Breast Cancer Phase II Trial of Sequential High-Dose

Home , Thiotepa

Bone Marrow Transplantation (2002) 30, 149–155  2002 Nature Publishing Group All rights reserved 0268–3369/02 $25.00 www.nature.com/bmt Breast cancer Phase II trial of sequential high-dose chemotherapy with paclitaxel, melphalan and cyclophosphamide, thiotepa and carboplatin with peripheral blood progenitor support in women with responding metastatic breast cancer

LT Vahdat1, C Balmaceda2, K Papadopoulos3, D Frederick3, D Donovan3, E Sharpe3, E Kaufman3, D Savage3, A Tiersten3, G Nichols3, J Haythe3, A Troxel4, K Antman4 and CS Hesdorffer3

1Weill Cornell Medical College, New York, NY, USA; 2Department of Neurology, Columbia University, New York, NY, USA; 3Division of Medical Oncology and Hematology, Department of Medicine, Columbia University, New York, NY, USA; and 4Division of Biostatistics of the Joseph Mailman School of Public Health, The Herbert Irving Comprehensive Cancer Center of Columbia College of Physicians and Surgeons, University of Columbia, New York, NY, USA

Summary: Keywords: stem cell transplant; breast cancer; multi- cycle chemotherapy; tandem transplants A single high-dose cycle of chemotherapy can produce response rates in excess of 50%. However, disease-free survival (DFS) is 15–20% at 5 years. The single most important predictor of prolonged DFS is achieving a Advanced breast cancer continues to be a highly treatable, complete response (CR). Increasing the proportion of albeit ultimately deadly disease, with a median survival of patients who achieve a complete response may improve 2 to 2.5 years.1 New cytotoxics and biologics may lengthen disease-free survival. Women with metastatic breast survival in the order of 1 to 5 months. However, long-term cancer and at least a partial response (PR) to induction disease-free survival is rare.2–4 chemotherapy received three separate high-dose cycles The research interest in very high-dose chemotherapy of chemotherapy with peripheral blood progenitor sup- sprang from the observation of a linear-log relationship port and G-CSF. The first intensification was paclitaxel between dose and tumor cell kill. Early clinical studies (825 mg/m2), the second melphalan (180 mg/m2) and the determined that 15 to 20% of women who achieved a com- third consisted of cyclophosphamide 6000 mg/m2 (1500 plete response as a consequence of a single high-dose cycle mg/m2/day ؋ 4), thiotepa 500 mg/m2 (125 mg/m2/day of chemotherapy as consolidation for responding metastatic ؋ 4) and carboplatin 800 mg/m2 (200 mg/m2/day ؋ 4) breast cancer maintained this response for longer than 5 (CTCb). Sixty-one women were enrolled and 60 com- years – in contrast to less than 5% observed in previous pleted all three cycles. Following the paclitaxel infusion studies.2 However, that the observation of improved sur- most patients developed a reversible, predominantly vival might be due to selection bias is suggested in a retro- sensory polyneuropathy. Of the 30 patients with spective review of a large database.5 measurable disease, 12 converted to CR, nine converted There are five randomized trials assessing high-dose to a PR*, and five had a further PR, giving an overall chemotherapy with autologous stem cell support as a response rate of 87%. The toxic death rate was 5%. No component of overall therapy in patients with metastatic patient progressed on study. Thirty percent are pro- breast cancer. Two of these trials demonstrate equivalence gression-free with a median follow-up of 31 months of a single high-dose cycle of chemotherapy with stem cell (range 1–43 months) and overall survival is 61%. Three support to maintenance chemotherapy.6,7 Survival was sequential high-dose cycles of chemotherapy are feasible doubled in the small French trial, a difference that was not and resulted in a high response rate. The challenge con- statistically significant.8 The two Duke University trials tinues to be maintenance of response and provides the compare a single high-dose cycle of chemotherapy after opportunity to evaluate strategies for eliminating mini- four cycles of conventional therapy vs observation alone, mal residual disease. with the high-dose therapy producing superior disease-free Bone Marrow Transplantation (2002) 30, 149–155. survival.9,10 Patients with relapse on the conventional dose doi:10.1038/sj.bmt.1703592 arm in these two Duke studies were then crossed over to high-dose therapy, obviating the survival comparison of conventional versus high-dose therapy. Correspondence: Dr LT Vahdat, Breast Cancer Unit, Weill Cornell Medi- Several arguments favor evaluation of sequential high- cal College, 425 East 61st Street, Eighth Floor, NY 10021, USA dose chemotherapy as compared to a single high-dose Received 10 January 2002; accepted 25 March 2002 cycle. First, curative chemotherapy regimens for testis, High-dose paclitaxel in metastatic breast cancer LT Vahdat et al 150 lymphoma and breast cancer in the adjuvant setting require coupled with symptomatic improvement and where appli- repetitive chemotherapy cycles. Second, the North Amer- cable falling tumor markers were sufficient. Progression of ican Autologous Bone Marrow Transplant Registry disease between cycles, or life-threatening grade 4 toxicity (ABMTR) data suggest that a complete response is associa- resulted in removal from the study. Patients were evaluated ted with a higher probability of remaining progression-free by a reference neurologist and nerve conduction studies than are a partial or non-response.11 The goal of this trial were performed at baseline and prior to the second high- of sequential high-dose chemotherapy was to attempt to dose cycle. increase the complete response rate to determine if an increased proportion of patients would remain disease-free. Treatment Paclitaxel is one of the more active agents against breast cancer to emerge in the past 20 years. Pre-clinical data in The treatment plan is outlined in Figure 1. Induction breast cancer cell lines and MDA-4 transplanted tumors in chemotherapy was delivered by the referring oncologist. C3Hf/Kam mice support a dose-concentration/response After documentation of at least a partial response in patients effect in breast cancer.12,13 In the standard dose range, a with measurable disease and after at least three cycles of modest improvement in response rate was observed after chemotherapy in patients with completely resected or radi- increasing the dose from 135 mg/m2 to 175 mg/m2 although ated disease, peripheral blood hematopoietic progenitors dose-limiting myelosuppression and neuropathy precluded were mobilized with chemotherapy and G-CSF (5 further escalation in dose and assessment of a dose- ␮g/kg/day subcutaneously) and a minimum of 3 ϫ 106 response.14 Our group has conducted a series of tandem CD34+ (CD45+/CD14Ϫ) mononuclear cells per kilogram transplant trials for women with responsive advanced breast were harvested and cryopreserved using previously pub- cancer. Our phase I trial of three separate high-dose cycles lished standard techniques.17 of chemotherapy with stem cell support consisted of dose- escalating paclitaxel followed by melphalan followed by Intensification 1: Paclitaxel with peripheral blood stem cell CTCb (cyclophosphamide, thiotepa, carboplatin). The support: After standard pre-medication with dexame- rationale for the melphalan and CTCb backbone derived thasone, cimetidine and diphenhydramine, paclitaxel at 825 from data generated by Ayash and colleagues,15 in which mg/m2 was administered as a continuous infusion over this tandem transplant was superior in terms of response 24 h. Approximately one-third of stem cells were infused and disease-free survival at 2 years of follow-up as com- 72 h later. Patients were discharged home after the stem pared to prior experience with CTCb alone. In our phase I cell infusion. trial of a dose escalation of paclitaxel as the first high-dose cycle of a tandem high-dose chemotherapy regimen, we Intensification 2: Melphalan with peripheral blood stem reported an overall response rate of 79%.16 At a median cell support: After recovery from intensification 1, patients follow-up of 60 months, 30% are disease-free and 45% received melphalan at 90 mg/m2/day for 2 consecutive days are alive. (180 mg/m2 total). On day 3, approximately one-third of stem cells were infused after hydration with 1 liter of iso- tonic fluid. This cycle was done predominantly as an out- Materials and methods patient.

Patient eligibility Intensiﬁcation 3: CTCb with peripheral blood stem cell support: With recovery to an ANC у1000/␮l, and in the Women aged 18 to 60 years with responding (complete or absence of platelet refractoriness, patients were admitted to partial response) histologically-documented stage 4 breast the hospital for the entire cycle. Cyclophosphamide 6000 cancer were eligible if hepatic (bilirubin р2 times normal, mg/m2 (1500 mg/m2/day), thiotepa 500 mg/m2 (125 SGOT р1.5 times normal), renal (creatinine Ͻ1.5 times mg/m2/day) and carboplatin 800 mg/m2 (200 mg/m2/day) normal) and cardiac (left ventricular ejection fraction у45%) functions and performance status (ECOG 0–1) At least 3 cycles of conventional dose induction were adequate. Exclusion criteria included central nervous chemotherapy system metastases, progression while on prior taxane Complete or partial response chemotherapy, a disease-free interval less than 12 months Harvest stem cells since completion of any taxane-containing adjuvant ther- Intensifications, each with PBSC + GSF support apy, pre-existing grade 3 or 4 neuropathy (NCI CTC), prior mitomycin C or cisplatin chemotherapy or a cumulative I: Paclitaxel (825 mg/m2) dose of more than 450 mg/m2 of anthracyclines. All II: Melphalan (180 mg/m2) patients gave written informed consent. This study was III: Cyclophosphamide 6000 mg/m2, thiotepa 500 mg/m2, approved by the Institutional Review Board of the Colum- carboplatin 800 mg/m2 bia Presbyterian Medical Center. Post-HDC consolidation therapy Patients with completely resected or irradiated metast- Surgery and/or radiotherapy if feasible ases were eligible provided that their metastases were not Anti-hormonal therapy for 5 years if tumor expresses ER or PR + previously refractory to chemotherapy. For patients with Bisphosphonates continued if on prior to HDC bone as the only site of metastases, radiographic evidence of tumor response (ie sclerosis of prior lytic lesions) Figure 1 Treatment schema.

Bone Marrow Transplantation High-dose paclitaxel in metastatic breast cancer LT Vahdat et al 151 were administered over 96 h on days Ϫ7toϪ3. Mesna Results 7500 mg/m2 (1500 gm/m2/day) was administered over 120 h. The remaining peripheral blood stem cells were Patient characteristics infused on day 0. The concomitant use of steroids, barbitu- From January 1997 until June 2000, 61 women entered this rates, acetaminophen during chemotherapy was prohibited to avoid affecting P450 drug metabolism. study. Patient characteristics are listed in Table 1. The median age for all patients was 46 years with a range of All patients had complete blood counts and chemistries 24 to 64 years of age. assessed daily. Prophylactic ciprofloxacin 500 mg twice a day, fluconazole and acyclovir (for HSV+ patients) was Forty-two women were initially diagnosed with localized breast cancer. Primary invasive breast cancer was bilateral begun when the ANC fell below 500/␮l. G-CSF (5 ␮g/kg/day subcutaneously) was begun after each stem cell in four patients. Six patients had a history of stage 1, 30 infusion and was continued until the ANC у1000/␮l for 2 stage II and 6 with stage III breast cancer. Ten patients were node negative at diagnosis, and 12 had у4 lymph consecutive days. After the first neutropenic fever, the Cipro was stopped and broad-spectrum antibiotics were nodes involved with breast cancer. Six patients had an ipsil- instituted. Patients were transfused with irradiated (2500 ateral breast tumor recurrence prior to their diagnosis of advanced breast cancer. Most patients received adjuvant rads) products for hemoglobin Ͻ8 gm/dl or platelets Ͻ20 000/␮l. chemotherapy (39) with 22 (56%) having received a doxorubicin-containing regimen and one also a taxane-containing adjuvant regimen. Post-intensification therapy: Following recovery from Thirty-four patients had undergone a modified radical three intensifications, sites of prior bulk disease were mastectomy, 20 a lumpectomy, axillary node dissection and excised or irradiated when feasible. Patients with estrogen breast radiation therapy. Eight patients had undergone chest and/or progesterone receptor-positive tumors received anti- wall radiation therapy as part of their primary therapy. The hormonal agents after completing high-dose therapy, when median disease-free interval from initial diagnosis of pri- appropriate. Patients who previously received bisphosphon- mary breast cancer to stage 4 disease was 47 months (range, ates were continued on this therapy also. If patients had 3–108 months). previously received trastuzamab, they had the option to continue this therapy. Initial presentation of Stage IV breast cancer: Nineteen patients (31%) had advanced breast cancer as their initial

Deﬁnition of terms and response Table 1 Patient characteristics

Hematologic recovery was measured from day 0 to ANC Variable No. % у500/␮l, and a platelet count Ͼ20 000/␮l unsupported by transfusion. Tumors were assessed by physical examination Patients entered 61 and imaging studies at entry and 4 to 6 weeks after dis- Patients completing all 3 cycles of chemotherapy 60 98 charge from the hospital. Hormone receptor status ER/PR+ 34 56 A complete (CR) or partial response (PR) is deﬁned as ER+/PRϪ 813 the complete disappearance or у50% reduction in the sum ER/PRϪ 16 26 of the products of the largest bi-perpendicular diameters of Unknown 3 5 all measurable disease for at least 4 weeks. Partial Predominant metastatic site Bone 16 26 response* (PR*) is the complete resolution of all soft tissue Soft tissue 14 23 or visceral disease with sclerosis of prior lytic bone lesions. Viscera 31 51 Stable disease is a Ͻ25% reduction in the bi-dimensional Age measurements of the lesions. Disease progression (POD) is Ͻ45 years 26 43 у an increase of 25% in the tumor size or the appearance of 45 years 35 57 new lesions. Initial diagnosis of stage 4 breast cancer 19 31

Prior primary breast cancer 42 69 Stage I 7 17 Statistical analysis Stage II T2N0 3 7 This was designed to have 90% power to detect a response No. of involved axillary lymph nodes rate of 70% vs an expected response rate of 50%, using a 1–31536 Simon design. Descriptive statistics are reported as 4–9614 у10 4 10 medians. Disease-free survival and overall survival are Type of primary surgery defined as the time from discharge from hospital after inten- Lumpectomy + node dissection + RT 20 33 sification 3 until disease progression or death, respectively, Modified radical mastectomy 37 61 and the curves were estimated by the Kaplan–Meier Biopsy 4 6 18 Adjuvant therapy product limit method. If the patient died prior to their Doxorubicin containing 22 56 discharge from the third cycle, inclusion in the survival Non-doxorubicin containing 18 46 analysis is as a toxic death. Taxane-containing 1 3

Bone Marrow Transplantation High-dose paclitaxel in metastatic breast cancer LT Vahdat et al 152 diagnosis. Predominant metastatic sites included bone (6), received glutamine in a second study to determine if symp- lymph nodes (5), lungs (4), liver (3), and chest wall (1). toms of peripheral neuropathy could be ameliorated.19 One patient had undergone tandem high-dose chemo- Myalgias required varying amounts of analgesia therapy with stem cell support as initial treatment for her (acetominophen to morphine sulfate) and were observed in diagnosis of advanced breast cancer at another Institution most patients. Constipation lasting up to 1 week was with a disease-free interval of 6 years prior to her recur- observed but no bowel obstruction occurred and this rence and subsequent entry onto this trial. problem resolved with aggressive bowel regimens.

Induction therapy: The majority of patients had one prior Intensification 2: Melphalan with peripheral blood progeni- regimen for metastatic breast cancer (range, 1–3). Patients tor support: Sixty patients received the second intensifi- received a median of six cycles of induction chemotherapy cation at a median of 25 days later (range, 18–50 days) after prior to the first intensification (range, 2–24 cycles). Ten the first intensification. Fifty-nine patients received this as patients underwent induction with a doxorubicin-based an outpatient. Forty-four of 60 patients were readmitted regimen, 26 with a taxane-based regimen, and 13 with both with neutroropenia/fever (37), nausea/vomiting (6) or sev- a doxorubicin-taxane combined regimen. After completion ere anemia (1). Thirteen patients were bacteremic with Sta- of induction, eight were in complete response and 30 in phylococcus epidermidis (11), Klebsiella pneumoniae (1), partial response. Sixteen patients had disease confined to Staphylococcus simulans (1). One patient had C. difficile bones and five had their only sites of disease resected after diarrhea. an initial PR to induction therapy and hence are inevaluable for treatment response to high-dose therapy. One patient Intensification 3: CTCb with peripheral blood stem cell had a complete resolution of soft tissue disease and had support: Sixty patients proceeded to the third intensifi- residual bone scan abnormalities (PR*). cation. The median interval between intensification 2 and 3 was 35 days (range, 23–66 days). Positive blood cultures Treatment were obtained in 17 patients. Isolated species included Sta- phylococcus epidermidis (10), Staphylococcus aureus (2), All toxicities are presented in Table 2. vancomycin-resistant Enterococcus faecalis (2), Pseudo- monas aeroginosa (2), Micrococcus (1), Streptococcus viri- Intensification 1: Paclitaxel with peripheral blood stem cell dans (1) Staphylococcus capitis (1), and yeast (1). Four support: Sixty-one patients were treated with paclitaxel. patients had C. difficile diarrhea. Ten patients (16%) Most patients were readmitted with neutropenia/fever developed dermatomal Herpes zoster either during or after (31%) and less frequently for severe mucositis/esophagitis the completion of therapy. (5%). Positive blood cultures were obtained in seven Three patients died of toxicity (5%). One toxic death patients. Isolated species included Staphylococcus epiderm- occurred at day +13 after the patient was discharged home idis (3), Staphylococcus hominis (2), Micrococcus (1), Pro- after intensification 3. This patient’s hospital course had prionibacterium acnes (1). Two patients developed supra- been uncomplicated. A post-mortem was unrevealing and ventricular tachycardia with conversion to normal sinus an arrhythmia is possible. The second toxic death was at rhythm with medical therapy. Neurotoxicity was predomi- day +56 after intensification #3. The cause was multifac- nantly sensory; however, motor weakness and autonomic torial including overwhelming sepsis from resistant symptoms were also observed in some patients. Both motor Pseudomonas aeroginosa, and vancomycin-resistant and sensory changes were reversible. Fourteen patients Enterococcus faecalis with severe disseminated intravascu-

Table 2 Toxicity data

Variable Paclitaxel No. (%) Melphalan No. (%) CTCb No. (%)

No. of patients 61 60 60 Readmissions 24 (39) 44 (73) NA CTC Grade 3/4 toxicities Stomatitis/esophagitis 21 (34) 12 (20) 33(55) Nausea/vomiting 7/0 (11/0) 22/11 (37/18) 14/9 (23/15) diarrhea 1 (2) 4 (7) 8 (13) constipation 4 (7) 0 0 VOD 0 0 0 Bacteremia 7 (11) 13 (22) 16 (27) C. difﬁcile 0 1 (2) 4 (7) Cardiac arrhythmia 2 (3) 0 1 (2) myocarditis 0 0 5 (8) Neurotoxicity (acute) sensory 17 (28) 0 0 motor 21(34) 0 0 Mortality 0 0 3 (5)

Bone Marrow Transplantation High-dose paclitaxel in metastatic breast cancer LT Vahdat et al 153 Table 3 Tumor responses At a median follow-up of 31 months, the progression- free survival is 30% (Figure 3). For those who achieved a Response Pre-HDC Post- HDC complete response, 11 of 21 (52%) remain progression- free. Seven of 12 (58%) patients who converted from a pre- CR 8 21 high-dose chemotherapy PR to a CR are disease-free. Only PR 30 5 one of the 10 patients with resolution of all soft tissue or PR* 1 10 Bone only 16 14 visceral disease and persistently abnormal bone scans Stage 4 NED 5 4 (PR*), is disease-free. The median disease-free interval for Stable disease 0 3 this group was 9 months (range 5–31 months). Two of 14 Inevaluable 3 patients who had disease confined to their bones are disease Total 60 60 free and two of the four patients who were stage 4 NED continue to be disease-free. lar coagulation which resulted in persistant lower GI bleed- Discussion ing and an unrelated aneurysmal CNS bleed. The third toxic death at day +39 from acute respiratory distress syndrome Complete response after high-dose chemotherapy continues following sepsis with resistant organisms including resist- to be the most significant prognostic factor for prolonged ant Pseudomonas aeroginosa, and vancomycin-resistant disease-free survival according to the North American Enterococcus faecalis. Autologous Bone Marrow Transplant Registry Hematologic: The median time to ANC у500/␮l and (NAABMTR) and multiple single institution trials. Stra- platelets to Ͼ20 000/␮l was similar to our phase I trial with tegies to increase the complete response rate include incor- a range from 6 to 10 days for ANC recovery and 13 days poration of new drugs on alternative schedules, the use of for platelet recovery.16 repetitive high-dose chemotherapy cycles and the use of novel post-consolidation strategies. This study has adopted the strategy of repetitive dosing Treatment response and the incorporation of new active agents. The advent of Of the 61 patients entered, 57 are available for evaluation. improved technology (peripheral blood stem cells and One patient refused to proceed past intensification 1, and growth factors) has made this a feasible strategy because three died of toxicity. Thus 57 patients are evaluable for of accelerated marrow recovery. Paclitaxel has been esca- time to progression and overall survival and are included lated in combination with other chemotherapy agents and in all analyses. The patient who did not proceed to intensi- incorporated into other high-dose regimens. The dose-limit- fication 2 and 3 is included in the toxicity analysis of inten- ing toxicity observed in these combination chemotherapy sification 1 only. studies were coma and an ARDS-like capillary leak syn- 2 20–23 Of the 30 patients evaluable for response, 12 patients drome at doses of 825 mg/m . We observed dose-limit- (40%) converted from a PR to a CR, nine converted to a ing but largely reversible peripheral neuropathy as a conse- PR* (30%), five additional patients (17%) had a further PR. quence of the high-dose paclitaxel. This neuropathy may 19 The PR to CR/PR* conversion rate is 70% for an overall be ameliorated with concurrent glutamine administration. response rate of 87% (Table 3 and Figure 2). All intensifications were given on time and the side-effect Three patients who presented with stage 4 disease profile was consistent with what has been reported in the underwent a mastectomy after completion of the high-dose literature from ours and other groups. chemotherapy. Two patients had residual microscopic Several issues remain outstanding. First, is whether pacli- invasive breast cancer and ductal carcinoma in situ and one taxel is the best agent to incorporate into this high-dose had a pathologic complete response. regimen. In this study at this dose and schedule, the com-

1.0

0.8

0.6 Partial responders 30 0.4 Probability

PR to CR PR to PR PR to PR* PR to SD PR to inevaluable 12 5 9 3 1 0.2 (40%) (17%) (30%) (10%) (3%) Overall survival Disease-free survival Figure 2 Responses for patients with measurable disease after complet- 0 ing high-dose chemotherapy. CR = complete response; PR = partial 010203040 response; PR* = partial response with complete resolution of soft tissue Time (months) or visceral abnormalities and solitary bone scan abnormalities; SD = stable disease. Figure 3 Kaplan–Meier curves of progression-free and overall survival.

Bone Marrow Transplantation High-dose paclitaxel in metastatic breast cancer LT Vahdat et al 154 plete response rate is quite high (70%). To date, none of Acknowledgements the other new chemotherapeutic drugs active in breast cancer appear to be good candidates for dose escalation based We would like to thank our patients and their families for support- on their toxicity profile in the conventional dose setting. ing this trial. We would also like to thank the nursing staff of When compared to our prior study of a dose escalation of 5GS for their professionalism and compassion. This study was paclitaxel (400–825 mg/m2) there was no significant differ- supported in part by US Public Health Service Grant P30- CA13696-21, NCI R21CA 66244-01 and P20CA 6244-01 and ence in the response rate or disease-free survival. However, Grant-in-Aid Programs of Amgen and Bristol Myers Squibb the incidence of transient peripheral neuropathy was Oncology. increased. The second issue is whether the paclitaxel should be combined with another agent that enhances the response rate without increasing toxicity. Flavopiridol, a cyclin- References dependent kinase signal transduction inhibitor that may 24 reverse drug resistance, may be a potential partner. 1 Clark G, Sledge GW, Osborne CK, McGuire WL. Survival The issue of repetitive dosing bears further study if this from first recurrence: relative importance of prognostic factors approach is to be a component of an overall treatment strat- in 1015 breast cancer patients. J Clin Oncol 1987; 5:55–61. egy of women with advanced breast cancer. Put into con- 2 Greenberg P, Hortobagyi G, Smith T et al. Long-term follow- text, a single high-dose cycle of chemotherapy with stem up of patients with complete remission following combination cell support for advanced breast cancer produces a response chemotherapy for metastatic breast cancer. J Clin Oncol 1996; rate of 40%, the median disease free interval is 12 months 14: 2197–2205. and the 5-year disease interval is 15–20%. Tandem high- 3O’Shaughnessy J, Vukelja S, Moiseyenko V et al. Results of a large, phase III trial of Xeloda/taxotere combination therapy dose cycles of chemotherapy with stem cell support appear versus taxotere monotherapy in patients with metastatic breast to produce a higher response rate (60–85%) with a median cancer. Breast Cancer Res Treat 2000; 53: Abstr. 381. disease-free interval of 24 months or greater depending on 4 Slamon D, Leyland-Jones B, Shak S et al. Use of chemo- the number of cycles administered. Although these are therapy plus a monoclonal antibody against HER2 for meta- indirect comparisons, it is certainly possible that in the static breast cancer that overexpresses HER2. New Engl J Med short term an impact may be observed and may serve as 2001; 344: 783–792. an ideal platform for the addition of non-cytotoxic agents 5 Rahman ZU, Frye DK, Buzdar AU et al. Impact of selection when minimal residual disease is the prerequisite for con- process on response rate and long-term survival of potential high-dose chemotherapy candidates treated with standard-dose sidering these varied agents. Immunotherapy approaches doxorubicin-containing chemotherapy in patients with meta- are being evaluated with mixed results to date. Certainly, static breast cancer. J Clin Oncol 1997; 15: 3171–3177. this is a potential group that might benefit from other mini- 6 Stadtmauer EA, O’Neill A, Goldstein LJ et al. Conventional- mal residual disease approaches such as the addition of dose chemotherapy compared with high-dose chemotherapy antisense compounds, anti-angiogenesis agents, and other plus autologous hematopoietic stem-cell transplantation for biologics such as trastuzamab and VEGF- antibodies. metastatic breast cancer. Philadelphia Bone Marrow Trans- Despite high response rates, the major challenge continues plant Group. New Engl J Med 2000; 342: 1069–1076. 7 Crump M, Gluck S, Stewart D et al. A randomized trial of to be to maintain this response and represents a unique high-dose chemotherapy wih autologous peripheral blood opportunity to evaluate minimal residual disease strategies stem cell support compared to standard therapy in women with in this population. metastatic breast cancer : a National Cancer Institute of Can- In conclusion, this study demonstrates the feasibility of ada (NCIC) Clinical Trials Group Study. Proc Am Soc Clin administering three sequential high-dose cycles of chemo- Oncol 2001; 20: 21a (Abstr. 82). therapy in women with metastatic breast cancer responding 8 Lotz JP, Cure H, Janvier M et al. High-dose chemotherapy to conventional dose chemotherapy. The toxic death rate is with hematopoietic stem cells transplantation for metastatic consistent with that reported in other high-dose studies in breast cancer: Results of the French protocol Pegase 04. Proc Am Soc Clin Oncol 1999; 18: 43a (Abstr. 161). patients with metastatic breast cancer. 9 Madan B, Broadwater G, Rubin P et al. Improved survival The larger issue is the role of high-dose chemotherapy with consolidation high-dose cyclophosphamide, cisplatin and in patients with advanced breast cancer. The first generation carmustine (HD-CPB) compared with observation in women randomized studies of a single cycle of high-dose chemo- with metastatic breast cancer (MBC) and only bone metastases therapy with stem cell support are now being reported and treated with induction adriamycin, 5-flourouracil, and metho- more than a dozen additional studies are underway. A few trexate (AFM): a phase three prospective randomized com- of these trials are evaluating multi-cycle high-dose chemo- parative trial. Proc Am Soc Clin Oncol 2000; 19: 48a therapy vs standard chemotherapy, although the optimal (Abstr. 184). 10 Peters W, Jones R, Vredenburgh J et al. A large prospective multi-cycle high-dose regimen is yet to be established. randomized trial of high-dose combination alkylating agents Given that the prognosis of metastatic breast cancer (CPB) with autologous cellular support as consolidation for remains poor, many women may be willing to participate patients with metastatic breast cancer achieving complete in studies intended to increase the proportion of patients remission after intensive doxorubicin-based induction therapy who achieve CR and then to study new strategies aiming (AFM). Proc Am Soc Clin Oncol 1996; 15: 121 (Abstr. 149). to eliminate occult residual disease. 11 Antman K, Rowlings P, Vaughn W et al. High dose chemotherapy with autologous hematopoietic stem cell support for breast cancer in North America. J Clin Oncol 1997; 15: 1870–1879.

Bone Marrow Transplantation High-dose paclitaxel in metastatic breast cancer LT Vahdat et al 155 12 McCloskey D, Davidson N. Paclitaxel-induced programmed 19 Vahdat L, Papadopoulos K, Lange D et al. Reduction of pacli- cell death in human breast cancer cells. Proc Am Assoc Can- taxel-induced peripheral neuropathy with glutamine. Clin cer Res 1995; 6: 416 (Abstr. 2482). Cancer Res 2001; 7: 1192–1197. 13 Milas L, Hunter N, Kurdoglu B et al. Kinetics of mitotic arrest 20 Mehra R, Browne V, Rondon G et al. Phase I/II study of and apoptosis in murine mammary and ovarian tumors treated multiple course high-dose CTC with PBSC infusion for meta- with taxol. Cancer Chemother Pharmacol 1995; 35: 297–303. static breast cancer. Proc Am Soc Clin Oncol 1997; 16: 100a 14 Gelmon K, Nabholtz J, Bontenal M et al. Randomized trial of (Abstr. 351). two doses of paclitaxel in metastatic breast cancer after failure 21 Mayordomo J, Yubero A, Cajal R et al. Phase I trial of high- of standard therapy. Ann Oncol 1994; 5: 198 (Abstr. 493). dose paclitaxel in combination with cyclophosphamide, thi- 15 Ayash LJ, Elias A, Wheeler C et al. Double dose-intensive otepa and carboplatin with autologous peripheral blood stem chemotherapy with autologous marrow and peripheral-blood cell rescue. Proc Am Soc Clin Oncol 1997; 16: 102a (Abstr. progenitor-cell support for metastatic breast cancer: a feasi- 358). bility study. J Clin Oncol 1994; 12:37–44. 22 Somlo G, Doroshow J, Synold T et al. High dose adriamycin, 16 Vahdat L, Papadopoulos K, Balmaceda C et al. Phase I trial cyclophosphamide and paclitaxel for patients with high risk of sequential high-dose chemotherapy with escalating dose and responsive stage IV breast cancer. Proc Am Soc Clin paclitaxel, melphalan, and cyclophosphamide, thiotepa and Oncol 1997; 16: 110a (Abstr. 385). carboplatin with peripheral blood progenitor support in 23 Stemmer S, Cagnoni P, Shpall E et al. High dose paclitaxel, women with responding metastatic breast cancer. Clin Cancer cyclophosphamide and cisplatin with autologous hematopo- Res 1998; 4: 1689–1695. ietic progenitor cell support: A phase I trial. J Clin Oncol 17 Papadopoulos KP, Ayello J, Tugulea S et al. Harvest quality 1996; 14: 1463–1472. and factors affecting collection and engraftment of CD34+ 24 Schwartz G, Werner J, Maslak P et al. Flavopiridol enhances cells in patients with breast cancer scheduled for high-dose the biological effects of paclitaxel: a phase I trial in patients chemotherapy and peripheral blood progenitor cell support. J with advanced solid tumors. Proc Am Soc Clin Oncol 1998; Hematother 1997; 6:61–68. 17: 188a (Abstr. 725). 18 Kaplan EL, Meier P. Nonparametric estimation from incom- plete observations. J Am Stat Assoc 1958; 53: 457–481.

Bone Marrow Transplantation