Allogeneic hematopoietic cell transplantation for metastatic breast cancer.

We reviewed 66 women with poor-risk metastatic breast cancer from 15 centers to describe the efficacy of allogeneic hematopoietic cell transplantation (HCT). Median follow-up for survivors was 40 months (range, 3-64). A total of 39 patients (59%) received myeloablative and 27 (41%) reduced-intensity conditioning (RIC) regimens. More patients in the RIC group had poor pretransplant performance status (63 vs 26%, P=0.002). RIC group developed less chronic GVHD (8 vs 36% at 1 year, P=0.003). Treatment-related mortality rates were lower with RIC (7 vs 29% at 100 days, P=0.03). A total of 9 of 33 patients (27%) who underwent immune manipulation for persistent or progressive disease had disease control, suggesting a graft-vs-tumor (GVT) effect. Progression-free survival (PFS) at 1 year was 23% with myeloablative conditioning and 8% with RIC (P=0.09). Women who developed acute GVHD after an RIC regimen had lower risks of relapse or progression than those who did not (relative risk, 3.05: P=0.03), consistent with a GVT effect, but this did not affect PFS. These findings support the need for preclinical and clinical studies that facilitate targeted adoptive immunotherapy for breast cancer to explore the benefit of a GVT effect in breast cancer.

Valganciclovir is safe and effective as pre-emptive therapy for CMV infection in allogeneic hematopoietic stem cell transplantation.

Despite significant advances in prevention and therapy, cytomegalovirus (CMV) infection continues to be an important cause of morbidity and mortality in the hematopoietic stem cell transplant (HSCT) recipient. The standard drug for pre-emptive therapy is intravenous ganciclovir (GCV). Valganciclovir (VGC), the oral pro-drug of GCV, has excellent bioavailability and is ideal for oral therapy. Since March 2002, VGC was adopted in our center for outpatient pre-emptive therapy in all patients undergoing allogeneic HSCT. Fifty-two allogeneic HSCT recipients were followed weekly via Digene hybrid capture assay. Patients with a positive assay were treated with VGC 900 mg p.o. b.i.d. x 14 days followed by 900 mg p.o. QD until at least 7 days after a negative test. Eighteen patients (14 sib, four MUD) had 30 episodes of CMV DNA detection treated with oral VGC. Median duration of therapy was 21 days (range 10-21 days). The rate of response was 93% (28/30) as confirmed by a negative assay within 14 days. No significant toxicity was encountered. Two patients failed oral VGC. One case of CMV enteritis was diagnosed in a patient with acute GVHD. Pre-emptive therapy of CMV infection with oral VGC is safe and effective in allogeneic HSCT recipients.

Ifosfamide, carboplatin, and etoposide: a new regimen with a broad spectrum of activity.

PURPOSE: To conduct a phase I/II evaluation of the combination of ifosfamide, carboplatin, and etoposide (ICE) to determine toxicity and activity in a variety of refractory malignancies. PATIENTS AND METHODS: Two hundred four patients, 13 to 64 years of age, with a variety of malignancies, including refractory breast cancer and Hodgkin's and non-Hodgkin's lymphoma, were treated with two cycles of ICE, consisting of intravenous ifosfamide 2 g/m2, carboplatin 400 mg/m2, and continuous infusion etoposide 600 mg/m2 administered in divided doses over 2 days. The regimen was repeated at approximately 28-day intervals. RESULTS: One hundred ninety-one patients (94%) received two cycles at full doses and were assessable for response and toxicity. Complete and partial responses were seen in breast cancer (20%, n = 93), non-Hodgkin's lymphoma (30%, n = 37), Hodgkin's disease (60%, n = 10), melanoma (9%, n = 11), a variety of sarcomas (20%, n = 10), and other malignancies (43%, n = 30). Myelosuppression was prominent, with significant neutropenia requiring frequent hospitalization for neutropenic fever, and thrombocytopenia and anemia requiring frequent platelet and RBC transfusions. However, the overall treatment-related mortality rate was only 3%. No other moderate to severe organ toxicity was seen at a frequency of greater than 1%. CONCLUSION: This regimen is active in a variety of refractory malignancies, with significant but tolerable hematologic toxicity. The addition of hematopoietic growth factors may allow further dose escalation.

Clinical significance of bone marrow metastases as detected using the polymerase chain reaction in patients with breast cancer undergoing high-dose chemotherapy and autologous bone marrow transplantation.

PURPOSE: The present study evaluates the clinical significance of detection of cytokeratin 19 (K19) in the bone marrow of patients with breast cancer undergoing high-dose chemotherapy (HDCT) and autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: We studied retrospectively cryopreserved bone marrow aspirates from 83 patients with high-risk stage II, III, and IV breast cancer obtained before bone marrow harvest but after induction chemotherapy. All samples were histologically negative for metastases. Polymerase chain reaction (PCR) for K19 was performed according to methods described previously and results were correlated with the probability of relapse following HDCT and ABMT. RESULTS: The incidence of occult metastases as defined by PCR for K19 message was 52% for 19 stage II, 57% for 14 stage III, and 82% for 50 stage IV patients (two-tailed P = .0075, chi 2 test). The probability of relapse at 3 years after ABMT was 32% and 94% for K19-positive stage II/III and stage IV patients, respectively, versus 10% and 14% for K19-negative stage II/III and stage IV patients, respectively. The difference was significant for stage IV patients (two-tailed P = .0002). CONCLUSION: It has been shown that PCR is a highly sensitive method to detect K19 message in the bone marrow. The incidence of K19 positivity in bone marrow increases significantly with advancing stage. In patients with breast cancer, especially metastatic breast cancer, undergoing HDCT and ABMT, the presence of K19 is associated with a poor prognosis.

Maximum-tolerated doses of ifosfamide, carboplatin, and etoposide given over 6 days followed by autologous stem-cell rescue: toxicity profile.

PURPOSE: A phase I dose-escalation study of ifosfamide, carboplatin, and etoposide (ICE) with autologous stem-cell rescue (ASCR) was conducted to determine the maximum-tolerated dose (MTD) of ICE given over 6 days. PATIENTS AND METHODS: One hundred fifty-four patients with a variety of poor-prognosis malignancies received escalating doses of ifosfamide 6,000 to 24,000 mg/m2, carboplatin 1,200 to 2,100 mg/m2, and etoposide 1,800 to 3,000 mg/m2 divided over 6 days. Mesna was administered in a dose equal to ifosfamide. ASCR was performed 48 hours after the completion of ICE. The source of stem cells was bone marrow (BM) in patients without BM micrometastases and peripheral-blood stem cells (PBSC) in patients with BM micrometastases. Patients were evaluated for hematologic and nonhematologic toxicities, as well as response to therapy. RESULTS: The MTD of the ICE regimen is 20,100 mg/m2 of ifosfamide, 1,800 mg/m2 of carboplatin, and 3,000 mg/m2 of etoposide. The dose-limiting toxicities of ICE were CNS toxicity and acute renal failure. Additionally, reversible elevations of serum creatinine levels were noted in 29% of patients treated at the upper dose levels. Forty-six patients were treated at the MTD. Severe, reversible mucositis and enteritis were the major nonhematologic toxicities seen at the MTD (78% and 33%, respectively). The overall mortality rate was 8% for all dose levels (4% at the MTD). At the MTD, the median times to an absolute neutrophil count > or = 0.5 x 10(9)/L, to a platelet count > or = 20 x 10(9)/L, and to discharge were 18, 22, and 24 days, respectively. The overall response rate was 40% for 77 patients with assessable disease at the time of treatment. CONCLUSION: ICE is well tolerated, with acceptable hematopoietic side effects and predictable organ toxicity.

High-dose chemotherapy with autologous hematopoietic stem-cell support for breast cancer in North America.

PURPOSE: To identify trends in high-dose therapy with autologous hematopoietic stem-cell support (autotransplants) for breast cancer (1989 to 1995). PATIENTS AND METHODS: Analysis of patients who received autotransplants and were reported to the Autologous Blood and Marrow Transplant Registry. Between January 1, 1989 and June 30, 1995, 19,291 autotransplants were reviewed; 5,886 were for breast cancer. Main outcomes were progression-free survival (PFS) and survival. RESULTS: Between 1989 and 1995, autotransplants for breast cancer increased sixfold. After 1992, breast cancer was the most common indication for autotransplant. Significant trends included increasing use for locally advanced rather than metastatic disease (P < .00001) and use of blood-derived rather than marrow-derived stem cells (P < .00001). One-hundred-day mortality decreased from 22% to 5% (P < .0001). Three-year PFS probabilities were 65% (95% confidence intervals [Cls], 59 to 71) for stage 2 disease, and 60% (95% Cl, 53 to 67) for stage 3 disease. In metastatic breast cancer, 3-year probabilities of PFS were 7% (95% Cl, 4 to 10) for women with no response to conventional dose chemotherapy; 13% (95% Cl, 9 to 17) for those with partial response; and 32% (95% Cl, 27 to 37) for those with complete response. Eleven percent of women with stage 2/3 disease and less than 1% of those with stage 4 disease participated in national cooperative group randomized trials. CONCLUSION: Autotransplants increasingly are used to treat breast cancer. One-hundred-day mortality has decreased substantially. Three-year survival is better in women with earlier stage disease and in those who respond to pretransplant chemotherapy.

Pilot study of a home-based aerobic exercise program for sedentary cancer survivors treated with hematopoietic stem cell transplantation.

We report a pilot study of a home-based aerobic exercise program in a group of 17 adult hematopoietic stem cell transplant (HSCT) recipients. Participants had received no cancer treatment for at least 6 months and reported leisure time physical activity less than 20 min per day and fewer than three times a week during the previous month. Following baseline assessments of aerobic fitness, fatigue symptoms, and quality of life, participants were placed on home-based aerobic exercise programs consisting of 20-40 min of activity in the target heart rate zone (40-60% predicted heart rate reserve) delivered in three to five sessions per week for 12 weeks. Subjects were supplied with electronic heart rate monitors and we encouraged program adherence using weekly telephone contacts and exercise diaries. In all, 32 of the 42 qualified candidates consented (acceptance=76%). Of these, 17 kept appointments for baseline assessments, four did not complete the study (attrition=46%), and no exercise-related adverse events were reported. Scores on measures of aerobic fitness, fatigue severity, and physical well-being improved (signed ranks test; P<0.05) during program participation. Our findings suggest that individually prescribed, home-based aerobic exercise is an acceptable, safe, and potentially effective intervention for improving physical functioning and fatigue in sedentary HSCT recipients.

Ifosfamide/carboplatin/etoposide chemotherapy for metastatic breast cancer with or without autologous hematopoietic stem cell transplantation: evaluation of dose-response relationships.

We conducted a phase I/II trial to investigate the activity of ifosfamide/carboplatin/etoposide given over 2 or 3 days (mini-ICE) to patients with anthracycline-refractory or recurrent metastatic breast cancer. In a companion phase I/II dose-escalation study, those patients with responsive or stable disease following either anthracycline-based chemotherapy or mini-ICE and with adequate organ function were then considered eligible for treatment with a 6-day ICE regimen (maxi-ICE) followed by autologous hematopoietic stem cell transplantation. Our results showed that the ICE regimen has activity against anthracycline-refractory metastatic breast cancer. A dose-response relationship was not apparent with the mini-ICE regimen; however, among patients receiving maxi-ICE, a dose-response relationship was suggested in those patients responding to anthracycline-based chemotherapy.

Analysis of dose-response relationships in the setting of high-dose ifosfamide, carboplatin, and etoposide and autologous hematopoietic stem cell transplantation: implications for the treatment of patients with advanced breast cancer.

Dose intensity appears to play a role in the treatment of breast cancer. Although many reports have been published regarding dose intensity using nonmyeloablative doses, little data have been presented in the setting of high-dose chemotherapy and autologous hematopoietic stem cell transplantation. The results of a retrospective review of a phase I/II trial evaluating the effect of escalating doses of ifosfamide/carboplatin/etoposide on survival of patients with locally advanced and metastatic breast cancer are discussed here. Patients were divided by ifosfamide dose: low dose (6,000 to 14,400 mg/m2) and high dose (17,100 to 24,000 mg/m2). Three-year event-free survival was no different between the two dose groups in patients with locally advanced disease (71% [low] v 56% [high]). In patients with metastatic disease, however, although the difference did not meet statistical significance, there did appear to be a trend toward improved survival with increased dose intensity (8% [low] v 25% [high]). Our results show that dose intensity may be important in inflammatory and metastatic breast cancer. This trend was seen in both anthracycline-responsive and -refractory patients. While further study of dose intensity in this setting is warranted, dose-intensive high-dose therapy with autologous hematopoietic stem cell transplantation can be considered for patients with advanced breast cancer.

Two novel high-dose treatment regimens for metastatic breast cancer--ifosfamide, carboplatin, plus etoposide and mitoxantrone plus thiotepa: outcomes and toxicities.

This report describes the results of two phase I/II dose escalation trials for the treatment of metastatic breast cancer. Successive groups of patients with metastatic breast cancer responsive to induction therapy following standard doses of chemotherapy were treated with escalating doses of ifosfamide (6,000 to 24,000 mg/m2), carboplatin (1,200 to 2,100 mg/m2), and etoposide (1,800 to 3,000 mg/m2) followed by autologous stem cell rescue. The maximum tolerated doses of these drugs were defined as ifosfamide 20,100 mg/m2, carboplatin 1,800 mg/m2, and etoposide 3,000 mg/m2. Major nonhematologic toxicity consisted of mucositis and enteritis, and the dose-limiting toxicities were central nervous system toxicity and acute renal failure. The overall treatment-related mortality rate was 4%. The event-free survival rate at 500 days for these patients was 31%. Patients with metastatic breast cancer refractory to all standard dose therapy were treated with escalating doses of mitoxantrone (45 to 105 mg/m2) and thiotepa (900 to 1,350 mg/m2) followed by autologous stem cell rescue. The maximum tolerated doses of these drugs were defined as mitoxantrone 90 mg/m2 and thiotepa 1,200 mg/m2 with mucositis and enteritis as the major nonhematologic toxicities and delayed myelosuppression as the dose-limiting toxicity. Twelve percent of the patients remain event free at 500 days and the treatment-related mortality rate for this group of heavily pretreated patients was 17%. These data suggest that patients with metastatic breast cancer may benefit from high-dose therapy and that treatment-related toxicity is tolerable.

High-dose ifosfamide/carboplatin/etoposide: maximum tolerable doses, toxicities, and hematopoietic recovery after autologous stem cell reinfusion.

We treated 115 patients in a phase I/II dose-escalation study of ifosfamide/carboplatin/etoposide (ICE) followed by autologous stem cell rescue. Patients treated had a variety of diagnoses, including breast cancer (high-risk stage II disease with eight or more positive nodes, stage III disease, and responsive metastatic disease), non-Hodgkin's lymphoma, Hodgkin's disease, acute leukemia in first remission, and various solid tumors that were responsive to induction therapy. Patients received autologous bone marrow stem cells or peripheral blood stem cells primed by one of several methods. The maximum tolerated dose of ICE was determined to be ifosfamide 20,100 mg/m2, carboplatin 1,800 mg/m2, and etoposide 3,000 mg/m2 when administered as a 6-day regimen. The dose-limiting toxicities included acute renal failure, severe central nervous system toxicity, and "leaky capillary syndrome" with hypoalbuminemia, profound fluid overload, and pulmonary insufficiency. Analysis of hematologic recovery based on stem cell source and influence of hematopoietic growth factor administration was undertaken. Hematopoietic growth factor use significantly reduced neutrophil engraftment time for patients receiving bone marrow stem cells, with evidence of earlier recovery times for patients receiving granulocyte colony-stimulating factor compared with granulocyte-macrophage colony-stimulating factor. Neutrophil recovery times varied based on the source of stem cells used, with the earliest engraftment times seen for patients receiving peripheral blood stem cells primed with cyclophosphamide and granulocyte colony-stimulating factor. Platelet recovery times were not statistically different for any of the subsets. In conclusion, the maximum tolerated dose of ICE has been defined, and the source of stem cells and the use of hematopoietic growth factors influence hematopoietic recovery.

Defining the role of novel high-dose chemotherapy regimens for the treatment of high-risk breast cancer.

We have explored several novel high-dose combinations in an attempt to increase antitumor activity while decreasing treatment-related toxicity. From October 1989 through June 1997, we performed phase I/II dose-escalation trials exploring novel high-dose regimens including ifosfamide/carboplatin/etoposide, mitoxantrone/thiotepa, and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ)/mitoxantrone/thiotepa. We have also evaluated busulfan/cyclophosphamide and cyclophosphamide/thiotepa/carboplatin in phase II trials. Three hundred ninety-three patients have been treated in these trials and followed for a minimum of 3 months. Event-free survival (including relapses and treatment-related mortality; +/-SE) at 3 years by stage and chemosensitivity is as follows: stage II, four to nine positive nodes (n=16), 52%+/-17%; stage II, greater than nine nodes (n=30), 46%+/-11%; stage III (n=59), 50%+/-8%; inflammatory stage III (n=15), 27%+/-17%; stage IV, anthracycline responsive (n=69), 19%+/-5%; stage IV, anthracycline refractory but responsive to salvage therapy with ifosfamide, carboplatin, and etoposide or paclitaxel (n=53), 12%+/-6%; stage IV, refractory (n=128), 5%+/-2%; and stage IV, not evaluable for response (n=23), 10%+/-8%. Treatment-related mortality was 4% for both phase I and II studies involving stage II breast cancer patients, 5% for stage III breast cancer, 15% for inflammatory breast cancer, and 18% for all stage IV breast cancers, responsive and refractory. We conclude that high-dose therapy for the treatment of high-risk early stage breast cancer or metastatic breast cancer results in durable remissions. Chemosensitivity to induction regimens remains the most important prognostic indicator, although long-term survival has been seen even in patients with highly refractory disease. Further studies are necessary to define optimal high-dose strategies based on stage and chemosensitivity of disease.

Use of PEG-rHuMGDF in platelet engraftment after autologous stem cell transplantation.

This paper summarizes a pilot, sequential dose-escalation study of PEG-rHuMGDF in patients with advanced malignancies who had delayed platelet recovery after autologous stem cell transplantation (ASCT). Patients were randomized to receive either placebo (n = 11) or PEG-rHuMGDF at 5 (n = 9), 10 (n = 6), or 25 (n = 7) microg/kg/day by subcutaneous injection for 14 days and were monitored for 5 weeks. Across all treatment groups, eight patients had platelet recovery to > or = 20 x 10(9)/l by day 21. The proportion of patients achieving platelet recovery, the median number of days and units of platelet transfusions were similar for the placebo and the PEG-rHuMGDF groups. PEG-rHuMGDF was well tolerated at all dosages. The incidence rates of adverse events in all groups were similar. No deaths on study, no drug-related serious adverse events, and no development of neutralizing antibodies to MGDF occurred.

Quality of life following bone marrow transplantation for breast cancer: a comparative study.

As more women are treated with bone marrow transplantation (BMT) for breast cancer, there is growing interest in quality of life (QOL) following treatment. Although there have been some clinical studies of QOL following BMT, this area has received little systematic attention. In particular, it is unclear how QOL for women treated with BMT for breast cancer differs from that which might be expected for 'healthy' women of about the same age. To address this issue, we compared QOL reported by women treated with autologous BMT for breast cancer with that of a group of women of similar age with no history of cancer. In addition, we examined the relationship of demographic factors, medical factors, and self-reported symptom prevalence, severity, and distress to QOL in post-BMT patients. All participants completed the SF-36 Health Survey developed from the Medical Outcomes Study (SF-36). Post-BMT patients also completed the ECOG Performance Status Rating Scale (PSR) and the Memorial Symptom Assessment Scale (MSAS). Results indicated that, compared to the women with no cancer history, post-BMT patients reported significantly impaired physical functioning, physical role functioning, general health, vitality, social functioning, and emotional role functioning. Impaired QOL following BMT was significantly associated with lower income, a longer time to engraftment, longer hospital stay, poor performance status, and greater symptom prevalence, severity, and distress. The problems identified in this study may be important targets for intervention when trying to improve QOL following BMT.

Patients' psychosocial concerns following stem cell transplantation.

Information regarding the nature, frequency, correlates and temporal trajectory of concerns of stem cell transplantation (SCT) recipients is critical to the development of interventions to enhance quality of life (QOL) in these individuals. This study examined psychosocial concerns in 110 SCT (87% autologous) recipients drawn from two SCT centers. Participants were a mean of 46 years of age and 17 months post-SCT (range 3-62 months). Information regarding current and past SCT-related concerns, performance status, and demographic characteristics was collected by telephone interview or questionnaire. Recipients reported a wide variety of psychosocial concerns following SCT. Recipients who were younger, female and evidenced a poorer performance status reported a larger number of post-SCT concerns. Examination of the temporal trajectory of concerns suggests that some concerns are salient throughout the course of post-SCT recovery (eg disease recurrence, energy level, 'returning to normal'), some are salient early in the course of recovery (eg quality of medical care, overprotectiveness by others), and others emerge later in the course of recovery (eg feeling tense or anxious, sexual life, sleep, relationship with spouse/partner, ability to be affectionate). Implications for the development of interventions to enhance post-SCT QOL are identified.

Phase I-II study of high-dose busulfan and cyclophosphamide followed by autologous peripheral blood stem cell transplantation for hematological malignancies: toxicities and hematopoietic recovery.

In a phase I-II study, we evaluated toxicities, tolerability, pace of engraftment, and tumor responses to high-dose bulsulfan and cyclophosphamide followed by autologous peripheral blood stem cell transplantation in patients with hematological malignancies. We treated 51 patients with various hematological malignancies involving the bone marrow with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) followed by reinfusion of autologous peripheral blood stem cells. Stem cells were previously collected during hematopoietic recovery after cyclophosphamide (100 mg/kg) and etoposide (600 mg/m2) followed by G-CSF (5 micrograms/kg/day). Neutrophil recovery (>0.5 x 10(9)/I) was rapid in the majority of patients (median 10 days after transplant, range 7-91 days), resulting in a low number of days with severe neutropenia (median 7 days, range 5-85 days) and with fever (median 5 days, range 1-13 days). Platelet recovery, however, was delayed in 60% of patients. There was one acute transplant-related death (2%). Four patients died of late, presumed infections, pulmonary complications (interstitial pneumonia). Tumor responses were documented in a significant proportion of these patients with high-risk hematological malignancies. We conclude that peripheral blood stem cell transplantation results in rapid recovery of neutrophils but variable recovery of platelets after high-dose busulfan and cyclophosphamide, when stem cells are harvested following priming with cyclophosphamide/etoposide and G-CSF. The regimen is well-tolerated with limited non-hematological toxicities and transplant-related mortality. While significant tumor responses were documented in this trial, the ultimate efficacy of the regimen needs to be further defined.

Syngeneic hematopoietic stem cell transplantation for women with metastatic breast cancer.

Metastatic breast cancer has been a common indication for autologous hematopoietic stem cell transplantation (HSCT). Previous reports indicate 3-year survival and progression-free survival (PFS) rates after autotransplant to be about 30 and 15%, respectively. Most deaths are from recurrent disease. One potential cause for high relapse rates is graft contamination with tumor. We describe 14 women with metastatic breast cancer transplanted between 1991 and 1998 with hematopoietic cells from identical twins. Median age was 41 y (range 34-50). Most women (12 of 14) were treated with mastectomy, and all received anthracycline-based regimens in their pretransplant course; nine women also received a taxane, seven radiotherapy and three hormonal therapy. Four women were in complete remission (one CR, three CRU) at transplant, five were in partial remission, two had stable disease and two had progressive disease. Eight women have died, one of treatment-related causes and seven of progressive breast cancer. Three-year survival was 48% (21-71%) and 3-year PFS was 21% (5-45%). Although the number of patients is small, outcomes for women transplanted with syngeneic grafts are similar to those of women receiving autologous grafts. This suggests that residual cancer in the patient is the major contributor to relapse after transplantation for breast cancer.

High-dose chemotherapy and autologous peripheral blood stem cell transplantation in patients with multiple myeloma and renal insufficiency.

Six patients with multiple myeloma and chronic renal insufficiency (serum creatinine >3.0 mg/dl), including four on dialysis, received high-dose busulfan and cyclophosphamide (BUCY) followed by autologous peripheral stem cell transplantation. Peripheral blood stem cells were collected after priming with cyclophosphamide, etoposide and G-CSF. Patterns of engraftment and toxicities were not apparently different from those seen in myeloma patients with normal renal function. There was one toxicity-related death, resulting from a massive spontaneous subdural hematoma. One patient died of disease progression 6 months after transplant, while the remaining four patients are alive and free of myeloma progression 6 to 39 months after high-dose therapy. Two of these patients have remained in complete remission for 28 and 39 months. Our experience suggests that high-dose therapy with BUCY and autologous peripheral blood stem cell rescue is feasible in patients with multiple myeloma and renal failure.

High-sensitivity detection of minimal residual breast carcinoma using the polymerase chain reaction and primers for cytokeratin 19.

We have developed a reverse transcriptase-polymerase chain reaction (RT-PCR) assay to identify breast carcinoma cells in bone marrow aspirates with high sensitivity and specificity. This assay relies on the detection of cytokeratin 19 (K19) RNA by nested primer PCR followed by annealing to a (32P)-labeled internal sequence probe and autoradiography. In reconstitution experiments, this assay is capable of detecting 10 fg of admixed mammary tumor RNA in 1 microgram of normal marrow RNA (a dilution of 1:10(7)). Thirty of 30 primary breast tumor specimens, 19 of 19 cytologically positive bone marrow aspirate specimens, and three of 11 aspirate negative/biopsy positive specimens showed detectable K19 transcript. This assay shows high specificity, with 50 of 52 negative control aspirates showing no detectable amplification product. False-positive amplification was noted in two of 18 aspirates obtained from patients with active chronic myelogenous leukemia. Of stage II and III postsurgical breast carcinoma patients with histologically negative bone marrows and no radiographic bone disease, 14 of 30 were K19 positive by PCR. RT-PCR analysis of K19 transcript is a highly sensitive and specific method of detecting and monitoring low-level metastatic disease in patients with primary carcinoma of the breast. The presence of K19 RNA in histologically negative bone marrows suggests that this assay may prove a powerful monitor for patients undergoing curative therapy as well as a novel prognostic indicator.

Intensive dose ifosfamide, carboplatin, and etoposide followed by autologous stem cell rescue: results of a phase I/II study in breast cancer patients.

We have recently treated 66 women with breast cancer with escalating doses of ifosfamide, carboplatin, and etoposide (ICE) followed by autologous stem cell rescue (ASCR). Patients received ifosfamide (6000-24,000 mg m-2), carboplatin (1200-2100 mg m-2), and etoposide (1800-3000 mg m-2) divided over 6 days with ASCR 48 h after completion of chemotherapy. Our patient population consisted of seven patients with stage II disease with eight or more positive nodes being treated in the adjuvant setting, 16 patients with a history of stage III or inflammatory breast cancer, and 43 patients with stage IV disease. Six patients were not evaluable for response due to early death from infection (three patients) and incomplete restaging (three patients). The overall response rate in patients with measurable metastatic disease was 50%. Of those patients with stage II disease, 85% remain alive and progression-free with a median follow-up of greater than one year. The two most frequent toxicities encountered were reversible elevations of liver function tests and mucositis/enteritis. The dose-limiting toxicities were central nervous system toxicity and nephrotoxicity.