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Targeted Therapies Timely
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AUGUST 2005 MULTIPLE MYELOMA Bortezomib vs high-dose
dexamethasone. Paul
Richardson and colleagues conducted a multicenter, open-label, phase III study in which 669 patients with relapsed
multiple myeloma were randomized (1:1) to receive the proteasome inhibitor
bortezomib or standard therapy with high-dose dexamethasone. Bortezomib 1.3
mg/m2 was administered intravenously on days 1, 4, 8, and 11 every
21 days for 8 cycles and on days 1, 8, 15, and 22 every 35 days for 3 cycles
for a maximum treatment period of 273 days. Dexamethasone 40 mg was
administered orally on days 1–4, 9–12, and 17–20 every 35 days for 4 cycles
and on days 1–4 every 28 days for 5 cycles for a maximum treatment period of
280 days. Patients treated with bortezomib had higher overall and complete response
rates (38% vs 18%; P <0.001 and 6%
vs <1%; P <0.001,
respectively) than patients treated with dexamethasone. The median time to
progression was 6.2 months for the bortezomib group and 3.5 months for the
dexamethasone group (P <0.001). In
addition, the survival rate at 1 year was greater in bortezomib group than in
the dexamethasone group (80% vs 66%; P
= 0.003). Grade 3 or 4 adverse events were reported in 75% and 60% of
patients in the bortezomib and dexamethasone groups, respectively. These
results demonstrated that bortezomib is a more effective therapy than
high-dose dexamethasone for patients with relapsed
multiple myeloma. ( CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) Fludarabine, cyclophosphamide,
rituximab (FCR) combination therapy. The results of 2 studies investigating the use of FCR in CLL patients
were recently reported. William Wierda and others administered
6 cycles of FCR to 177 patients with previously treated CLL (34 patients
[19%] had previously received FC). The overall and complete response (CR)
rates were 73% and 25%, respectively. Twelve (32%) of 37 complete responders
tested achieved molecular remissions in bone marrow. Myelosuppression was the
most common toxicity. Grade 4 neutropenia, grade 4 thrombocytopenia, and
grade 3 or 4 anemias occurred in 66%, 18%, and 24% of patients, respectively.
In the second study, Michael Keating and colleagues
treated 224 patients with previously untreated advanced CLL with 6 cycles of FCR.
The overall response rate was 95%, and CR was achieved in 70% of patients. Fewer than 1% CD5- and CD19-coexpressing cells were
detected in bone marrow after therapy in 138 (67%) of 207 patients tested. Grade
3 or 4 neutropenia occurred during 52% of the treatment courses and one third
of the patients had more than one episode of infection. Thus, FCR produced
high CR rates in both previously treated and previously untreated CLL
populations. In addition, several patients achieved flow cytometric and
molecular remissions. However, FCR therapy was associated with a high rate of
severe myelosuppression and infection. Long-term follow-up is needed to
confirm the clinical benefit of this therapy. An editorial by Thomas Lin and others cautions that because the Keating trial of treatment-naïve patients is a phase II
noncomparative study, it is not appropriate to compare these results with
those of previous studies as the effect of demographic features on efficacy
outcomes is not known in the absence of a control arm. (Wierda W, et al. J Clin Oncol. 2005;23:4070–4078,
Keating MJ, et al. J Clin Oncol. 2005;23:4079–4088, and Lin TS, et
al. J Clin Oncol 2005;23:4009–4012.) NON-HODGKIN’S LYMPHOMA (NHL) Long-term results of rituximab
plus CHOP (R-CHOP) in diffuse large B-cell lymphoma (DLBCL). Pierre Feugier and associates analyzed the long-term
outcomes of elderly patients with DLBCL treated in a study comparing CHOP
(cyclophosphamide, doxorubicin, vincristine, and prednisone) with R-CHOP. With
a median follow-up of 5 years, event-free, progression-free, disease-free,
and overall survival remained statistically superior in patients treated with
R-CHOP than with CHOP. No long-term toxicities were reported in patients
treated with R-CHOP. The authors suggest that R-CHOP become the standard regimen
for treating elderly patients with DLBCL. (Feugier P,
et al. J Clin
Oncol 2005;23:4117–4126) Myelodysplasia and acute myeloid
leukemia following NHL therapy. Two
papers report treatment-related myelodysplastic syndromes (MDS) and acute
myeloid leukemia (AML) after fludarabine, mitoxantrone, and dexamethasone (FND)-containing
regimens or monoclonal antibody therapies for patients with NHL. After a
median follow-up of 5 years, MDS was observed in some patients following
therapy with FND while no cases of MDS/AML were reported in 76 patients
receiving I131 tositumomab as initial therapy. An analysis of 995
patients with NHL who had been treated with tositumomab and I131 tositumomab
with or without previous chemotherapy showed the annualized incidence of MDS/AML
to be no greater than that expected after the patients' prior chemotherapy. (Bennett JM, et al. Blood 2005;105:4576–4582 and Mclaughlin
P, et al. Blood 2005;105:4573–4575) BREAST CANCER Addition of trastuzumab to
chemotherapy improves neoadjuvant results. Aman Buzdar and
colleagues randomized patients with HER2-positive operable breast cancer to 4
cycles of paclitaxel followed by 4 cycles of epirubicin, cyclophosphamide,
and fluorouracil or the same regimen with weekly trastuzumab for 24 weeks. After
the completion of neoadjuvant therapy, patients underwent segmental or total
mastectomy and an evaluation for axillary disease. The trial's data
monitoring committee stopped the study after 34 patients had completed
therapy due to the superior results observed in the trastuzumab plus
chemotherapy group. The pathologic complete response (pCR) rates were 25% and
66.7% in the chemotherapy alone and trastuzumab plus chemotherapy groups,
respectively (P = 0.02). A decrease
of >10% in cardiac ejection fraction developed in 5 chemotherapy-treated
patients and 7 trastuzumab plus chemotherapy–treated patients. However, no
congestive heart failure events were reported. These data indicate that the
addition of trastuzumab to chemotherapy significantly increased pCR rates in
patients with operable HER2-positive breast cancer. (Buzdar
AU, et al. J Clin
Oncol. 2005;23:3676–3685) |
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