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Targeted Therapies Formerly
BioOncology Watch www.tgt-therapies.com |
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SEPTEMBER 2004 METASTATIC COLORECTAL CANCER Cetuximab vs. cetuximab plus irinotecan. Previous
reports have demonstrated that cetuximab has activity in colorectal
cancers refractory to fluorouracil and irinotecan. In the present study, David Cunningham et
al randomized (2:1 ratio) 329 patients with metastatic colorectal cancer that
progressed during or within 3 months after treatment with an irinotecan-based
regimen to receive cetuximab (initial dose of 400 mg/m2 i.v.
followed by weekly infusions of 250 mg/m2) plus irinotecan or
cetuximab alone. Patients whose
disease progressed while receiving cetuximab monotherapy were allowed to add
irinotecan to their regimen. The
combination therapy group achieved a higher response rate (22.9% vs. 10.8%)
and a greater median time to progression (4.1 vs. 1.5 months) compared to
patients in the monotherapy group.
However, median overall survival was similar in both treatment groups
(8.6 vs. 6.9 months). The development
of adverse events was similar to those expected with irinotecan alone. These findings suggest that cetuximab circumvents
irinotecan resistance and that the combination of cetuximab and irinotecan
should be preferred over cetuximab monotherapy for patients with
irinotecan-refractory colorectal cancer.
In an accompanying editorial, Deborah Schrag discusses moral and
societal issues posed by the high financial cost of new anti-cancer drugs such
as cetuximab. For example, the
doubling of median survival attained over the past decade for patients with
advanced colorectal cancer has been associated with a 340-fold increase in
drug costs for the first 8 weeks of treatment. Dr. Schrag points out that escalating drug
costs threaten the ability of the public to pay for health care and that the
public sector and the pharmaceutical industry must develop a better process
for pricing. She concludes that the US
federal government, as the largest health care payer, should lead these
discussions and that the American public must confront difficult questions
regarding how much will we as a society spend on the treatment of advanced
cancer and to what extent we will allow the ability of a patient to pay to determine
the treatment utilized. (Cunningham D, et al. N Engl J Med 2004;351:337-345 and Schrag D. N Engl J Med 2004;351:317-319) NON-HODGKIN'S LYMPHOMA (NHL) Combination chemotherapy plus rituximab. The
therapeutic approach to follicular lymphoma (FL) remains controversial and
ranges from palliative monotherapy to high-dose chemotherapy supported by
autologous stem cell transplantation.
Pier Luigi Zinzani and colleagues conducted a multicenter study in
which previously untreated patients with CD20+ FL were randomized to receive
up to 6 cycles of either FM (fludarabine 25 mg/m2 i.v. on Days 1
to 3 every 21 days plus mitoxantrone 10 mg/m2 i.v. on Day 1 every
21 days) (n = 68) or CHOP (cyclophosphamide 750 mg/m2 i.v. on Day
1, doxorubicin 50 mg/m2 i.v. on Day 1, vincristine 1.4 mg/m2
i.v. on Day 1, and oral prednisone 100 mg/day on Days 1 to 5 every 21 days)
(n = 72). Patients who achieved
complete clinical and molecular remissions (bcl-2/IgH-negative) received no
further treatment. Patients who
achieved clinical partial remission (PR) or who had clinical complete
remission (CR) but remained bcl-2/IgH-positive received rituximab 375 mg/m2
i.v. weekly for 4 weeks. Nonresponders
were discontinued from the study.
FM-treated patients compared to CHOP-treated patients had higher rates
of clinical CR (68% vs. 42%) and clinical CR plus molecular remission (39%
vs. 19%). Further therapy with
rituximab resulted in the achievement of clinical CR plus molecular remission
in 55 of 95 (58%) treated patients.
The final clinical CR plus molecular remission rates in the FM and
CHOP groups were 71% and 51%, respectively.
However, the higher rate of clinical CR and molecular remission for
the FM group did not translate to a significant improvement in
progression-free survival (PFS) or overall survival (OS) time compared to the
CHOP group. This study showed that FM
therapy resulted in higher rates of clinical CR and molecular remission
compared to CHOP therapy and that sequential rituximab therapy is
effective. (Zinzani PL, et al. J Clin Oncol 2004;22:2654-2661) Phase I study of I-131-labeled chimeric 81C6
monoclonal antibody. There is a correlation between increased tumor
stromal expression of the extracellular matrix protein tenascin-C and
aggressiveness of B-NHL. Thus, David
Rizzieri and colleagues performed a phase I study of 131I -81C6, a
radiolabeled monoclonal antibody directed against tenascin-C (N = 9). Three patients received a dose of 40 mCi
and 2 patients developed hematologic toxicity that required stem cell
infusion. Subsequently, 6 patients
received a dose of 30 mCi and 2 patients developed hematologic toxicity that
required stem cell infusion. However,
1 patient achieved a CR and 1 patient had a PR. The clearance of 131I-81C6
whole-body activity was mono-exponential with a mean half-life of 110
hours. Clearance from tumor sites was
generally slower and the mean absorbed dose in tumor was 963 cGy compared to
67 cGy for the whole body. These
findings suggest that 131I-81C6 has activity against NHL. Future trials will evaluate methods to
minimize binding in the bone marrow and to maximize tumor exposure. (Rizzieri DA, et al. Blood 2004;104: 642-648) ANDROGEN-INDEPENDENT PROSTATE CANCER (PC) Phase 1 study of radiolabeled anti-prostate-specific
membrane antigen monoclonal antibody. J591 is a monoclonal antibody directed against the
extracellular domain of prostate-specific membrane antigen. Matthew Milowsky et al performed a phase 1
study of yttrium-90-labeled J591 (90Y-J591) in which 29 patients with
progressive androgen-independent PC received up to 3 retreatments. The dose-limiting toxicity was
thrombocytopenia and the maximum tolerated dose was determined to be 17.5
mCi/m2. Two patients had
decreases in serum prostate-specific antigen levels associated with objective
measurable disease responses, and 6 patients had stable disease. These data suggest that 90Y-J591 has
therapeutic potential in patients with androgen-independent PC and warrants
further study. (Milowsky MI, et al. J Clin Oncol 2004;22:2522-2531) |
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