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Management of Metastatic Cutaneous Melanoma

Management of Metastatic Cutaneous Melanoma

ABSTRACT: The results of treatment for metastatic melanoma remain disappointing. Single-agent chemotherapy produces response rates ranging from 8% to 15%, and combination chemotherapy, from 10% to 30%. However, these responses are usually not durable. Immunotherapy, particularly high-dose interleukin (IL)-2 (Proleukin), has also shown a low response rate of approximately 15%, although it is often long-lasting. In fact, a small but finite cure rate of about 5% has been reported with high-dose IL-2. Phase II studies of the combination of cisplatin-based chemotherapy with IL-2 and interferon-alfa, referred to as biochemotherapy, have shown overall response rates ranging from 40% to 60%, with durable complete remissions in approximately 8% to 10% of patients. Although the results of the phase II single-institution studies were encouraging, phase III multicenter studies have reported conflicting results, which overall have been predominantly negative. Various factors probably explain these discrepancies including different biochemotherapy regimens, patient selection, and, most importantly, “physician selection.” Novel strategies are clearly needed, and the most encouraging ones for the near future include high-dose IL-2 in combination with adoptive transfer of selected tumor-reactive T cells after nonmyeloablative regimens, BRAF inhibitors in combination with chemotherapy, and the combination of chemotherapeutic agents and biochemotherapy with oblimersen sodium (Genasense).

The treatment of advanced melanoma
remains a great challenge,
with patient survival dictated
primarily by the site and pace of
the disease.[1] Patients with melanoma
and distant metastatic disease have
a 5-year survival rate of less than 5%.
Median survival for these patients
ranges from 6 to 9 months, but it can
vary depending on several prognostic
parameters. For instance, patients with
metastases to the skin, subcutaneous
tissue, distant lymph nodes, or lungs
have median survivals ranging from
12 to 15 months, whereas patients with
metastases in the liver, brain, or bones
have median survivals of only 3 to
4 months.[1]

Treatment options include chemotherapy,
immunotherapy, and the
combination of chemotherapy and
interleukin (IL)-2 (Proleukin) and interferon
(IFN)-alfa, referred to as biochemotherapy.
This article will
provide a brief overview of the major
treatment options, with a special focus
on the results of cisplatin-based
biochemotherapy regimens in patients
with advanced melanoma.

Chemotherapy Alone

The most active chemotherapeutic
drugs in the treatment of advanced
melanoma include dacarbazine
(DTIC-Dome), temozolomide (Temodar),
cisplatin, the 2-chloroethylnitrosoureas
(carmustine [BiCNU],
lomustine [CeeNU], and fotemustine),
the vinca alkaloids (vincristine and
vinblastine), and the taxanes (paclitaxel
and docetaxel [Taxotere]).[2]
Observed overall response rates to
these single agents have usually
ranged from 7% to 20%, with complete
remissions observed in fewer
than 5% of patients.[2] Furthermore,
responses are usually not durable. Although
no single agent is clearly more
active than dacarbazine alone, a recent
randomized phase III study comparing
dacarbazine (n = 117) with
fotemustine (n = 112) showed a trend
for a higher response rate (15.5% vs
7.2%, P = .053) and overall survival
(7.4 vs 5.8 months, P = .073) favoring
the fotemustine arm.[3]

Temozolomide is an imidotetrazine
derivative that, at physiologic pH,
spontaneously converts to MTIC, the
active metabolite of dacarbazine.[2]
It has the advantages of being absorbed
orally and possessing better
central nervous system penetration.
In a phase II study in patients with
metastatic melanoma, temozolomide
was well tolerated and produced objective
responses in 21% of patients,
including complete responses in
5%.[4] Of interest, one of four patients
with cerebral metastases exhibited
a partial response.

A subsequent phase III trial compared
temozolomide (200 mg/m2/d
orally for 5 days every 4 weeks) to
dacarbazine (250 mg/m2/d intravenously
for 5 days every 3 weeks) in
305 patients without brain metastases.[
5] Temozolomide produced apparent
improvement in median
progression-free survival (1.9 vs 1.5
months) and health-related quality of
life relative to dacarbazine, but had
no significant impact on response rate
(13.5% vs 12.1%) or overall survival
(7.7 vs 6.4 months).[5] Of note, in a
subset of patients who had regularly
scheduled computed tomography scans
of the head, fewer central nervous system
relapses were observed in the patients
receiving temozolomide.

Using novel dosing schedules and
combinations, investigations of temozolomide
are continuing. Regimens
involving multiple doses per day or
prolonged daily exposure have been
studied in an effort to circumvent
DNA repair processes and more optimally
coordinate with radiation therapy
schedules. A temozolomide dose
of 75 mg/m2 daily for 6 weeks has
been determined to be the maximum
tolerated dose for the prolonged daily

The pilot experience of Hwu et al
suggested a synergistic interaction
between temozolomide and thalidomide
(Thalomid). The authors subsequently
conducted a phase II study of
temozolomide, 75 mg/m2/d for 6
weeks, with thalidomide, 200 mg at
bedtime (escalating to 400 mg if well
tolerated), in 38 patients without brain
metastases. They observed 1 complete
and 11 partial responses, for an overall
response rate of 32%.[6]

The results of a randomized phase II
study with a total of 180 patients
assigned to temozolomide alone, temozolomide
plus IFN-alfa, and temozolomide
plus thalidomide showed
overall response rates of 9%, 18%,
and 15%, respectively, providing further
support for a synergistic interaction
between temozolomide and
thalidomide.[7] Furthermore, temozolomide
and thalidomide were better
tolerated than temozolomide and IFNalfa.
Hwu et al[8] more recently reported
preliminary data in patients
with central nervous system metastases
and identified two complete responses
and one partial response
among 11 treated patients. These data
are clearly encouraging, and this combination
is undergoing further evaluation
by other investigators.

Another interesting and promising
strategy is the combination of
dacarbazine with bcl-2 antisense
(oblimersen sodium, Genasense).[9]
Preliminary results of a recently completed
phase III randomized trial
comparing dacarbazine alone vs dacarbazine
plus oblimersen were recently
released.[10] A total of 771 patients
were included in this large study, which
showed an increased response rate
(11.7% vs 6.8%, P = .019) and time to
progression (74 vs 49 days, P = .0003)
for the combination arm but only a
trend toward improved overall survival
(9.1 vs 7.9 months, P = .18).

Other Combinations
The next step will be to incorporate
oblimersen with other agents,
particularly in biochemotherapy strategies.
Most chemotherapeutic agents
are inactive in previously treated patients.
Paclitaxel, however, has shown
activity even in patients who failed
prior chemotherapy. For instance,
Zonder et al[11] reported a 13% response
rate with weekly paclitaxel
(150 mg/m2 over 1 hour for 6 weeks
followed by 2 weeks' rest) among 15
treated patients and Bedikian et al[12]
reported a response rate of 15.6% in
32 assessable patients treated with a
regimen of paclitaxel at 90 mg/m2 IV
over 80 minutes every 4 days for three
cycles, repeated every 3 weeks.

Combination chemotherapy, including
well-known regimens such as CVD
(cisplatin/vinblastine/dacarbazine) and
the Dartmouth regimen (cisplatin/carmustine/
dacarbazine/tamoxifen), has
produced responses in about 10% to
30% of patients (in phase III studies),
but durable complete responses have
been rare.[2] In three phase III studies
comparing combination chemotherapy
with single-agent dacarbazine, results
showed only a slight increase in response
(not statistically significant) favoring
the chemotherapy combination
but no improvement in overall survival.[
2] In this author's opinion, combination
chemotherapy should be
considered when the objective response
is important, as for instance, in patients
with metastases in the head and neck
region or brachial plexus involvement.

Immunotherapy Alone

The disappointing results observed
with chemotherapy alone shifted the
attention of many investigators to the
biologic agents, of which IFN-alfa and
IL-2 have been the most extensively
studied. High-dose IL-2 results in
overall responses in approximately
15% of patients, with durable remissions
in about 5%.[13,14] Despite the
low response rate, high-dose IL-2 has
curative potential.

Because the response rate to highdose
IL-2 is low and toxicity high,
great effort has been made to identify
predictors of response. The National
Cancer Institute (NCI) experience sug-
gests that patients with only subcutaneous
and/or skin metastases have a
significantly higher chance of responding
(overall response: 53%)
compared with patients with visceral
metastases (overall response: 10% to
15%).[15] Furthermore, a recent study
from the NCI suggested that pretreatment
molecular profiling may allow
us to better separate responders from
nonresponders.[16] Lower-dose IL-2
regimens, IFN-alfa, or other immunotherapy
approaches have generally
produced lower response rates and few
durable remissions.[17]

Based on preclinical data that suggested
a synergistic interaction between
IFN-alfa and IL-2, these biologics have
been combined in various clinical studies
of patients with advanced melanoma.
Overall response rates have ranged
from 10% to 41%, with the average
being 20%.[2] In a small randomized
trial, however, the combination of IL-2
plus IFN-alfa failed to produce a statistically
significant higher response rate
than IL-2 alone.[18]

Novel Strategies
A promising and novel strategy was
recently reported by Rosenberg's
group and consisted of adoptive transfer
of highly selected tumor-reactive
T cells directed against overexpressed
self-derived differentiation antigens
after a nonmyeloablative regimen with
cyclophosphamide (Cytoxan, Neosar)
and fludarabine (Fludara).[19] Of 13
patients who previously failed standard
therapy, including high-dose
IL-2, 6 achieved a partial response.
Five of the responders demonstrated
signs of autoimmune reaction such as
vitiligo and anterior uveitis. This approach,
although complex and expensive,
is very promising and will likely
be evaluated in other cancers.

High-dose IL-2 (NCI regimen) was
also evaluated in patients who failed
prior biochemotherapy. In the University
of Pittsburgh experience, of 18 patients
treated, 3 achieved a complete
remission.[20] In our experience at the
Hospital Sirio-Libanes, of 10 patients
treated, 1 patient achieved a complete
remission of 6-month duration, and 3
achieved a partial response. All responses
were of rapid onset. A representative
patient, who did not respond
to concurrent biochemotherapy and
achieved a solid partial response to
high-dose IL-2 is shown in Figure 1.

Another strategy still under evaluation
is the combination of subcutaneous
IL-2 with histamine dihydrochloride.
A subgroup analysis of a randomized
phase III trial comparing subcutaneous
IL-2 therapy with and without histamine
suggested an improvement in
overall survival in patients with liver
metastases.[21] This finding, however,
remains to be confirmed by another
randomized trial specifically addressing
this patient cohort.


The limited results observed with
chemotherapy and immunotherapy
alone have prompted many investigators
to empirically combine chemotherapy
drugs with IL-2 and IFN-alfa,
referred to as "biochemotherapy" or
"chemoimmunotherapy."[1] Of all the
currently employed treatment modalities
for metastatic melanoma, cisplatin-
based regimens combined with
biologic agents such as IFN-alfa and
IL-2 appear to have attained the highest
response rates.[1] The combination
of IL-2 or IFN-alfa with non-cisplatinbased
regimens was disappointing and
rapidly abandoned.

Phase II Studies of Cisplatin-
Based Biochemotherapy

Phase II studies of cisplatin-based
biochemotherapy regimens have
shown overall response rates ranging
from 40% to 60%, with complete remission
rates on the order of 10% to
20%.[22-34] Durable remissions exceeding
5 years were seen in approximately
5% to 10% of patients. Of
interest, relapses occurring beyond
2 years were distinctly uncommon,
suggesting that these patients exhibiting
durable responses may be
"cured."[22,24-26] Furthermore, re
sponse to biochemotherapy is usually
rapid and observed after the first cycle.
A representative case is shown in
Figure 2.

The results of select phase II studies
with IL-2 administered intravenously
are shown in Table 1.[22-28,32-34]
One of the most popular regimens
developed at M. D. Anderson Cancer
Center is the CVD regimen administered
concurrently with IL-2 and IFNalfa
for a maximum of six cycles.
Tumor responses were observed in
34 of 53 patients (64%), with 20%
complete responses and 9% durable
complete responses.[25] In another
study, this regimen was modified in
an effort to reduce toxicity. Modifications
included antibiotic and granulocyte
colony-stimulating factor (G-CSF
[Neupogen]) prophylaxis, prohibition
of long-term central venous access,
and restriction to a maximum of four
cycles of therapy. Tumor responses
were seen in 19 of 40 evaluable patients
(response rate: 48%) including
8 complete responses.[28] Biochemotherapy
was also evaluated as secondline
therapy in melanoma patients and
found to have negligible activity in
this patient population, producing an
overall response rate of only 6% compared
with 37% in previously untreated

O'Day et al recently reported the
use of IL-2 and granulocyte macrophage
colony-stimulating factor (GMCSF
[Leukine]) as maintenance
therapy in patients who achieved a
partial response or stable disease on
biochemotherapy. Preliminary results
of this pilot experience were encouraging
in terms of progression-free and
overall survival, compared with historical
controls.[35] A larger phase II
multicenter trial has been initiated in
an effort to confirm these results.

  • Efforts to Reduce Toxicity-Many
    of these biochemotherapy regimens require
    inpatient treatment because they
    have substantial toxicity. A number
    of investigators have endeavored to
    develop regimens with less toxicity
    that could be administered in the outpatient
    setting (Table 2).[29-32,36]
    They simplistically replaced IL-2 administered
    intravenously with the
    subcutaneous route and frequently
    reduced the IL-2 dose to improve
    tolerance. Unfortunately, biochemotherapy
    regimens involving subcutaneous
    administration and lower doses
    of IL-2 appear to produce lower response
    rates than were generally
    observed with regimens involving intravenous

    For example, Flaherty et al[32] reported
    the results of a randomized
    phase II trial of two outpatient biochemotherapy
    regimens involving
    dacarbazine, cisplatin, and IFN-alfa
    with IL-2 administered either intravenously
    or subcutaneously. There were
    16 responses including 5 complete
    responses in the 44 patients who received
    the IV IL-2 regimen (response
    rate: 36%), compared with only 6 responses
    (including 1 complete) in the
    36 patients assigned to receive the
    subcutaneous IL-2 regimen (response
    rate: 17%).[32]

    In addition, a study in which patients
    were randomly assigned to receive
    either the Dartmouth regimen
    or the Dartmouth regimen preceded
    by IL-2 administered subcutaneously
    (day -2 to 0) and followed by IFNalfa
    (days 1 to 3) showed no difference
    in response rate (22% for
    biochemotherapy vs 27% for the Dartmouth
    regimen alone), median duration
    of response (2.8 vs 2.5 months),
    or survival (5 vs 5.5 months).[36] The
    lower overall response rates for the
    biochemotherapy regimens involving
    subcutaneous IL-2 in these two studies
    relative to the intravenous IL-2
    biochemotherapy regimens mentioned
    previously suggest a potential schedule,
    dose, and route of administration
    effect for IL-2 in biochemotherapy

Results of Meta-analysis
Two recent meta-analyses suggested
improved response rates and
possibly improved survival for combinations
involving cisplatin, IL-2, and
IFN-alfa, compared with either chemotherapy
or immunotherapy alone.
In one analysis of 631 patients, biochemotherapy
regimens produced
a response rate of 45% compared to
21% and 15% with IL-2 and IFN or
IL-2 alone, respectively. Survival,
however, was not significantly different
between groups (10.5 months),
with 20% and 10% survival rates at 2
and 5 years.[37]

Another meta-analysis that analyzed
154 studies involving over 7,000
patients revealed the highest response
rate of 47% for patients who received
cisplatin, dacarbazine, IL-2, and IFNalfa.[
38] The results of these two metaanalyses
clearly support the phase II
data that show a higher response rate
for biochemotherapy compared to chemotherapy
or immunotherapy alone.


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