Systemic Treatments for Advanced Cutaneous Melanoma

Systemic Treatments for Advanced Cutaneous Melanoma

ABSTRACT: The treatment of advanced cutaneous melanoma remains disappointing. Single-agent cytotoxic drugs usually produce response rates of less than 20%, though newer agents, particularly fotemustine and temozolomide, show some promise, especially in patients with brain metastases. Combination chemotherapy regimens yield response rates of 20% to 40%, but durable complete remissions are uncommon. Interferon-alfa and interleukin-2 alone produce response rates of 10% to 20%, 3% to 5% of which are durable. Vaccines and monoclonal antibodies have low level activity in advanced disease but may play a role in the adjuvant setting. The combinations of cisplatin-based regimens plus IFN-alfa and IL-2 have produced overall response rates of 50% to 60% and complete responses in 20% of patients, about half of which are durable. The toxicity of these regimens is severe, however, and their impact on survival remains to be established. [ONCOLOGY 9(11):1149-1168, 1995]


Cutaneous malignant melanoma is becoming a more common neoplasm.
In 1995, an estimated 34,000 cases of melanoma will be diagnosed
in the United States and 7,200 deaths due to melanoma will occur
[1]. By the year 2000, it is estimated that 1 of every 75 Americans
will be diagnosed with melanoma.

Early primary melanoma is highly curable, but once the disease
becomes widely disseminated, it is nearly always fatal. The survival
time for patients with metastatic disease ranges from 6 to 9 months
when metastases are detected in multiple organ sites. Patients
with skin, subcutaneous tissue, and distant lymph node metastases
have the longest survival, averaging 12 to 15 months, whereas
patients with liver, brain, and bone metastases have a median
survival of only 3 to 4 months [2].

The treatment of metastatic melanoma remains unsatisfactory, and
thus far survival has been determined primarily by the extent
and pace of the disease, rather than by the treatment strategy.
In this article, we provide an overview of the systemic treatment
options for advanced cutaneous melanoma, with emphasis on the
more novel therapeutic approaches.


Single-Agent Chemotherapy

The only single agent approved for the treatment of melanoma is
dacarbazine, which produces response rates of 10% to 20% but results
in complete remission in less than 5% of treated patients [2].
Responses have been observed mainly in soft tissues, ie, skin,
subcutaneous tissue, lymph node, and lung metastases, and are
usually short-lived, ranging from 3 to 6 months. Although complete
responses are rare, approximately one-fourth of complete responders
do attain long-term remissions [2].

The antitumor activity of the nitrosoureas currently available
in the United States-carmustine (BCNU [BiCNU]), and lomustine
(CCNU [CeeNu])-is similar to that of dacarbazine, with response
rates ranging from 10% to 20% [2]. Patients previously exposed
to dacarbazine have an even lower response rate to the nitrosoureas
than do untreated patients.

Fotemustine, a new agent of this class, has recently been studied
in Europe. This novel chloroethyl nitrosourea with an amino acid-phosphonyl
adduct has a mechanism of action involving rapid metabolic conversion
and consequent alkylation of thioenzymes involved in DNA synthesis.
In addition, it rapidly crosses the blood-brain barrier, possibly
through an amino acid transport system. A multicenter phase II
study of fotemustine with 153 assessable patients showed a response
rate of 30% in previously untreated patients and 24% overall [3].
Most importantly, a response rate of 20% was observed in 85 patients
with brain metastases, and some of the responses were durable

Other classes of chemotherapeutic agents with antitumor activity
include the vinca alkaloids and platinum compounds, including
cisplatin (Platinol) and carboplatin (Paraplatin), which have
reported response rates of 10% to 20% [2]. A new lipid-soluble
dihydrofolate reductase inhibitor, piritrexim (taken orally),
produced a response rate of 23% in 31 evaluable patients [5].
Interestingly, responses were seen in previously treated as well
as previously untreated patients.

Taxanes, including paclitaxel (Taxol) and docetaxel (Taxotere),
agents that inhibit disassembly of the microtubule complex, have
also been evaluated in metastatic melanoma. In two phase II trials,
3 complete responses and 4 partial responses were observed among
53 melanoma patients [5]. Docetaxel has produced similar response
rates, with 3 responders in 27 patients studied [6,7]. Further
exploration of the taxanes in combination with other cytotoxic
agents is warranted.

Another new agent, temozolomide, which is entering phase II studies
in the United States, deserves special mention. This agent is
an imidazotetrazine derivative that spontaneously converts in
vivo to MTIC (methyl triazeno imidazole carboxamide), the active
metabolite of dacarbazine, and crosses the blood-brain barrier
efficiently in animal models. Temozolomide has shown significant
antitumor activity in preclinical studies, and responses have
been seen in phase I trials in patients with melanoma (with and
without brain metastases) and in patients with primary brain tumors

A recent European phase II study in 49 assessable patients with
metastatic disease demonstrated a 6% complete response rate and
a 21% total response rate [8]. In this series, four patients had
brain metastases, one of whom attained a partial response. The
possible utility of this agent awaits further phase II data.

Combination Chemotherapy

Based on the independent activity of dacarbazine and the nitrosoureas,
several studies combining the two agents were performed in the
late 1970s. These studies failed to show the superiority of the
combination regimens over dacarbazine alone [2]. Dacarbazine also
has been combined with dactinomycin (Cosmegan), vinca alkaloids,
cisplatin, and fotemustine. The observed response rates with the
two-drug combinations have ranged from 20% to 35%, which are not
clearly superior to response rates achieved with dacarbazine alone

Combinations of three or more drugs with or without dacarbazine
also have been investigated. A three-drug combination regimen
of BCNU, hydroxyurea (Hydrea), and dacarbazine tested by the Southwest
Oncology Group (SWOG) produced an overall response rate of 27%
in 178 patients, with response duration averaging 6 months [2].

A regimen combining bleomycin, Oncovin, lomustine, and dacarbazine
(BOLD), developed in the late 1970s at Duke University, produced
a 40% response rate (9% complete responses) in a total of 72 assessable
patients [2]. Subsequent studies with the BOLD regimen failed
to confirm these initial results, however; overall response rates
in these later studies ranged from 4% to 20% [5].

Among combination chemotherapy regimens not including dacarbazine
that were developed in the late 1970s and early '80s, a combination
of bleomycin (Blenoxane), vinblastine, and cisplatin showed response
rates ranging from 22% to 43% in several trials [2]. More recently,
various groups have reported their results combining dacarbazine,
cisplatin, and a vinca alkaloid (either vinblastine or vindesine
[Eldisine]) [2]. The response rates achieved with this three-drug
combination ranged from 24% to 45%, which appear to be superior
to rates reported with dacarbazine alone.

Phase III Trials--Despite the abundance of phase II studies
exploring different combinations of cytotoxic drugs, there have
been only a limited number of phase III trials comparing dacarbazine
alone with combination chemotherapy or comparing different combination
regimens. The results of these phase III trials are summarized
in Table 1 [9-16]. Except for the SWOG study reported by Costanzi
et al [12], which showed a significant improvement in response
rate for combination chemotherapy vs dacarbazine, all the trials
were extremely small and therefore had insufficient power to detect
significant differences in response rate or survival. In addition,
some of the studies combined dacarbazine with relatively inactive
drugs. Thus, it is not surprising that none of the studies showed
a significant difference in survival and only one study revealed
a significant improvement in response rate.

The final results of the Cancer Community Oncology Program study,
which compares dacarbazine alone with cis-platin, vinblastine,
and dacarbazine (CVD) should be available in the near future [16].
Also, investigators at Memorial Sloan-Kettering Cancer Center
are currently evaluating the combination of cisplatin, BCNU, dacarbazine,
and tamoxifen vs dacarbazine alone. Pending the results of these
and other controlled studies, dacarbazine alone remains the standard
for initial chemotherapy treatment of metastatic melanoma.


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