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are here: Home: CCU 2 | 2003: Howard
S Hochster, MD
Edited comments by Dr Hochster
Use of oxaliplatin-containing regimens
as first-line treatment of metastatic disease
I have been very impressed with the responses in my practice
to oxaliplatinbased therapy. There does not appear to be
a difference in response rates across first-line studies
of various combinations — whether FOLFOX, FOLFIRI or
IFL — but the studies do not reflect the magnitude
of responses I’ve seen in clinical practice — for
example, patients with extensive liver metastases in whom
an oxaliplatin-containing regimen reduced the tumor burden
to one or two sites. While that’s still a partial response,
the amount of cytoreduction by oxaliplatin is impressive.
The data suggest you can administer either irinotecan or
oxaliplatin as first-line therapy, but there’s been
a paradigm shift. Intergroup N9741 demonstrated clear superiority
of FOLFOX 4 with oxaliplatin and infusonal 5-FU over a bolus
IFL regimen, and I’m not sure that the results would
have been different if infusional 5-FU had been used with
irinotecan. Patients tolerate oxaliplatin better, and the
responses are more impressive. Off study, I’m using
a modified FOLFOX regimen, with leucovorin on day one followed
by a 46-hour 5-FU infusion after a bolus.
Systemic therapy of patients presenting
with metastatic disease
I have treated quite a few patients in this situation,
without resecting the primary tumor. Many patients could
have undergone surgery, but with a large number of liver
metastases, our paradigm has shifted. We give chemotherapy
first to see if we can reduce the liver metastases to an
operable volume, then we remove the residual liver disease
and the primary at the same time. I recall a woman who presented
with minimal GI symptoms. Colonoscopy revealed a lesion involving
approximately 30 percent of the circumference of the colon,
but it was not obstructive. The lesion wasn’t friable
and bleeding was minimal, but she had abnormal liver function
tests, right upper quadrant discomfort and extensive hepatic
metastases.
After six months of FOLFOX, she was restaged for consideration
of surgery, and her colon was absolutely clear of tumor by
endoscopy and CT scan. The area presumed to have been the
primary tumor was biopsied, and she appeared to have a complete
pathologic remission of the primary tumor. She also had a
partial response of the liver metastases; a small volume
of tumor remained, but it was too diffuse for resection.
Local therapy for liver metastases
Local therapy for liver metastases is a real “Pandora’s
box.” We have numerous ways to treat gross liver metastases — resection,
freezing, microwaving, embolizing, injecting itrium-labeled
glass spheres or ethanol. Unfortunately, none of these extend
survival. This is a very difficult concept to communicate
to patients.
Most people believe that you’re going to live longer
if you can resect the metastases. Sometimes that’s
true, especially if you have another chemotherapy to administer
after the resection. Local therapies need to be coupled with
effective chemotherapy; otherwise, you’re just treating
the gross disease. I look forward to any trial demonstrating
the role of local therapies. The only one demonstrating any
survival benefit is resection of a solitary liver metastasis
followed by 5-FU. Hopefully, the cooperative groups will
address these questions with appropriate clinical trials.
Management of patients with metastatic
disease and poor performance status
I use combination chemotherapy — oxaliplatin/5-FU
or irinotecan/5-FU regimens — in otherwise healthy
patients with poor performance status that is disease-related.
I recall a few patients who presented with severe debilitation,
extensive liver involvement and intrahepatic jaundice, whose
primary care physicians wanted to refer to hospice.
I treated those patients with combination chemotherapy;
they have responded favorably, and have been resurrected
with improvement in performance status and reduced jaundice.
The key was to treat them with appropriate doses — to
use dose reductions if necessary — and to initially
proceed very slowly. With older patients, who may have cardiac
problems and other comorbidities, I may use single-agent
fluoropyrimidines.
Prevention of oxaliplatin-related neuropathy
Erick Gamelin, a neurologist who works with Aimery de Gramont,
studied the neurophysiology of oxaliplatin-associated neuropathy.
He discovered the oxalato portion of oxaliplatin actually
becomes a chelating agent once it’s dissolved from
the platinum. Oxalato strips off the bivalent cations (calcium
and magnesium), opens up sodium channels and causes an intense
depolarization that can damage nerves. He postulated that
administration of calcium and magnesium salts before and
after oxaliplatin administration could prevent depolarization.
Gamelin presented data from a nonrandomized study comparing
patients treated with calcium and magnesium salts before
and after oxaliplatin to those who were untreated with the
cation salts. The treated patients had much less acute neuropathy
and could tolerate greater cumulative doses.
We use this Gamelin approach as our standard of care in
patients treated with oxaliplatin. Patients uniformly report
much less acute neurotoxicity. Our patients receive much
more oxaliplatin because they don’t have to discontinue
treatment due to cumulative neuropathy. I believe this regimen
will reduce Grade II and III neuropathy by one-half. A Phase
III trial in Europe is currently evaluating this approach,
so we’ll soon have confirmation of its effectiveness.
Challenges in treatment decision-making
Oncologists are struggling to determine the most appropriate
candidates for combination chemotherapy, which agents should
be utilized and how 5-FU should be administered. If you treat
many patients with colorectal cancer, it’s easier to
adapt to administering infusional therapy, but in the United
States, the use of infusional therapy has many barriers,
including insurance-related concerns. Randomized studies
will inform us if we need to use infusional 5-FU or if we
can substitute an oral agent, such as capecitabine.
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