High-dose chemotherapy and hematopoietic stem cell transplantation for breast cancer: past or future?

Given that each year in the United States 180,000 new cases of breast cancer are diagnosed, with about 44,000 women succumbing to the disease, and that breast cancer is the second leading cause of cancer-related death in women, it is clear that existing therapy fails a large number of patients. Recently, a number of novel strategies have been developed in attempts to improve survival. These include agents used at very high dose requiring stem cell support. High-dose chemotherapy (HDC) with hematopoietic stem cell transplantation (HSCT), most frequently in the form of peripheral blood progenitor cell transplantation (PBPCT), is an highly active treatment approach in appropriate patients and the current data relating to this modality will be reviewed here. This article will attempt to place the recent randomized studies in perspective, to highlight the strengths and limitations of the data, and to offer some thoughts on future directions for the field.

Nonablative allogeneic hematopoietic stem cell transplantation.

During the past few years there has been an explosion of knowledge in nonablative allogeneic stem cell transplantation. This approach to transplantation relies more on the creation of "immunologic space" for engraftment rather than the more traditional approach of creating "physical space" by the application of either intensive radiation or chemical therapy. Nonablative allogeneic stem cell transplantation holds the promise of allowing powerful alloimmune responses to eradicate disease processes while minimizing the initial treatment-related morbidity and mortality, and it appears to be the necessary enabling platform by which to apply allogeneic cellular therapy. Intuitively, this approach should broaden the eligibility for potentially curative allogeneic transplantation in various disease categories, reduce initial hospitalization costs, and at the same time have a positive impact on quality of life. We review the current published data relating to this approach including the underlying principles, the preparative regimen, disease indications, preliminary results in hematologic and solid malignancies, and certain correlative immunologic evaluations.

High-dose chemotherapy and CD34-selected peripheral blood progenitor cell transplantation for patients with breast cancer metastatic to bone and/or bone marrow.

Fifty women with breast cancer metastatic to bone or bone marrow involvement on light microscopy at the time of initial evaluation were treated with high-dose chemotherapy (HDC) and peripheral blood progenitor cell (PBPC) transplantation with CD34(+) cell selection using the Isolex 300i system. All patients received induction chemotherapy. PBPC were mobilized with chemotherapy and granulocyte colony-stimulating factor. The median CD34(+) progenitor purity was 94.7% (range 72-98.7%) and recovery 38.4% (range 21-60%). Forty-eight hours after HDC with cyclophosphamide, cisplatin and carmustine, PBPC were reinfused. Median time to neutrophil count >0.5 x 10(9)/l was 9 (range 9-12) days and to platelet transfusion independence 11 (4-30) days. These data demonstrate that selected CD34(+) PBPCs allow rapid hematologic reconstitution after HDC. During follow-up, 23% of patients developed herpes zoster. Two patients developed cytomegalovirus infections. Three patients developed fungal infections. The development of these infections was not associated with steroid use but appeared more frequently in patients with diabetes mellitus. Seventy-four per cent of patients received steroids for pulmonary toxicity. Treatment-related mortality was 4%. Progression-free survival and overall survival at 35 months was 22.4% and 40.5%, with a median of 11.4 months and 15.4 months, respectively.

Cardiac sequelae of doxorubicin and paclitaxel as induction chemotherapy prior to high-dose chemotherapy and peripheral blood progenitor cell transplantation in women with high-risk primary or metastatic breast cancer.

Doxorubicin plus paclitaxel has been shown to be an active regimen for metastatic breast cancer and is now frequently used as adjuvant therapy for high-risk primary breast cancer. Initial studies reported a higher than expected rate of cardiac toxicity with this regimen. We studied 105 patients with either high-risk primary breast cancer or metastatic breast cancer who were treated with doxorubicin (60 mg/m2) and 3-h infusions of paclitaxel (175 mg/m2) cycled every 3 weeks. Patients received three cycles of chemotherapy for high-risk primary or four cycles for metastatic disease. Patients then proceeded to high-dose chemotherapy (HDC) (STAMP I cyclophosphamide, cisplatin and carmustine) and peripheral blood progenitor cell transplantation (PBPCT). Patients underwent radionuclide multi-gated angiograms (MUGA) before and following induction chemotherapy and following HDC. During induction chemotherapy 40 (38%) of the patients had a reduction in left ventricular ejection fraction (LVEF). Fourteen had a decrease of 20% or greater and two were mildly symptomatic from CHF. There was additional reduction in the LVEF after HDC with a median value for LVEF of 59% (range, 20-78%). During HDC 10 patients developed clinical signs of congestive heart failure (CHF). Five patients responded to diuretic therapy and did not require any additional treatment. Four patients responded to vasodilation and/or digoxin with improvement in cardiac function. A clinically significant decrease in cardiac function was found in a small number of patients after induction chemotherapy and HDC with PBPCT. The majority of the patients tolerated this regimen without problems. Although there was a decline in LVEF as measured by radionuclide MUGA this did not prevent the majority of patients from proceeding with HDC. Bone Marrow Transplantation (2000).

High-dose chemotherapy and peripheral blood progenitor cell transplantation in the treatment of breast cancer.

Each year in the USA, 180,000 new cases of breast cancer are diagnosed and about 44,000 women die of the disease. Current primary treatment consists of adjuvant chemotherapy and hormone therapy, and statistics show that combination chemotherapy favorably influences the outcomes in both node-negative and node-positive primary disease. However, a significant number of breast cancer patients succumb to the disease, and nearly every patient diagnosed with metastatic breast cancer will be dead within five years. High-dose chemotherapy (HDC) and peripheral blood progenitor cell transplantation (PBPCT) are based upon laboratory and clinical observations of the ability to modify growth properties of quiescent and replicating cancer cells. A large number of HDC and PBPCT regimens have been evaluated for treatment of metastatic breast cancer, and recent autologous bone marrow transplantation data indicate that three HDC regimens (CPB, CTCb and cytoxan and thiotepa) predominate. Unfortunately, negative media coverage surrounding and subsequent to the presentation of preliminary findings reported at the May 1999 American Society of Clinical Oncologists, that were not allowed adequate follow-up time for full analysis of treatment results, has had a detrimental effect on the ability to conduct trials in this area. Several randomized trials have been conducted in both the metastatic and high risk primary disease settings. Thorough analysis of these studies indicates an evaluable improvement in favor of HDC and PBPCT in three of the four randomized studies performed in metastatic breast cancer and two of the four high risk primary studies. Also, initial evaluations found that quality of life appeared comparable in patients receiving either HDC or not. Each randomized trial studied asks a different question and, depending on the intensity of HDC regimen, the intensity and duration of the standard dose chemotherapy control and the schedule of events in relation to induction chemotherapy, the outcomes may be quite variable. Still, certain general trends are indentifiable. HDC alone will not completely cure breast cancer and should be considered as part of an overall therapeutic plan. In some of these studies, significantly longer follow-up is required before definitive analysis can be completed.

High-dose chemotherapy with hematopoietic rescue as primary treatment for metastatic breast cancer: a randomized trial.

PURPOSE: The aims of this study were to compare in a randomized trial the results of high-dose versus conventional-dose chemotherapy as first-line treatment for metastatic breast cancer. The comparison included complete response (CR) rate, duration of response, and duration of survival. PATIENTS AND METHODS: Ninety patients were entered onto a study to compare two cycles of high-dose cyclophosphamide 2.4 g/m2, mitoxantrone 35 to 45 mg/m2, and etoposide (VP16) 2.5 g/m2 (HD-CNV) versus six to eight cycles of conventional-dose cyclophosphamide 600 mg/m2, mitoxantrone 12 mg/m2, and vincristine 1.4 mg/m2 (CNV) as first-line treatment for metastatic breast cancer. The high-dose regimen included either autologous bone marrow or peripheral-blood stem-cell rescue. All 90 patients are assessable. RESULTS: The response rates were significantly different. The overall response rate for HD-CNV was 43 of 45 (95%), with 23 of 45 patients (51%) achieving CR. Twenty-four of 45 patients (53%) who received conventional CNV have responded, with only two patients achieving CR. Both duration of response and duration of survival were significantly longer for patients, who received HD-CNV. Toxicity of the high-dose therapy was moderate in most patients. Grade 2 to 3 mucositis and hematologic suppression that required supportive treatment was universal, but hematologic recovery to a neutrophil count more than 500/microL and platelet count more than 40,000/microL occurred at day 18 (median) after therapy. CONCLUSION: HD-CNV appears to be a promising schedule that results in a significant proportion of CRs and increased survival in patients with metastatic breast cancer.

P-glycoprotein immunostaining correlates with ER and with high Ki67 expression but fails to predict anthracycline resistance in patients with advanced breast cancer.

In an attempt to further define the clinical utility of p-glycoprotein immunostaining in breast cancer, we examined 101 specimens from patients with advanced breast cancer. There was a significant correlation between estrogen receptor status and p-glycoprotein expression but only for low levels of p-glycoprotein. Premenopausal status appeared to correlate with increased p-glycoprotein expression, but this probably reflects patient selection as premenopausal patients had higher prior exposure to anthracyclines and were more likely to have received chemotherapy as initial treatment. P-glycoprotein expression was highly significantly correlated with expression of the proliferation related antigen Ki67, suggesting that p-glycoprotein expression may well be cell cycle dependent, with overexpression occurring in rapidly cycling cells. These findings may explain reported findings of modulation of p-glycoprotein expression by agents such as anti-oestrogens. P-glycoprotein positive staining did not, however, predict chemotherapy treatment failure or survival duration.

Single high-dose etoposide and melphalan with non-cryopreserved autologous marrow rescue as primary therapy for relapsed, refractory and poor-prognosis Hodgkin's disease.

A simplified schedule of high-dose chemotherapy (HDC) consisting of melphalan (140 mg m-2) plus VP16 (2.5 g m-2) given over 12-18 h together with autologous non-cryopreserved autologous bone marrow transplant (ABMT) was used for treatment of relapsed (37 patients) and refractory (seven patients) patients and as first-line treatment (four patients) for poor-prognosis Hodgkin's disease. Two patients had a second HDC-ABMT after relapse following prior HDC-ABMT, giving a total of 50 procedures among 48 patients. The haematological recovery rate was 98% with a complete response rate of the Hodgkin's disease of > 90%. Factors significantly influencing response rate were performance status and the presence of liver involvement. Thirty-nine patients are alive, with 37 in continuous complete remission. The median duration of survival and median duration of remission have not been reached at a median follow-up time of 45 months. Adverse prognostic factors for survival were disease status at the time of HDC-ABMT (refractory versus relapse, with primarily refractory patients showing significantly poor survival) and the presence of liver involvement. High-dose chemotherapy with short-duration chemotherapy and non-cryopreserved bone marrow is an effective and safe treatment modality for patients with relapsed and poor-prognosis Hodgkin's disease.

Seizures and neurocysticercosis in black men.

Men from a working population of black gold-miners were studied prospectively during an 8-month period to determine the incidence and aetiology of seizures in this population. Computed tomography (CT) of the brain was the primary investigation. From the total population of 97,000, 175 men with seizure disorders were admitted to the study and of these 165 underwent brain CT. In addition 138 subjects, who had brain CT for reasons other than seizures during the study period, served as controls. Sixty-three patients (38%) and 20 controls (14%) (P less than 0.0005) were considered to have definite or possible neurocysticercosis (NCC). Focal cerebral atrophy was the next most common abnormality and was found in 38 patients (23%) and 4 controls (3%) (P less than 0.0005). Otherwise unsuspected diagnoses, including tuberculoma, cerebral contusion and subdural haematoma, were made on CT in 10 cases. In 43% of patients with definite NCC, there was CT evidence of active disease and these subjects might be suitable candidates for treatment with antiparasitic chemotherapy. The high frequency of NCC in both the seizure patients and the control group indicates a need for more active public health measures. CT of the brain was extremely useful in determining seizure aetiology in this population.

Comparison of cefotaxime with ceftriaxone given intramuscularly 12-hourly for community-acquired pneumonia.

Cefotaxime 1 g intramuscularly (i.m.) 12-hourly was compared with ceftriaxone 1 g i.m. 12-hourly in adult patients requiring hospitalization with uncomplicated community-acquired pneumonia. Fifty-two patients were enrolled and two were subsequently withdrawn, leaving 50 patients who completed the study; 23 received cefotaxime and 27 received ceftriaxone. Clinical cure was achieved in 49 of the 50 patients (98%). One treatment failure occurred in a patient who received ceftriaxone. The only significant pathogen isolated from the pretreatment sputum cultures was Streptococcus pneumoniae (50%). All isolates were sensitive to both drugs. Cefotaxime 1 g i.m. 12-hourly was as effective as ceftriaxone in the treatment of patients with uncomplicated community-acquired pneumonia requiring hospital admission.

Captopril in hypertensive black men in southern Africa.

A group of 55 black men with mild or moderate hypertension who were being treated with methyldopa, prazosin, and a thiazide diuretic in combination with sotalol, were studied before and after changing their treatment to captopril and a thiazide diuretic. The level of blood pressure control was similar in the 11 men with mild hypertension but the 44 men with moderate hypertension were less well controlled with captopril and a thiazide diuretic. In the men with moderate hypertension the mean increase in the systolic blood pressure after the change in treatment was 4.7 mmHg (not significant) and in the diastolic pressure 6.2 mmHg (P less than 0.02). The mean blood pressure was higher during treatment with captopril in 37 men and lower in 18 men (P = 0.01). Thirty-seven men found both regimens acceptable and 33 of these men preferred the captopril regimen; however, 15 men said they did not like the captopril regimen while only 4 men did not like the methyldopa/prazosin regimen (P less than 0.01). Side-effects from the captopril regimen were reported by 18 of the men and from the methyldopa/prazosin regimen by 6 men (P less than 0.02). It was concluded that the captopril/thiazide regimen was less effective than the methyldopa/prazosin/sotalol/thiazide regimen for the control of moderate hypertension in this population of black men. Although the men who liked both regimens preferred the captopril regimen, that regimen was associated with significantly more side-effects and was disliked by more of the men than was the methyldopa/prazosin regimen.

Features of systemic sclerosis (scleroderma) in South African goldminers.

Systemic sclerosis is more common among men exposed to silica-containing dust than in the general male population. The clinical features of systemic sclerosis in a group of 24 black goldminers are described. The better-known presenting features of systemic sclerosis, including Raynaud's phenomenon and dysphagia, were rare in this population. Initial presentation was usually with nonspecific features including swelling of the feet or hands, weakness, arthralgia or symptoms of respiratory or cardiac disease. Clinical evidence of pleural or pericardial involvement was more common than is usually described in non-occupational systemic sclerosis. Interstitial lung disease was frequently encountered and renal disease was rare.

Adriamycin cellular transport: methodological aspects.

A rapid and simple method for determination of cellular uptake of adriamycin is described. The method is based on the principle that active uptake is proportional to alterations of drug distribution, measured as a fraction of time, between suspending medium and cells, the volume of each having been accurately determined. Cellular drug uptake can be calculated by the use of a simple distribution formula. This method represents a compromise between indirect measurement of the loss of drug from suspending medium and direct measurement of drug uptake following cell separation, washing, and lysis. This method should be applicable to the measurement of cellular uptake of a wide range of drugs.

Idarubicin plus Cytarabine versus Doxorubicin plus Cytarabine in Induction Therapy for Acute Non- Lymphoid Leukaemia: A Randomized Trial.

A randomized trial comparing idarubicin plus cytarabine (IDA/Ara-C) with doxorubicin plus cytarabine (ADM/Ara-C) in induction therapy for ANL,L was carried out. The IDA/Ara-C regimen consisted of idarubicin 20 mg/m(2) p.o. given on days 1, 2 and 3 plus cytarabine 25 mg/m(2) as a loading dose followed by 100 mg/m(2) by continuous infusion daily × 7 days. The ADM/Ara-C regimen consisted of adriamycin 30 mg/m(2) on days 1, 2 and 3 and the same dose of cytarabine. Patients who responded to the first cycle with at least 502, reduction of marrow blasts received a second treatment cycle followed by a consolidation cycle of the same treatment for those in CR at the end of 2 cycles. 35/52 (6770 receiving ADM/Ara-C achieved CR, with 25 (48%) patients in CR after a single treatment cycle. 28/48 (58%) receiving ADM/Ara-C achieved CR of whom 11 (23%) went into remission after the first treatment cycle. IDA/Ara-C caused less nausea and vomiting, less stomatitis, a shorter duration of neutropenia and less need for platelet support than ADM/Ara-C. The median duration of CR is 62 weeks for IDA/Ara-C and 48 weeks for ADM/Ara.-C. These differences are not statistically significant. Clinical cardiotoxicity occurred in 4/48 patients treated with ADM/Ara-C. No clinical cardiac toxicity was observed in those receiving IDA/Ara-C. The mean post-treatment ejection fraction was, in addition, lower for ADM/Ara-C than for IDA/Ara-C. It is concluded that IDA/Ara-C is an effective and safe induction therapy for ANLL.

Lack of a significant independent effect of race on survival in breast cancer.

In an analysis of 2033 patients with breast cancer from two population groups presenting to the Combined Breast Clinic of the Johannesburg and Hillbrow Hospitals, black patients were found to present with more advanced stage disease (P much less than 0.0001) and to have a poorer prognosis within each stage than whites (P less than 0.005- less than 0.001). Intrastage inhomogeniety was indicated by the finding that black patients had significantly more advanced T and N categories within stage grouping as compared to white patients (P = 0.013-P less than .001). A multivariate analysis controlling for age, T and N in nonmetastatic showed that when these factors were taken into consideration there was no significant independent effect of race on survival. The data indicate that the poorer prognosis which has been previously reported for black patients probably results from intrastage variability of disease bulk, supporting the use of the TNM rather that the stage grouping system for prognostication. Age differences also were evident when the two population groups were compared, with breast cancer in blacks appearing to present at an earlier age. Further analysis showed that these age differences were related to the age structure of the two populations and that breast cancer probably does not occur at a younger age in black subjects. Ethnic origin, does not appear to play a significant independent role in the prognosis of breast cancer in women.

Subacute myelopathy: an unusual paraneoplastic complication of Hodgkin's disease.

We report a case of Hodgkin disease presenting with a subacute myelopathy without evidence of metastatic involvement of the spinal cord. The systemic disease responded to conventional chemotherapy, but the myelopathy only improved after intrathecal dexamethasone was added to the treatment program, beta-2-microglobulin levels in the cerebrospinal fluid were elevated at presentation. Following the use of intrathecal corticosteroids there was a decrease of CSF beta-2-microglobulin levels. The possible significance of these findings is discussed.

Treatment of hairy cell leukaemia with recombinant alpha-interferon.

Of 10 patients with hairy cell leukaemia treated with 3 mU recombinant alpha-interferon daily, 9 showed clinical haematological response--including 2 patients who achieved complete remission. Unmaintained responses have continued for as long as 18+ months after completion of therapy. There was no significant toxicity associated with this treatment schedule.