SAN ANTONIODocetaxel (Taxotere), doxorubicin (Adriamycin), and  cyclophosphamide (TAC) improved overall survival by 30% and disease-free  survival by 28% at 5 years, compared with the standard combination of flu-orouracil,  doxorubicin, and cyclophosphamide (FAC) as adjuvant therapy for women with  node-positive, early-stage breast cancer, John R. Mackey, MD, reported at the  26th Annual San Antonio Breast Cancer Symposium (abstract 43). 

Dr. Mackey, of the Cross Cancer Institute, Edmonton, Alberta, Canada,  reported the second planned interim analysis of the Breast Cancer International  Research Group (BCIRG) 001 study with 55 months of follow-up.

This Aventis-sponsored study is a head-to-head comparison of docetaxel-based  chemotherapy and fluorouracil-based chemotherapy in 1,491 pre- and  postmenopausal women with stage T1-3, N1, M0 breast cancer. Eligibility  criteria included no prior systemic therapy or radiotherapy for breast cancer,  age of 70 or younger, and definitive surgical treatment of mastectomy or  breast-conserving surgery that included axillary lymph node dissection. 

The primary study endpoint is disease-free survival. Secondary endpoints are  overall survival, toxicity, quality of life, and evaluation of pathologic and  molecular markers for predicting efficacy. Enrollment began in June 1997 and  was completed in June 1999, including patients from 111 sites in 20 countries. 

After surgery, patients were randomized to TAC (n = 745) or FAC (n = 746).  Planned subgroup analyses include hormone-receptor status and nodal involvement  (one to three vs four or more positive nodes). Most patients had at least 2-cm  tumors, two thirds had one to three positive nodes, and 75% were  hormone-receptor positive.

Tumor samples were collected from 95% of patients for analysis of hormone-  receptor status, HER-2 amplification, and other characteristics. Quality of  life analyses are being done, and Dr. Mackey said they will be presented this  year.

The first planned interim analysis of this study, with a median follow-up of  33 months, was presented at the American Society of Clinical Oncology 2002  annual meeting (abstract 141) and showed significant improvement in  disease-free survival in favor of TAC. The data reported by Dr. Mackey  confirmed and extended these findings. This second interim analysis was done  after 400 disease-free survival events. The final analysis will be after 590  events.

For disease-free survival, Dr. Mackey reported 172 events on TAC and 227 on  FAC. Five-year disease-free survival using intent-to-treat analysis was 75% on  TAC vs 68% on FAC (HR 0.72, 

 = .0010). For overall survival, there were  91 events on TAC and 130 on FAC. Overall survival at 5 years was 87% on TAC and  81% on FAC (HR 0.70, 

The TAC advantage was seen in both HER-2-positive and HER-2-negative  patients. The TAC/FAC disease-free survival hazard ratio was 0.61 (

 =  .0118) in HER-2-positive patients, and 0.76 (

Disease-free survival was also significantly better for TAC vs FAC for  patients with one to three positive nodes (HR 0.61, 

 = .0009).  Disease-free survival with TAC was better in patients with four or more  positive nodes but not significantly so (HR 0.83, 

 = .17). There was no  interaction of nodal status per se with disease-free survival, Dr. Mackey said.

The benefits of TAC were significant in both hormone-receptor-positive and  hormone-receptor-negative patients. 

Febrile neutropenia was 24.7% with TAC vs 2.5% with FAC (

 < .005),  but this did not result in more moderate to severe infections in patients who  received TAC. Grade 3 or 4 neutropenia was 65.5% vs 49.3% (

 < .05). The  study protocol did not include prophylactic G-CSF (Neupogen). There were no  toxic deaths or long-lasting toxicities on either arm.

Dr. Mackey said that the total number of second primary cancers was lower  with TAC than with FAC and that there has been no sign of leukemogenesis,  although this is being watched closely. 

"TAC produced a significant increase in disease-free survival with a 28%  reduction in risk of relapse and an overall survival advantage with a 30%  reduction in mortality. The disease-free survival advantage was irrespective of  nodal status, estrogen-receptor status, or HER-2 status," Dr. Mackey said.  "This establishes docetaxel as a source of major clinical benefit in the  adjuvant treatment of early, node-positive breast cancer. We are confident that  this docetaxel-based treatment can cure more women than one of the standard  chemotherapy regimens." 

A statement from Aventis said that the company "plans to use the phase III  study data to support submissions for US and European Union approval in early  2004 for the use of Taxotere in treating early-stage operable breast cancer  with involved axillary lymph nodes."

Articles

SAN ANTONIO-Docetaxel (Taxotere), doxorubicin (Adriamycin), and cyclophosphamide (TAC) improved overall survival by 30% and disease-free survival by 28% at 5 years, compared with the standard combination of flu-orouracil, doxorubicin, and cyclophosphamide (FAC) as adjuvant therapy for women with node-positive, early-stage breast cancer, John R. Mackey, MD, reported at the 26th Annual San Antonio Breast Cancer Symposium (abstract 43).

Adjuvant Docetaxel Bests FAC in Breast Ca

SAN DIEGOThe addition of rituximab (Rituxan) to CHOP  chemotherapy has resulted in a dramatic improvement in outcome for patients of  all ages with diffuse large B-cell (DLBC) lymphoma in a retrospective study  from British Columbia. Improvements were greatest among the elderly population  in the study, Laurie Sehn, MD, clinical assistant professor, British Columbia  Cancer Agency and University of British Columbia, said at the 45th Annual  Meeting of the American Society of Hematology (abstract 88).

She said that in 2000, GELA (Groupe d’Etude des Lymphomes de  l’adult) reported the results of a randomized controlled trial showing improved  outcome with the addition of rituximab to CHOP chemotherapy for elderly  patients with DLBC lymphoma. 

"Based on these initial results, the British Columbia Cancer  Agency implemented a new provincial policy on March 1, 2001, recommending the  combination of CHOP and rituximab for all newly diagnosed patients with  advanced-stage DLBC lymphoma," Dr. Sehn said. "We are presenting a  population-based retrospective analysis comparing outcomes over a 3-year  interval." 

The study ran from September 1, 1999, through August 31,  2002: 18 months prior to (pre-Ritux) and 18 months following (post-Ritux) this  policy change. The cases were identified from three sources: the British  Columbia Provincial Cancer Registry, the British Columbia Cancer pharmacy  records, and the Lymphoma Clinical Database. 

Patients were included, Dr. Sehn said, if they were older  than 16 years of age; had a biopsy-proven newly diagnosed DLBC lymphoma; had  clinically advanced-stage disease (stage III-IV; stage I-II with B symptoms or  bulky tumors, or a contraindication to radiation) or testicular DLBC (any  stage); and were treated with an anthracycline-based regimen with curative  intent. 

Dr. Sehn noted that cases were excluded if they were HIV  positive; had CNS involvement; had evidence of transformation from indolent  lymphoma; were never treated due to frailty, refusal, or rapid clinical  deterioration; or received therapy with only palliative intent. 

Researchers identified 294 patients, of whom 142 were pre-Ritux  and 152 were post-Ritux. The patients ranged in age from 19 to 86 (median, 63). 

Other patient characteristics included low International  Prognostic Index (IPI) score (24%), low-intermediate IPI score (24%),  high-intermediate IPI score (25%), high IPI score (27%), elevated LDH (65%),  and bulky disease greater than 10 cm (42%). 

Dr. Sehn said there were no significant differences in age,  IPI distribution, serum LDH, or presence of bulky disease between the pre-Ritux  and post-Ritux groups. 

Although the policy implementation date recommending the use of  rituximab was March 1, 2001, in actuality 9% of patients in the pre-Ritux group  received rituximab with chemotherapy, compared with 85% in the post-Ritux  group. More patients in the pre-Ritux group received radiation therapy (25% vs  15% post-Ritux, 

The median follow-up for living patients is 34 months for  the pre-Ritux group and 17 months for the post-Ritux group.

Among all patients, 2-year progression-free survival was 52%  pre-Ritux and 71% post-Ritux (

 = .0009) (see Figure). Among those aged  60 or older (n = 167), 2-year progression-free survival was 44% pre-Ritux and  73% post-Rutux (

 = .0018), compared with 60% and 70%, respectively (

= .18), for those under age 60 (n = 127). 

Two-year overall survival pre- and post-Ritux was 53% and  77%, respectively, for all patients (

 = .0001); 40% and 67% for those  age 60 or older (

 = .0033), and 69% and 87% for those under age 60 (

In multivariate analysis controlling for age, IPI score, and B symptoms,  pre-Ritux or post-Ritux treatment remained a strong, independent predictor of  outcome (

SAN DIEGO-The addition of rituximab (Rituxan) to CHOP chemotherapy has resulted in a dramatic improvement in outcome for patients of all ages with diffuse large B-cell (DLBC) lymphoma in a retrospective study from British Columbia. Improvements were greatest among the elderly population in the study, Laurie Sehn, MD, clinical assistant professor, British Columbia Cancer Agency and University of British Columbia, said at the 45th Annual Meeting of the American Society of Hematology (abstract 88).

Adding Rituximab to CHOP Chemo Improves DLBC Lymphoma Outcomes

SAN ANTONIOIntensity of immunostaining for the gene  BP1 (beta protein 1) correlates with breast cancer aggressiveness, and  detection of BP1 in otherwise apparently normal tissue specimens may be a  marker for early detection of breast cancer, Patricia E. Berg, PhD, said at the  26th San Antonio Breast Cancer Symposium (abstract 41). 

Dr. Berg, associate professor of biochemistry and molecular  biology, George Washington University Medical Center, reported data comparing  BP1 expression in various types of breast cancer with samples from normal  breast reduction and with apparently normal breast cells from breast cancer  patients.

Dr. Berg said that BP1 is a master regulator gene and part  of the homeobox gene superfamily of transcription factors important in early  development. The gene maps to chromosome 17q21-22.

Dr. Berg’s group previously reported that the BP1 gene is  expressed in the bone marrow of 63% of acute myeloid leukemia (AML) patients.  Further research showed that BP1 was activated in 80% of invasive ductal  carcinoma patients, whereas adjacent normal cells and most normal control  subjects were negative for BP1 expression (Fu et al: 

The study also showed that BP1 is highly correlated with  estrogen-receptor (ER) status. Dr. Berg said that 100% of ER-negative breast  tumors were BP1 positive vs 73% of ER-positive tumors (

 = .03).  Further, among African-American breast cancer patients, who have a higher  breast cancer mortality than whites, 89% were BP1 positive, compared with 57%  of white patients. "These findings suggest that the expression of BP1 may be  associated with breast cancer aggressiveness," she said.

The objectives of this study were to determine whether  protein and mRNA expression of BP1 correlate, and whether BP1 protein is  expressed in both invasive ductal carcinomas and in situ lesions. The  researchers used a polyclonal antibody to BP1 to immunostain paraffin sections  from patients with a variety of in situ and invasive breast lesions (n = 100),  and from normal controls who had reduction mammoplasties (n = 34).

Among the normal controls, 12% of samples stained positive  for BP1, although less than 5% of the cells in those positive samples were BP1  positive. The number of BP1-positive tumors was 35% in intraductal hyperplasia,  50% in sections from in situ tumors, and 80% in invasive ductal tumors.  Interestingly, a subset of cells in invasive and in situ cancers that appeared  normal in fact stained positive for BP1. 

Staining for BP1 was relatively homogenous in invasive  ductal carcinoma and heterogenous in ductal carcinoma in situ. "The frequency  and intensity of BP1 staining increase with tumor aggressiveness," Dr. Berg  said. 

In tissues that contain normal, in situ, and invasive tumor  cells, she said, the invasive cells stained most intensely for BP1, followed by  in situ tumor cells. "Intensity is an indicator of BP1 expression, so the most  intensely staining cells, which are also the most aggressive tumors, produce  the most BP1 protein." 

Further, she stated that activation of BPI in the earliest breast tumors  indicates that BP1 may be a useful detector of early breast cancer.

SAN ANTONIO-Intensity of immunostaining for the gene BP1 (beta protein 1) correlates with breast cancer aggressiveness, and detection of BP1 in otherwise apparently normal tissue specimens may be a marker for early detection of breast cancer, Patricia E. Berg, PhD, said at the 26th San Antonio Breast Cancer Symposium (abstract 41).

BP1 Expression May Be Indicator of Early Breast Cancer

SAN DIEGOThere have been no reported cases of  treatment-related myelodysplastic syndrome and acute myeloblastic leukemia (tMDS/tAML)  in patients with low-grade non-Hodgkin’s lymphoma (NHL) treated initially with  the Bexxar therapeutic regimen (tositumomab and iodine-131 tositumomab). 

John M. Bennett, MD, Professor of Medicine, Laboratory  Medicine and Pathology, Emeritus, at the University of Rochester Medical  Center’s James P. Wilmot Cancer Center, presented the study at the 45th Annual  Meeting of the American Society of Hematology (abstract 91). 

Dr. Bennett explained that the study was an update of data  presented at the ASH conference 2 years ago. The concern was that patients with  low-grade NHL typically receive many cytotoxic regimens and local external-beam  radiotherapy over the 8- to 12-year course of their disease, and virtually all  of these agents are intrinsically carcinogenic. As a consequence, one of the  potential complications of therapy is MDS and AML. Indeed, the estimated  actuarial risk of tMDS/tAML associated with chemotherapy and radiotherapy at 8  years ranges from 4% to 17%. 

Since 1990, more than 1,500 patients with low-grade NHL have  been treated with the Bexxar therapeutic regimen, which specifically targets  CD20 on normal and malignant lymphocytes and delivers both gamma and beta  radiation. Dr. Bennett noted that many durable long-term remissions have been  reported in patients treated with the Bexxar therapeutic regimen (see article  on page 13). "We investigated whether the systemic radiation from the Bexxar  therapeutic regimen increases the incidence of tMDS/tAML over that observed in  patients exposed to known leukemogenic agents," Dr. Bennett said. 

The masked, independent review looked at 1,071 patients who  were enrolled in seven studies of Bexxar therapy. Of these, 995 patients had  relapsed/refractory low-grade NHL and had received a median of three prior  cytotoxic regimens, including alkylating agents, platinums, topoisomerase II  inhibitors, antimetabolites, and external-beam radiation therapy to greater  than one marrow-bearing region. The other 76 patients had follicular NHL and  received the Bexxar regimen as their initial therapy. 

All patients had less than 25% bone marrow involvement. The  mCi dose of the Bexxar therapeutic regimen was adjusted to deliver 65 or 75 cGy  total body radiation dose depending on the patient’s pre-Bexxar platelet count  (100,000 to 150,000/mm

Dr. Bennett reported that among 995 heavily pretreated  patients, there were 35 investigator-reported cases of tMDS/tAML, with a median  follow-up of 2 years. In contrast, among the 76 previously untreated patients,  there have been no reported cases of tMDS/tAML, with a median follow-up of 4.6  years.

A single-reference hematomorpholo-gist reviewed the  available pre- and post-Bexxar bone marrow samples from the 35 tMDS/tAML  patients in a blinded fashion. After this review, the incidence of tMDS/tAML in  these Bexxar studies was reduced by 37%. 

The reviewers found that two patients had no evidence of MDS  with stable pre- and post-Bexxar blood counts and one had asplastic anemia  before Bexxar therapy. Significantly, 9 patients were found to have tMDS in  their pre-Bexxar marrow (see Figure), and 1 patient had AML (erythroleukemia). 

The annualized incidence of tMDS/tAML for previously treated  patients was 1.6% a year based on investigator assessments (35 cases), and 1.1%  a year based on the independent hematomorpholo-gist’s assessment (22 confirmed  cases).

Given the considerable variability in the incidence of tMDS/tAML in  low-grade NHL patients in the literature (an average of 10% in 10 years) and  the variety of statistical methods and diagnostic criteria used, Dr. Bennett  said that treatment decisions must be based on risk-to-benefit ratios that are  "reasonable and rational."

SAN DIEGO-There have been no reported cases of treatment-related myelodysplastic syndrome and acute myeloblastic leukemia (tMDS/tAML) in patients with low-grade non-Hodgkin’s lymphoma (NHL) treated initially with the Bexxar therapeutic regimen (tositumomab and iodine-131 tositumomab).

Bexxar: Low Risk of Secondary MDS/AML

SAN DIEGO Doubling the standard dose of imatinib mesylate (Gleevec) to 800  mg provided more complete cytogenetic responses (CCRs) more quickly with higher  rates of PCR (polymerase chain reaction) negativity than the standard dose (400  mg) in patients with previously untreated early-stage chronic myeloid leukemia  (CML). 

The 400-mg dose was established as a standard dose based on somewhat  arbitrary criteria, said Jorge E. Cortes, MD, associate professor of medicine,  M.D. Anderson Cancer Center, in that phase I dose-finding trials of 25 to 1,000  mg showed a dose response without identifying a maximum tolerated dose. 

Standard 400-mg doses in this population produce CCRs in the 70% to 80%  range in previously untreated patients and in the 40% to 60% range in patients  who have failed interferon therapy, Dr. Cortes said at the 45th Annual Meeting  of the American Society of Hematology (abstract 94). Molecular complete  remissions (undetectable levels of Bcr-Abl translocation by PCR), which  correlate with likelihood of disease progression, occur in only the 4% to 10%  range at this dose.

Initial experience with higher imatinib doses (600 mg and 800 mg) has been  promising in patients with cytogenetic resistance or relapse after 400 mg, Dr.  Cortes said.

To assess front-line therapy in patients with Philadelphia positive or  Bcr-Abl positive early chronic phase CML, the investigators gave oral daily  doses of imatinib 800 mg (400 mg twice daily) to 114 patients, and compared the  results with those of a prior study among 50 patients receiving the 400-mg  daily dose. 

In both studies, nearly all patients had a complete hematologic response.  Overall, CCRs were reported in 78% of patients in the 400-mg study (median  follow-up, 31 months) and in 90% of patients in the 800-mg study (median  follow-up, 16 months, 

 = .01). By 3 months, 52% of patients receiving  800 mg had attained a CCR, compared with 36% in the standard-dose group (

  = .0005). By 6 months, the respective CCR rates were 82% and 52%. 

The investigators also evaluated the quantitative PCR percentage ratio (%QPCR  = Bcr-Abl transcripts × 100/Abl) at different time points. After 6 months, 38%  of patients at the higher imatinib dose had reached values lower than 0.05%,  which represents about a 3 log reduction from baseline. By 12 months, 60% were  below this level. 

"We have shown previously that patients achieving CCRs with QPCR less than  0.05% have a significantly longer duration of response," Dr. Cortes commented. 

He also noted that the cumulative incidence of patients attaining  undetectable levels of Bcr-Abl by nested PCR was significantly higher for the  high-dose imatinib group at 18 months and 24 months (28% and 48% vs 7% and 17%,  respectively, for the standard-dose group, 

 = .001). No patients in the  800-mg group and four in the standard-dose group had disease transformation to  blast phase (mostly in those not achieving CCR).

Toxicities were similar in the two groups, Dr. Cortes said, with liver  dysfunction seen in 10% at 400 mg and 7% at 800 mg, and rash at 6% in both  groups. More patients treated with 800 mg had decreases in neutrophils and  platelets, but these frequently improved in 2 to 3 months, with a minority of  patients requiring dose reductions. Growth factors will be given routinely in  future trials, he noted.

Dr. Cortes concluded that high-dose imatinib offers faster complete CCRs and  more PCR negativity at the cost of more common myelosuppression. "I feel very  comfortable from these data that we have treated enough patients to say that  the higher dose is better. I offer it to every patient," he said.

SAN DIEGO- Doubling the standard dose of imatinib mesylate (Gleevec) to 800 mg provided more complete cytogenetic responses (CCRs) more quickly with higher rates of PCR (polymerase chain reaction) negativity than the standard dose (400 mg) in patients with previously untreated early-stage chronic myeloid leukemia (CML).

Oncology NEWS International Vol 13 No 2

Adjuvant Docetaxel Bests FAC in Breast Ca

Adding Rituximab to CHOP Chemo Improves DLBC Lymphoma Outcomes

BP1 Expression May Be Indicator of Early Breast Cancer

Bexxar: Low Risk of Secondary MDS/AML

Doubling Imatinib Dose Ups CML Response Rates