom the American Cancer Society. Presented in part at the Health Improvement Institute- and National Institutes of Health-sponsored 1991 Forum on Emerging Treatments for Breast Cancer. Address reprint requests to Karen Antman, MD, Dana-Farber CancerInstitute, 44 Binney St, Boston, MA 02115. 0 1992 by American Society of ClinicalOncology. 0732-183X/9211001-0002$3.00/0
102
Journal of Clinical Oncology, Vol 10, No 1 (January), 1992: pp 102-110
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CTCB WITH MARROW SUPPORT IN BREAST CANCER
developing an effective but less toxic regimen, with the assumption that a regimen with a low mortality rate would be required to allow its use in an adjuvant setting in women with poor prognoses. Thiotepa is an active drug in breast cancer. In preclinical studies using cultured human breast cancer cells or murine mammary cancer growing in vivo, thiotepa and cyclophosphamide (or an activated form, 4 hydroperoxy-cyclophosphamide) showed striking synergy or marked additivity through four orders of magnitude of tumor-cell cytotoxicity.7 In addition, continuous exposure to cyclophosphamide or thiotepa was superior to bolus administration.8 The first clinical trial combined continuous infusion of 6 g/m 2 cyclophosphamide and escalating doses of thiotepa with dose-limiting mucositis. The response rate in advanced, generally refractory breast cancer was 75% (six of eight).' Carboplatin was then added to the cyclophosphamide-thiotepa doublet to increase response and decrease the emergence of drug resistance. Cisplatin and carboplatin are active in untreated breast cancer.' 0 12 However, neurologic and renal toxicity preclude significant dose escalation of cisplatin. Carboplatin has little renal or neurotoxicity, and its dose-limiting toxicity at standard doses (myelosuppression) makes it ideal for escalation with autologous marrow support.13 Cyclophosphamide, thiotepa, and carboplatin (CTCb) proved less toxic than cyclophosphamide, BCNU, and cisplatin.' 4 Two of 27 patients died of multiorgan failure in the phase I study (7.4%) at doses above that chosen for the phase II dose. The enhanced safety and tolerance of CTCb did not appear to compromise its antineoplastic efficacy. The response rates in refractory breast cancer for CTCb and cyclophosphamide, BCNU, and cisplatin were 86% and 83%, respectively.9,14,15 Using high-dose therapy in lymphoma and leukemia as a model, such regimens are most likely to benefit patients with minimal residual disease such as in an adjuvant setting or in patients with small amounts of metastatic disease who have had very good partial responses (PRs) or CRs to standard induction therapy. An intensification regimen associated with a low mortality rate and that achieves the goal of delivery of significantly increased doses of agents known to be active at standard doses would be a prerequisite to this type of trial in breast cancer.14 This study was designed to examine the CR and total response rates and the duration of response after a single course of high-dose CTCb in women with metastatic breast cancer responding to standard-dose therapy.
103 METHODS PatientSelection Women aged 18 to 55 years with metastatic or unresectable breast cancer responding to a standard-dose chemotherapy regimen were assessed by history, physical examination, pathologic review, hepatic and renal chemistries, ECG, chest roentgenogram, pulmonary function testing, computed tomography (CT) of the head, and bilateral posterior iliac crest biopsies. Patients with bone marrow or CNS metastases, significant hepatic, renal, or cardiopulmonary impairment, performance status greater than 1, or prior pelvic radiation were excluded. Patients referred for this trial were given doxorubicin, fluorouracil, and methotrexate; however, patients referred with a response to other regimens were also eligible.
Supportive Care and Bone Marrow Reinfusion The techniques of bone marrow harvest under general anesthesia, cryopreservation, reinfusion, and supportive care have been previously reported."
Therapy Patients received continuous intravenous infusion CTCb over 96 hours (day -7 to -3 through separate ports of multiple lumen indwelling central venous catheters) followed in 72 hours by autologous bone marrow reinfusion (day 0). Cyclophosphamide 1.5 g/m2/d (for a total dose of 6 gm/mz) was given with bladder irrigation to prevent cystitis. Thiotepa 125 mg/m 2 /d (500 mg/m 2 total dose) and carboplatin 200 mg/m 2/d (800 mg/m2 total dose) were administered concurrently. When feasible, sites of prior bulk disease or residual disease after high-dose therapy were resected or radiated.
Response Criteria Lesions were measured before the initiation of chemotherapy. Palpable tumors and those visible on chest roentgenogram were measured weekly. More complicated imaging studies were delayed until reverse isolation was discontinued. CR or PR was defined as the disappearance of all tumor or a 50% to 99% reduction in the product of the bidimensional measurements, respectively, for a minimum of 4 weeks. PR (bone scan-positive) was further identified as the subset of patients with complete resolution of all soft tissue disease, sclerosis of prior lytic bone lesions, but continuing activity by bone scan in areas of prior uptake. Disease progression was defined as a greater than 25% increase in tumor size or the appearance of any new lesions. Patients who died early of toxicity were considered unassessable (UA) for response, although tumor progression was coded if observed. Survival and time to disease progression were calculated from the date of marrow reinfusion.
RESULTS Between May 1988 and September 1989, 29 women were entered on study. Patient characteristics are listed in Table 1. The median follow-up is 28 months from
autotransplant (range, 19 to 33 months). The median time to treatment failure for all 29 patients was 6 months after marrow transplant (or 10 months from start of induction therapy). The median survival is undefined (at
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104
ANTMAN ET AL Table 1. Patient Characteristics
Patients entered Median age, years (range) Prior adjuvant therapy Prior induction regimens for metastatic or inoperable disease 1 2 Receptor-positive Estrogen Progesterone Not done or insufficient material obtained Prior marrow involvement Predominant disease site Lung Lymph nodes Liver Bone Skin Breast
No.
%
29 39 (27-55) 14
100
24 5
83 17
9 5 4 2
31 17 14 7
8 6 5 4 4 2
28 21 17 14 14 7
48
least 20 months from the time of transplant) because 15 of the 29 women remain alive. Toxicity Absolute granulocytopenia, fevers, and thrombocytopenia developed in all patients (Table 2). One patient died early of CNS bleeding before reingraftment despite intensive platelet support. A second patient had poor platelet engraftment at the time of her death on day 108 of progression of massive liver metastases, hepatic insufficiency, and gastrointestinal bleeding. Of the remaining 27 patients with full engraftment, the median Table 2. Toxicity of High-Dose CTCb Toxicity
No.
%
Patients Toxic deaths Hematologic Bleeding Sepsis Fungal infection Infectious pneumonitis Drug-associated interstitial pneumonitis Transient congestive heart failure Renal Creatinine level 1.5-3 mg/dL Creotinine level > 3 mg/dL Gross hematuria Hepatic Bilirubin level 2-5 mg/dL Bilirubin level 5-6 mg/dL Stomatitis transiently precluding oral intake
29 1*
100 3
2 8 3 0 0 6
7 28 10 0 0 21
5 1 3
17 3 10
5 3 8
17 10 28
*A second patient with poor platelet engraftment died of progression of massive liver metastases, hepatic insufficiency, and gastrointestinal bleeding on day 108.
time to recovery of granulocytes to greater than 500/[tL was 21 days (range, 10 to 51 days); to platelet independence greater than 20,000/pIL without transfusion, 23 days (range, 10 to 81 days). The median number of total hospital days was 32 (range, 22 to 113 days). One patient who had received prior melphalan later developed myelodysplasia. Six patients developed transient congestive heart failure lasting 1 to 6 days at a median of 10 days (range, 8 to 13 days) after marrow reinfusion. All six patients had tachycardia, tachypnea, rales, and weight gain, and five had a documented cardiac gallop. On chest x-ray all six patients had interstitial edema or alveolar edema with a pleural effusion. One of the six developed cardiomegaly. Symptoms in all patients resolved with treatment with diuretics with or without vasodilators. This constellation of symptoms was believed to represent transient cyclophosphamide cardiotoxicity. While patients had a substantial obligatory fluid intake from antibiotics and blood products over the course of their 4- to 6-week hospitalization, there was no other immediately apparent explanation for the temporary cardiac decompensation in these patients. There was no evidence of peripheral edema to suggest a capillary leak syndrome. A serum bilirubin level above 5 mg/dL occurred in three patients. None of these patients had ascites, abrupt weight gain, or right upper quadrant tenderness suggestive of venoocclusive disease of the liver. Hepatomegaly developed in only one of the three patients that proved to be late enlargement of her known liver metastases, originally identified by CT. One patient had a conjugated bilirubin level of 3.3 when her total bilirubin level peaked at 6.0 mg/dL and was found to be Coombs' test-positive, suggesting a mixed mechanism for hyperbilirubinemia. Bilirubin in two patients fluctuated with blood transfusions. Slight transaminase elevations followed elevated bilirubin in all three patients. Alkaline phosphatase was elevated slightly in two and substantially in one. Stomatitis was moderate in seven patients and precluded oral intake in eight. No patient required intubation. Response Responses to high-dose therapy and the current status of patients are listed in Table 3. Time to treatment failure is 19 months (Fig 1A) for those who achieved a CR (or an abnormal bone scan as the only residual evidence of disease) versus 5 months for patients with only a PR (26 and 9 months from the initiation of chemotherapy for metastatic disease, respectively). Time
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105
CTCB WITH MARROW SUPPORT IN BREAST CANCER
Table 3. Responses to High-Dose Therapy and the Current Status of Patients by the Response of Breast Cancer to Standard Therapy Before High-Dose Therapy CR* No Measurable Disease (10)t Prognostic variables Prior adjuvant chemotherapy Prior adjuvant doxorubicin Prior chemotherapy for metastatic disease AFM chemotherapy as induction Disease-free interval < 6 months after diagnosis Visceral disease (eg, lung, liver) Bone metastases Results after high-dose therapy with marrow support Toxic death Resection of sites of prior bulk disease Radiotherapy to sites of prior bulk disease No progression Median months to progression from transplant Follow-up for patients without progression Months from induction Months from transplant
PR* CR (3)t
PRt (4)t
5 2 3 4 4 3 0
1 0 0 3 1 2 1
3 2 0 4 0 0 4
5 4 2 5 3 8 2
0 0 0 4 16
1 0 1 1 6
0 0 1 1 21
0 2 3 1 5
33 29
32 27
37 26
25-43 17-31
PR(12)t
Abbreviations: AFM, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), fluorouracil, and methotrexate. *Response to standard-dose therapy.
"tResponseto high-dose therapy (n). SPatients with complete resolution of all soft tissue disease but continuing activity on bone scan in areas of prior uptake.
to treatment failure and survival for the group as a whole are shown in Fig lB. Because of multiple and visceral disease sites, postintensification resection or irradiation of prior bulk or residual disease proved feasible in only five patients. Ten patients entered the study in CR; four have not progressed. Of the 15 patients who were in PR at the time of high-dose therapy, three converted to CR (20%; 90% confidence interval, 6% to 44%) and one has not progressed. Of the four patients who underwent transplantation with a positive bone scan as their only evidence of residual disease, one has not progressed. Of A l.0
1.0
B
0.8
0.8
J• 0.6 o
S0.6
i,
i.
S0.4
0.4 i,,.1t .... I-.. I.
0.2
0.2
......... ............ . . ... ....I .. .. .. ... .. ... •
I
S0.0
0.0 0
10
20 Months
30
40
0
10
20
30
40o
Months
Fig 1. (A) Disease-free survival and survival are shown for the group as a whole. Survival time (-): 15 censored, 14 failed, 29 total. Time to failure (..--): 7 censored, 22 failed, 29 total, 6 median. (B) Time to treatment failure is shown for patients who achieved a CR to either standard- or high-dose therapy (including patients with PRs whose only site of residual disease was a positive bone scan) versus those who never achieved a CR. CR + PR (-): 6 censored, 11 failed, 17 total, 19 median. PR (....): 1 censored, 11 failed, 12 total, 5 median.
those with PRs after marrow transplantation, one patient with biopsy-proven hepatic metastases has had no progression of residual abnormalities on CT of the liver. Of the seven patients who have not progressed, the predominant sites of disease were (one patient each) liver, lung, bone, chest wall, bilateral lymph nodes, skin, and breast. Five were estrogen receptor- and progesterone receptor-negative. One with multiple liver metastases was estrogen receptor- and progesterone receptorpositive, and testing for receptors was not performed on one patient. Two patients had received adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF), and five had had no adjuvant chemotherapy. (Thus, none of those without progression had received adjuvant doxorubicin.) Four responded to the initial induction regimen; one had no response to initial melphalan therapy for metastases but then responded to cyclophosphamide, doxorubicin, and fluorouracil (CAF) chemotherapy. Two received postintensification therapy; one underwent radiation after a needle biopsy-proven CR of a large breast mass and a 3-cm lymph node. A second patient with estrogen receptor-positive disease with a PR of liver metastases after transplantation was placed on tamoxifen. DISCUSSION The principles of dose-response and combination chemotherapy were basic to the design of treatment
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ANTMAN ET AL
regimens for malignancies now curable with chemotherapy (eg, leukemias, lymphomas, and testis and breast cancer in the adjuvant setting)."6 " Skipper et al20'23 estimated the spontaneous rate of mutations conferring resistance to a single drug as one in 106 to 10' cancer cells. Therefore, the likelihood of the spontaneous emergence of drug resistance is high in patients with visually apparent tumor, suggesting that combinations of active noncrossresistant agents with different mechanisms of action are essential to decrease the emergence of drug resistance. Agents are then selected with different dose-limiting toxicities, resulting in subadditive toxicity in combination. These strategies can then be used to design high-dose regimens for use with marrow transplant. Clinically, the importance of dose in breast cancer has been extensively debated. 2426 Data from the few randomized trials at doses feasible without growth-factor or stem-cell support are not conclusive. These trials are difficult to interpret because the doses planned in the high-dose arms varied only 10% to about threefold higher than the low-dose arms. Because the serum levels for a given dose of drug commonly vary fivefold, the bioavailability of agents given in these trials must overlap considerably. In addition, the actually delivered dose (which is not always included in the report) is often not significantly different from that delivered on the lowerdose arm. Nevertheless, there are significant differences in about half of the trials, and the trends in the remaining trials are generally in favor of the higher-dose arm (Table 4). Of particular note for patients with untreated metastatic disease, the response rates (11% to 70%) and survivals (13 to 22 months) are reasonably representative of results achievable with conventionaldose therapy in this population. In this phase II study, CTCb was demonstrated to be
an intensification regimen with a low mortality rate, which achieved the goal of delivery of significantly increased doses of agents known to be active at conventional doses in breast cancer. While profound myelosuppression and some mucositis was considered acceptable, agents with organ toxicity such as doxorubicin or BCNU were avoided in the construction of this high-dose regimen.1 4 Nevertheless, a 21% to 28% incidence was observed of transient moderate renal, cardiac, and hepatic toxicity. The use of continuous infusions of the three drugs may decrease peak drug levels associated with toxicity. For example, a divided-dose schedule of cyclophosphamide is less cardiotoxic in primates than the same dose given as a single bolus infusion. 35 The cytotoxicity of cyclophosphamide, unlike most alkylating agents, is enhanced in actively proliferating cancer cells.37 Cyclophosphamide also differs from other alkylating agents in that cytotoxicity was enhanced when a given total dose was divided and administered in multiple doses in vivo but not in tissue culture.8 Because cyclophosphamide induces its own metabolism, the half life is shortened, and the total alkylating capacity (area under the curve) is significantly increased when it is administered as multiple daily doses, particularly at high 3 total doses." This may explain the lack of schedule effect in vitro using the activated 4-hydroxycyclophosphamide. Thus, a multiple dose (ie, continuous infusion schedule) may exploit these unique properties of cyclophosphamide. As predicted by modeling experiments and also observed in studies of marrow transplant in patients with leukemia and lymphoma, the duration of PRs were short. The impact of less than 2 logs of tumor cytotoxicity (ie, a PR) is small if tumor-growth kinetics are assumed to be Gompertzian.'3 CRs (whether achieved after induction or after intensification) appear to be
Table 4. Randomized Studies of Dose in Breast Cancer Response Rate (%) Reference 27
Tannock et al Hoogstraten et al'8 Tormey et al" 30 Malik et al, Hortobagyi et a131 32 Beretta et a1 O'Bryan et al13 33 O'Bryan et al" Forastiere et a134 3 Samal et al
TTF (%)
Survival (months)
Stage/Prior Chemotherapy
No.
Regimen
LD
HD
LD
HD
LD
HD
IV/None IV/None IV/None IV/None IV/Limited IV/Limited IV/Extensive IV/Extensive IV/Extensive
133 283 165 60 103 103 68 37 23
CMF CMFVP CMF ± P FAC x 3 CMF A A P P
11* 40* 57 39 32 32 6 0 0
30* 59* 63 70 50 30 24 21 0
7 10 5* 15
7 8 9* 11
13* 14 14* 22
16* 14 16* 19
3 0
3 0
Abbreviations: TTF, time to treatment failure; CMFVP, CMF plus vincristine and prednisone; CMF ± P, CMF with or without prednisone; FAC, fluorouracil, doxorubicin, and cyclophosphomide; A, doxorubicin; P, cisplotin; HD, high dose; LD, low dose. *Significant difference between LD and HD.
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CTCB WITH MARROW SUPPORT IN BREAST CANCER
107
relatively durable, as did responses in patients with only residual positive bone scans and sclerosis on x-ray. There are too few patients to draw any conclusions regarding prognostic variables. Nevertheless, none of the seven patients without progression after transplantation had received prior adjuvant doxorubicin (and five had had no adjuvant chemotherapy). Visceral versus soft tissue disease did not predict for durability of remission; the predominant sites of disease were different in each of these seven patients. Although patients with large bulky tumors or many sites of disease responded to both standard- and high-dose therapy, they were less likely to achieve CRs or durable responses. Theoretically, the use of an induction regimen reduces tumor bulk, decreases the number of cells resistant to the high-dose regimen, and allows the selection of patients with sensitive tumors for high-dose therapy. Alternatively, several cycles of conventional-dose therapy could induce multidrug or specific resistance or allow the growth of partially resistant clones. Nevertheless, a number of investigators have chosen this strategy. In the 267 women who underwent transplantation after some response to conventional-dose therapy (Table 5), 59% had achieved CRs to either conventional-dose therapy or high-dose therapy with marrow transplant. At the time of data analysis, 28% were in continuous CR.4' From the experience gained so far, several regimens designed for breast cancer yield both a high CR rate and relatively durable remissions in patients responding to standard-dose chemotherapy. Response rates of 30% to
50% in refractory breast cancer (with CRs in 10% to 20% of patients) provide evidence of a dose-response relationship." Intensification early in the course of malignant disease, after a good response to standarddose therapy yields a CR rate higher than the 10% to 20% reported with standard-dose therapy. With follow-up intervals of 18 to 40 months from the time of transplant (24 to 44 months from the beginning of induction therapy), these unmaintained responses appear to be relatively durable (16% to 30% in continuous CR, Table 5). For patients with metastatic disease, attempts to improve further the therapeutic index of high-dose chemotherapy using other active agents, modulation of chemotherapeutic agents to address mechanisms of resistance, or the use of two or more high-dose treatments are currently underway. Based on the currently available data, a number of randomized trials are being planned or are already underway to address the impact of dose or dose rate, as well as to delineate optimal timing for dose-intensive therapy. Certainly, the study of a high-dose regimen with documented activity in metastatic disease as primary or adjuvant therapy for patients with inflammatory, stage III disease, or stage II disease with more than 10 positive lymph nodes is now totally appropriate. Stage II and III patients with no macroscopic metastatic disease and whose primary lesions can be adequately treated with local therapy provide an optimal group in which to test the efficacy of dose or dose rate in a prospective randomized trial. Unlike most
Table 5. Results of High-Dose Therapy With ABMT in Responding Stage IV Breast Cancer Response After Induction CR
Response to ABMT
RR
CR
Reference
Agents
No.
No.
%
No.
%
Livingston etal"' 4 243 Gisselbrecht et al , Vaughan (personal communication, 1990) Vincent et oal" Gisselbrecht (personal communication, 1990) Maraninchi (personal communication, 1990) 5 Spitzer et al, "46 Dunphy et al0", Jones et a149"5 Antman (present report) Williams et a1,52 Bitran and Williams5 3 55 Kennedy et al,s4, Beveridge et 0al" Vaughan (personal communication, 1990) 5 9 Rosti et al," " Leoni et al Mulder et al," Willemse et al" Slease et a16 Total
C/TBI C/TBI CT or P/TBI L CL Mitox CL/Mitox CPE CPB CTCb CT CT CTH C/MC/Vb CE/Tam CB
7 5 7 15 18 5 58 39 29 22 20 12 9 10 11 267
2 1 3 7 6 1 20 17 10 6 8 3 4 10 5 104
29 20 43 47 33 20 34 44 34 27 40 25 44 100 45 39
7 5 5 14 14 2 49 35 29 19 20 12 7 10 11 240
100 100 71 93 78 40 84 90 100 86 100 100 78 100 100 90
No. 3 5 4 12 11 5 31 25 17* 12 9 3 6 10 7 160
Follow-Up After ABMT Continuous CR
%
Toxic Death
No.
%
Duration (months)
43 100 57 80 61 100 53 64 59* 55 45 25 67 100 64 60
0 0 3 3 2 0 2 8 1 2 0 2 0 1 2 26
1 1 1 1 9 3 13 10 6 3 5 3 5 3 6 70
14 20 14 7 50 60 22 26 21 14 25 25 56 30 55 26
42+ 30 40+ 18 1-18 4-18 40 20/9-34 19-35 17 10-20 2-10 1-9+ 21 10/2-21
Abbreviations: B, BCNU; C, cyclophosphamide; Cb, carboplatin; E, etoposide; H, hydroxyurea; L, melphalan; MC, mitomycin; Mitox, mitoxantrone; NA, data not available; P, cisplatin; T, thiotepa; Tom, tamoxifen; TBI, total-body irradiation; Vb, vinblastine; RR, response (PR+ CR) rate. *Includes four patients with resolution of all soft tissue disease but sclerosis of previous lytic lesions and residual positive bone scan.
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ANTMAN ET AL
patients with metastatic disease, such patients have not received prior adjuvant chemotherapy, have only microscopic metastatic disease, and their performance status
factors and peripheral-blood progenitor-cell support significantly lower the costs, dose-intensive therapy may prove both effective and cost-effective.6 7
is generally excellent. Concurrent studies of prophylactic antibiotics, colonystimulating factors, and peripheral-blood stem-cell support may substantially decrease the morbidity and the length of admissions for these patients, significantly decreasing the cost of this mode of therapy.63 -66If growth
ACKNOWLEDGMENT We thank the house staffs of the Beth Israel Hospital and the Brigham and Women's Hospital and the nursing staffs of 12W at the Dana-Farber Cancer Institute and 4S of the Beth Israel Hospital.
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