Metastatic Melanoma: Chemotherapy

Emilio Bajetta, Michele Del Vecchio, Chantal Bernard-Marty, Milena Vitali, Roberto Buzzoni, Olivier Rixe,
Paola Nova, Stefania Aglione, Sophie Taillibert, and David Khayat

The incidence of cutaneous melanoma has been rapidly MONOCHEMOTHERAPY

increasing, with an estimate of 47,700 new cases diag-
nosed in 2000 in the United States. In the early phase of
its natural history, melanoma is cured in most cases by
surgery, but once the metastatic phase develops, it is
almost always fatal. The treatment of metastatic mel-
anoma remains unsatisfactory. Systemic therapy has
not been successful up to now, with very low response
rates to single-agent chemotherapy. Polychemo-
therapy has increased the response rate (RR), without
a significant improvement in overall survival. Immuno-
therapy alone is able to induce only a few durable
complete responses (CRs). New chemotherapeutic and
biologic agents are now available and promising com-
bined approaches targeting the tumor by several dif-
ferent mechanisms are desirable and will probably rep-
resent the future modality of treatment.
Semin Oncol 29:427-445. Copyright 2002, Elsevier Science
(USA). All rights reserved.
M ELANOMA IS NOTABLE for its rapid rise
in incidence worldwide, with a yearly in-
crease of about 5%, and for its frequent occurrence
in young adults. Furthermore, melanoma has high
mortality rates in the advanced phase of its natural
and clinical history.1
Even if surgery represents the cure in the early
phase of disease, the prognosis in the metastatic
phase remains very poor. Currently, disseminated
melanoma is not curable. In fact, the median sur-
vival of stage IV patients is about 6 to 7.5 months,
with a 5-year survival of approximately 6%, so that
not cure, but rather maintenance of a good quality
of life is the primary objective of the medical
treatments in this phase of disease. Currently, mul-
tiple therapeutic approaches are used in patients
with metastatic melanoma, including chemother-
apy and biologic therapies, both as single treat-
ments and in association.
Advanced melanoma has a poor prognosis. Che-
motherapy is ineffective in most cases because of
the intrinsic/extrinsic resistance of melanoma
cells. Nevertheless, the mechanisms underlying
such a chemoresistant cell phenotype remain
mostly unknown. Human melanomas may have
altered apoptotic pathways and fewer proapoptotic
molecules.2
This review will analyze the currently available
therapeutic options and discuss ongoing and future
possibilities.
Systemic medical management has failed to sig-
nificantly improve the survival of patients with
nonresectable melanoma. The chemotherapeutic
agents with reproducible activity against mela-
noma include dacarbazine (DTIC), the platinum
analogs, various nitrosoureas, and tubular toxins,
such as vinca alkaloids and taxanes.3,4 The activities
of the various agents are summarized in Table 1.
DTIC and Analogs
Dacarbazine or dimethyl-triazeno-imidazol car-
boxamide (DTIC) is the most active single agent,
with a response rate (RR) of about 20%.5,6 How-
ever, complete responses (CRs) are rare (ⱕ5%),
with higher percentages in patients bearing cuta-
neous/subcutaneous and lymph node disease. The
median response duration is only 4 to 6 months.
DTIC is globally well tolerated, and its major side
effects are limited to nausea and vomiting. Bone
marrow suppression is modest (with a nadir of
leukocytes and platelets in the third or fourth
week), and both alopecia and fatigue are minimal,
allowing most patients to maintain their normal
level of activity while undergoing therapy. Photo-
sensitivity is more likely to occur when single high
dosages are used. Long-term follow-up of patients
treated with DTIC alone shows that less than 2%
can be anticipated to survive for 6 years. Vein
thrombosis and hepatic necrosis are rare. DTIC
remains the only cytotoxic drug approved by the
US Food and Drug Administration (FDA) for the
treatment of metastatic melanoma.
Commonly used schedules of DTIC include 200
to 250 mg/m2/d administered intravenously (IV)
for 5 consecutive days, or 850 to 1,000 mg/m2 IV
From the Medical Oncology Unit B, Istituto Nazionale per lo
Studio e la Cura dei Tumori, Milan, Italy; and the Department of
Medical Oncology, Pierre et Marie Curie University, Paris, France.
Address reprint requests to Professor Emilio Bajetta, Director of
the Operative Unit of Medical Oncology B, Istituto Nazionale per
lo Studio e la Cura dei Tumori, via Venezian 1, 20133 Milan,
Italy.
Copyright 2002, Elsevier Science (USA). All rights reserved.
0093-7754/02/2905-0002$35.00/0
doi:10.1053/sonc.2002.35238

Seminars in Oncology, Vol 29, No 5 (October), 2002: pp 427-445 427

428 BAJETTA ET AL

Table 1. Clinical Trials of Single-Agent Chemotherapy Other Than Dacarbazine in Melanoma

No. of Evaluable Objective RR

Drug Dose Patients No. of PRs No. of CRs (%)

Alkylating agents and nitrosoureas

Estramustine 12 mg/kg 26 3 0 12
Ifosfamide 1.2-3 g/m2 48 3 1 8
Mitolactol (dibromodulcitol) 100-1800 mg/m2 139 8 2 7
Lomustine (CCNU) 130 mg/m2 41 4 1 12
Semustine (methyl CCNU) 40-225 mg/m2 47 10 1 23
Carmustine (BCNU) 75-110 mg/m2 66 6 2 12
Chlorozotocin 120-175 mg/m2 161 12 4 10
Fotemustine 100 mg/m2 69 17 2 26
Hormonal agents
Tamoxifen 20 mg/d-100 mg/m2 172 7 5 7
Megestrol 500 mg/day 20 0 0 0
Plant-derived agents
Paclitaxel 125-275 mg/m2 63 10 2 19

over 1 hour on day 1 only, with cycles of DTIC
administered every 3 to 4 weeks. The use of new
powerful antiemetic agents has significantly re-
duced the emetogenic effects of DTIC, allowing
the more convenient 1-day schedule of therapy to
be administered in an outpatient setting. In our
institutions (Istituto Nazionale Tumori [INT] of
Milan and Salpêtrière Hospital of Paris), we use
DTIC monochemotherapy in elderly patients with
a limited performance status or concomitant dis-
ease.
A randomized phase III trial using dacarba-
zine ⫾ Bcl-2 antisense oligodeoxynucleotide
G3139 in stage III/IV melanoma patients is ongo-
ing in order to facilitate DTIC killing by making
tumor cells more sensitive to the drug.7
Currently in the advanced phase of evaluation,
the imidazotetrazinic derivative, temozolomide
(TMZ), a dacarbazine analog, shows five potential
advantages related to its pharmacokinetic and bio-
chemical properties8: (1) high oral bioavailability;
practically, 100% of the orally administered dosage
enters into the bloodstream. This results in better
compliance and patient acceptability of the treat-
ment, with a consequent favorable impact on the
quality of life. (2) Spontaneous conversion, at
physiologic pH, into the active metabolite methyl-
triazeno-imidazole-4-carboxamide (MTIC) via a
process that does not require metabolic activation;
on the contrary, DTIC needs the intervention of
the cytocrome P450-dependent hepatic microso-
mal enzymatic system. (3) Ability to cross the
blood-brain barrier reaching the central nervous
system (CNS) at a pharmacologically active con-
centration. Its concentration in the CNS is ap-
proximately 28% to 30% of its plasma concentra-
tion. This property of penetration of third spaces
(such as CNS other than ascites fluid) was dem-
onstrated in several different animal models and,
in particular, in Rhesus monkeys, that represent a
predictive model of the pharmacokinetics in hu-
man cerebrospinal fluid (CSF). In such a model,
the diffusion was approximately 30% to 40%. (4)
TMZ is associated with a myelosuppression gener-
ally less severe and not cumulative, if compared to
that induced by nitrosoureas and other alkylating
agents. (5) Greater possibility of dose/schedule
modulation.
In a phase I/II study of 60 patients with ad-
vanced disease, Bleehen et al observed three CRs
and nine partial remissions (PRs), with a global
RR of 21%.9 The CRs were obtained in patients
bearing lung metastases, while a PR was observed
in brain metastases. The median response duration
was 5.5 months (range, 0.5 to 29.5⫹ months).
TMZ was generally well tolerated, with moderate
hematologic toxicity.
A large European multicenter phase III trial
prospectively compared the clinical activity of
TMZ (200 mg/m2/d for 5 consecutive days, every 4
weeks) versus that of DTIC (250 mg/m2/d for 5
consecutive days, every 3 weeks), in previously
CHEMOTHERAPY IN MELANOMA
untreated patients with metastatic melanoma. The
results of the two treatments nearly overlapped in
terms of RR, toxicity profile, time to progression
(TTP), and overall and disease-free survivals (OS
and DFS); nevertheless, TMZ showed an advan-
tage in terms of improvement in the quality of
life.10
A case report from Italy described a near CR of
multiple brain metastases (0.5 to 1 cm in size) in a
melanoma patient after six cycles of TMZ at a dose
of 200 mg/m2/d for 5 days every 4 weeks.11
TMZ has also been examined in phase I trials in
association with cisplatin (CDDP) and has been
shown to be safe at the studied dosages.12
There are many ongoing trials and new propos-
als using TMZ.13 The INT in Milan is currently
investigating TMZ in brain metastases from mel-
anoma/non–small cell lung cancer (NSCLC)/
breast cancer, in patients pretreated with whole-
brain or stereotactic radiotherapy (RT) (a wash-
out period of 4 weeks is requested prior to starting
chemotherapy) and in patients not previously
treated with RT. The TMZ dose is 150 mg/m2/d
for 7 consecutive days every other week. There are
suggestions that admininistration of TMZ in mul-
tiple doses per day or as a prolonged daily admin-
istration may overcome some chemotherapy drug-
resistance mechanisms.
An ongoing trial by the European Organization
for Research and Treatment of Cancer (EORTC)
is examining the ability of TMZ associated with
whole-brain RT to induce clinical responses.14
Another objective could be the reduction of the
RT daily fraction dosage, thereby decreasing the
medium- to long-term sequelae related to RT.
Other trials are investigating the use of polyche-
motherapy regimens containing TMZ, especially
as first-line therapy in stage IV patients with brain
metastases in association with metastases in other
sites; TMZ associated with other chemotherapeu-
tic agents (eg, carboplatin at Mount Vernon Hos-
pital), or angiogenesis inhibitors (eg, thalidomide,
National Cancer Insitute [NCI]/Memorial Sloan-
Kettering Cancer Center) in stage IV or stage III
unresectable disease; combination with alkyl-
O6alkylguanine transferase (AGT)-depleting agents
(O6-benzylguanine [BG]); and association with
other drugs potentially effective in preventing or
treating brain metastases, such as fotemustine.
429
Cisplatin and Carboplatin
Cisplatin and carboplatin have shown modest
activity in patients with metastatic melanoma.
Cisplatin, as single-agent therapy, induced a 15%
to 16% RR with a short median duration (3
months).15,16 The well-known side effects of cis-
platin are nephrotoxicity, neurotoxicity, ototoxic-
ity, vomiting, and myelosuppression. Evidence
that the activity of cisplatin may be dose-depen-
dent has come from a review of single-arm studies.
Cisplatin administered at doses up to 150 mg/m2
in combination with amifostine (WR2721), a
thiol derivative with protective effects on bone
marrow and kidney, produced tumor responses in
53% of patients.17 However, responses were all
partial, and the median response duration was only
4 months.
A randomized phase II trial conducted by the
Eastern Cooperative Oncology Group (ECOG)
compared cisplatin at 150 mg/m2 plus amifostine
to cisplatin alone at 120 mg/m2. While both reg-
imens showed activity, unacceptable renal and
gastrointestinal toxicity, as well as ototoxicity,
were observed on both treatment arms.18
In our experience, high-dose cisplatin (40 mg/
m2/d IV for 4 consecutive days every 3 weeks, with
a maximum of six courses) in association with
reduced glutathione and natural interferon alpha
(IFN-␣) in DTIC-resistant metastatic melanoma
patients resulted in such toxicity that accrual was
stopped and none of the patients completed the
therapeutic program. There were two PRs and two
patients with stable disease among 12 treated.19
Carboplatin has been less extensively tested in
melanoma,20 and its value relative to cisplatin,
DTIC, TMZ, or other single agents remains to be
determined.
The combination of cytarabine (Ara-C) with
both cisplatin and carboplatin showed limited ac-
tivity in the treatment of metastatic melanoma
patients, and the cost-benefit ratio was detrimen-
tal.21,22
Guven et al treated 15 DTIC-resistant meta-
static melanoma patients with a combination reg-
imen of cisplatin (100 mg/m2) and carboplatin
(200 mg/m2) in order to increase the platinum
dose while avoiding severe side effects.23 At a
median follow-up of 10.7 months (range, 4 to 18
months), two patients were in CR and two in PR,
for an overall RR of 26.4%. Furthermore, three
430
Table 2. Efficacy of Fotemustine as Monotherapy
No. of Evaluable % RR
Study Patients (CR ⫹ PR)
Jacquillat24 153 24
Calabresi25 30 20
Retsas26 24 17
EORTC27 125 12
Schallreuter28 19 47
Total 351 20%
95% confidence interval (16%-24%)
patients had SD. The median response duration
was 7.1 months, and the median OS was 12.5
months, with eight patients still alive at the time
of publication. The most notable side effects were
hematologic (especially leukopenia and thrombo-
cytopenia), gastrointestinal, and neurologic. Nev-
ertheless, in all but one patient, the therapy was
not interrupted. The authors concluded that even
on a small sample size in this preliminary study,
such a combined chemotherapy represents an ac-
tive and well-tolerated therapeutic option as sec-
ond-line treatment in DTIC-resistant metastatic
melanoma patients.
Nitrosoureas
Nitrosoureas (carmustine [BCNU], lomustine
[CCNU], and semustine [methyl CCNU]) are ac-
tive single agents, inducing a variable percentage
of objective responses from 13% to 18%.15,16 Con-
sidering their ability to cross the blood-brain bar-
rier, the potential advantage of such drugs was
their activity on brain metastases, but that does
not happen in clinical practice at the conven-
tional dosages. Furthermore, this category of anti-
cancer drugs induces a prolonged myelodepression
(especially thrombocytopenia), with a late nadir
even after 4 to 5 weeks.
Fotemustine (FTMU) is probably the most ac-
tive nitrosourea in metastatic melanoma; it has
been demonstrated to cross the blood-brain barrier
significantly due to its chemical characteristics.
FTMU was tested as monotherapy in five phase II
trials on 351 patients24-28; the RR was 20% to 25%
with a CR rate of 5% to 8%. Notably, it was the
first drug to show significant efficacy in brain me-
tastases (average RR of 21%). The median re-
BAJETTA ET AL
Median Response Duration % Brain RR/No. of Patients
(weeks; range) With Brain Metastasis
22 (7-80) 9/36
20 (12-60) 1/4
23 (16-35) 1/9
26 (17-70) 5/30
18 (13-52) 2/4
18-26 18/83 (21%)
12%-30%
sponse duration ranged from 18 to 26 weeks (Ta-
ble 2). FTMU induced a 30.7% RR in patients at
first disease relapse.
The recommended schedule includes an induc-
tion treatment with FTMU 100 mg/m2 IV over 1
hour, once a week, for 3 consecutive weeks, fol-
lowed by a period of rest (4 weeks), and then
maintenance treatment (same dose every 3 weeks)
started on day 56. The toxicity of FTMU is mostly
hematologic, with 35% grade 3 to 4 thrombocyto-
penia (nadir, day 35) and 45% grade 3 to 4 neu-
tropenia (nadir, day 44). Eight percent of patients
present grade 3 to 4 nausea/vomiting.
Vinca Alkaloids
Among these microtubule toxins, the most fre-
quently used drugs are vindesine and vinblastine.
RR is about 14%. This activity has led to their
use in some combination chemotherapy and
biochemotherapy regimens. Peripheral neuro-
pathy and myelodepression are the main side ef-
fects.15,16,29
Taxanes
Recently, the activity of the taxanes (paclitaxel
and docetaxel) has been analyzed. The RR was
16% to 17%.30,31 Although further studies are
needed to confirm these results, the available data
have led to the use of paclitaxel as second- or
third-line chemotherapy.
An analog of paclitaxel, BMS-184476, is cur-
rently under investigation in an international mul-
ticenter phase II trial, including the INT. The
rationale underlying such a trial is based on some
pharmacokinetic and pharmacodynamic peculiar-
ities of this analog when compared to the classic
CHEMOTHERAPY IN MELANOMA
taxanes. In particular, we have to consider a supe-
rior antitumor activity in several in vitro tumor
models, including tumor cells with the multidrug
resistance (MDR) phenotype, a potentially lower
neurotoxicity, and a lower risk of hypersensitivity
reactions due to its higher solubility in aqueous
cosolvent system containing surfactant. In this
phase II study, metastatic melanoma patients pre-
viously treated with DTIC/interleukin-2 (IL-2) re-
ceive BMS-184476 at a dosage of 50 mg/m2 on
days 1 and 8 every 4 weeks. Tumor status is reas-
sessed following two cycles, and, in case of objec-
tive response or SD, the patient can receive up to
12 courses of treatment.
Another taxane derivative, epothilone, is being
tested in an international phase II study, including
the Salpêtrière Hospital in Paris, in metastatic
melanoma patients who have failed to respond to
IL-2– based treatment.
A liposoluble inhibitor of dihydrofolate-reduc-
tase, piritrexim, orally administered, induced a re-
sponse rate of 23% in 31 evaluable patients, which
included two CRs and five PRs.32 Interestingly,
these responses were obtained both in previously
untreated and in previously treated patients.
In an alternating dose schedule, piritrexim and
DTIC produced a poor RR.33
HORMONAL THERAPY
The natural history of melanoma, as well as
some epidemiologic data, suggest a certain rela-
tionship with the estrogens. Melanoma is infre-
quently seen before puberty, with the exception of
familial cases, and the peak incidence in females
coincides with the late childbearing years and the
beginning of menopause. Some cases of spontane-
ous regression following parturition or periods of
widespread dissemination during pregnancy have
been reported. In addition, females, especially in
postmenopausal status, have a more favorable
prognosis in terms of better survival rates. Estrogen
receptors are present in benign nevi of melanoma
patients and in tumor cells, but not in benign nevi
from normal individuals. These data support the
hypothesis that melanoma is estrogen-dependent,
and that binding the estrogen receptor could result
in a molecular alteration associated with the neo-
plastic transformation of normal, benign nevi.
Other investigators have failed to confirm these
findings.34
Tamoxifen, an agent with antiestrogen activity,
431
alone at standard or high doses has little activity in
metastatic melanoma.35
POLYCHEMOTHERAPY
The role of polychemotherapy in the treatment
of metastatic melanoma remains uncertain. Sev-
eral different combination regimens of singly ac-
tive agents have been evaluated in single-institu-
tion phase II trials, with objective RRs in limited
series of 30% to 50%.36 The polychemotherapeu-
tic schemes have been realized by combining ac-
tive single agents. The more commonly tested
combinations are presented in Table 3. A clear
synergistic or additive effect could not be demon-
strated. It is important to emphasize that most of
the clinical responses obtained using polychemo-
therapy are of short duration and quite similar to
those observed in the monochemotherapy setting.
Two of the most active regimens reported are the
three-drug combination of cisplatin/vinca alkaloid/
DTIC (CVD) and the four-drug combination of cis-
platin/DTIC/BCNU/tamoxifen (CDBT).37-39
The CVD regimen, which consists of DTIC,
cisplatin, and a vinca alkaloid (vinblastine in the
version developed by Legha and coworkers at the
M.D. Anderson Cancer Center and vindesine in
the Italian version of the Biological Response
Modifier in Melanoma [BREMIM] group) induced
a RR of 35% to 40%.37 In Legha’s studies, the CR
rate was 4%, with a median response duration of 9
months.
In a randomized multicenter trial of CVD versus
DTIC alone, which recruited approximately 150
patients, the CVD arm induced a RR of 19%
compared with 14% in the other arm. There were
no differences in response duration or survival.40
In a feasibility trial, we used cisplatin (30 mg/
m2/d for 3 consecutive days) plus vindesine (2.5
mg/m2 on day 1 only) plus DTIC (250 mg/m2/d for
3 consecutive days) every 3 weeks plus IFN-␣ (3
MIU intramuscularly three times per week contin-
uously) versus DTIC (800 mg/m2 on day 1) plus
IFN-␣ at the same dosage.41 We recruited 51 mel-
anoma patients (50 of whom were evaluable) and
observed three CRs, two PRs, and five SD in the
CVD arm versus two PRs and four SD in the
DTIC arm. The treatment was well tolerated in
both of the arms. No grade 4 nonhematologic
toxicity was observed. Grade 3 hypotension and
anorexia occurred in 2% of patients treated with
the CVD regimen. Grade 2 peripheral neuropathy
432 BAJETTA ET AL

Table 3. Clinical Trials of Combination Chemotherapy in Melanoma

No. of Evaluable Objective RR

Drug Dose Patients No. of PRs No. of CRs (%)

DTIC and cisplatin combination 130 27 6 25

DTIC 200-750 mg/m2
Cisplatin 15-100 mg/m2
DTIC and cisplatin combinations with vindesine 155 38 11 32
DTIC 250-450 mg/m2/d
Cisplatin 50-100 mg/m2/d
Vindesine 3 mg/m2/d
DTIC and cisplatin combinations with vinblastine 157 30 5 22
DTIC 150-800 mg/m2
Cisplatin 20-50 mg/m2
Vinblastine 1.6-5 mg/m2
DTIC and cisplatin combinations with BCNU 20 1 1 10
DTIC 220 mg/m2 qod
Cisplatin 25 mg/m2 qod
BCNU 150 mg/m2/6 wk
Vinblastine/bleomycin/cisplatin combination 20 0 0 0
Vinblastine 6 mg/m2
Bleomycin 15 mg/m2
Cisplatin 50 mg/m2
Vinblastine/bleomycin/cisplatin combination with
DTIC and DBD 42 10 1 26
Vinblastine 3-6 mg/m2
Bleomycin 15 mg/m2
Cisplatin 50 mg/m2
DTIC 800 mg/m2
DBD 125 mg/m2
BCNU/DBD combination 20 3 1 20
BCNU 180 mg/m2
DBD 100 mg/m2
Cisplatin-based agents with tamoxifen therapy 40 17 4 53

Abbreviations: DTIC, dacarbazine; BCNU, carmustine; DBD, dibromodulcitol.

affected only 2% of cisplatin-treated patients. De-
lay but not dose reduction or use of growth factors
was necessary in some cases for grade 3 to 4 my-
elotoxicity. Only one case of grade 4 neutrothrom-
bocytopenia was observed in the CVD arm. Neu-
tropenia was reversible and not associated with
infections; therefore, no antibiotic therapy was
administered. Neutropenia did not last more than
2 weeks. Analogous comments can be made for
thrombocytopenia, which did not cause hemor-
rhagic sequelae. The observation of clinical activ-
ity and an acceptable toxicity profile for this CVD
regimen lead to its use in the biochemotherapeutic
setting in association with IL-2 and IFN for the
first-line treatment of patients with metastatic
melanoma.
Another active combination is the four-drug
regimen of cisplatin, DTIC, BCNU, and tamox-
ifen (CDBT or Dartmouth regimen) developed by
Del Prete et al at Dartmouth University.38 Patients
were treated with cisplatin 25 mg/m2 and DTIC
220 mg/m2 IV daily for 3 days every 3 weeks,
BCNU 150 mg/m2 IV every 6 weeks, and tamox-
ifen 10 mg orally twice daily continuously. The RR
was 46% among 141 patients (16 CRs and 49
PRs), with a median response duration of more
than 7 months. Side effects included mild to mod-
erate bone marrow suppression and moderate nau-
sea and vomiting predominantly on day 1 of each
cycle.
The impression that polychemotherapy does
not yield results clinically superior to those of
monochemotherapy was confirmed in the recent
publication of an ECOG randomized study. The
CHEMOTHERAPY IN MELANOMA
association of polychemotherapy and endocrine
therapy (Dartmouth regimen) was studied and the
results were not significantly different in terms of
RR and survival compared to those of DTIC
alone.42 The benefit of tamoxifen was attributed to
the potentiation of the action of the cytotoxic
chemotherapy rather than to tamoxifen’s anties-
trogenic effects. Unfortunately, over the past sev-
eral years, as data from larger clinical studies have
accumulated, the high RRs reported in the initial
studies have not been reproduced. A phase II study
performed by the Southwest Oncology Group
(SWOG) evaluated the activity of the Dartmouth
regimen in 79 previously untreated metastatic
melanoma patients. The overall RR was only 15%
(95% confidence interval, 8% to 25%) and the
median survival was 9 months. Toxicities were
significant and appeared to be higher compared to
the historic experience with single-agent therapy.
In an Italian multicenter trial, the DTIC/anties-
trogen regimen was significantly superior to DTIC
alone in terms of responses and survival, chiefly
among females.43 Successive randomized trials
have not confirmed such data (North Central
Cancer Treatment Group [NCCTG] and Mayo
Clinic study, Creagan et al).44 Among 117 pa-
tients in the Italian trial, the RR was 28% and the
median survival was 41 weeks for patients receiv-
ing DTIC plus tamoxifen versus only a 12% RR
and 23-week median survival for patients treated
with DTIC alone.43 This trial suffered from a small
sample size and an imbalance in prognostic factors.
The NCI of Canada conducted a double-blind,
placebo control trial comparing RRs and survival
among 200 patients receiving the Dartmouth reg-
imen with and without tamoxifen.45 There was no
statistically significant difference between the two
groups in either overall RR (30% with tamoxifen
v 21% without tamoxifen) or survival. This trial
remains the most convincing regarding the lack of
benefit of adding tamoxifen to multiagent chemo-
therapy.
In a small, randomized trial comparing DTIC
versus DTIC plus high-dose IFN-␣2, the combined
therapy produced more CRs and PRs (12 and 4,
respectively, among 30 patients) compared to the
DTIC-alone arm (two CRs and four PRs). The
median response duration and survival were signif-
icantly prolonged when DTIC was combined with
IFN-␣2 .46
A large-scale prospective randomized four-arm
433
two-by-two factorial phase III trial (ECOG 3690)
on 280 patients compared DTIC alone versus
DTIC/tamoxifen versus DTIC/IFN versus DTIC/
IFN/tamoxifen. This trial, which re-examined the
benefit of both tamoxifen and IFN-␣2b, failed to
confirm the initial encouraging data (RR, 18%;
median TTF, 2.6 months; median survival, 9.1
months; identical for all four arms). No benefit
from tamoxifen was seen in this well-conducted
trial. More than 30% of the tamoxifen-treated
patients showed thromboembolic events.47
The main reason for such large discrepancies in
the findings from single-institution studies and
those from large multicenter cooperative trials is
most likely selection bias. Differences in perfor-
mance status, percentages of patients with visceral
involvement, and number of metastatic sites are
the basis of this idiosyncrasy; in fact, all of these
factors are known to have an impact on both RR
and OS. This underscores the importance of large
multicenter trials to define more precisely the ef-
ficacy of new treatment options.
Furthermore, successive attempts to increase the
dosage of tamoxifen (40 to 200 mg/d) in associa-
tion with chemotherapy (cisplatin) had no impact
on the overall response rate, and the toxicity was
substantial.48 Therefore, there is currently no evi-
dence supporting the addition of IFN-␣ or tamox-
ifen to DTIC in metastatic melanoma.
In an American randomized multi-institutional
trial comparing CVD to DTIC alone, the initial
analysis suggested that CVD was superior with
regard to response rate, duration of response, and
survival.40
The four-drug combination of bleomycin, vin-
cristine, CCNU, and DTIC (the BOLD regimen)
was first evaluated 25 years ago. Initial studies
produced a response rate of 40%, with 9% CRs.49
Follow-up phase II studies failed to confirm these
results, with subsequent RRs falling to from 4% to
20%50,51 and a recent update of this trial could not
confirm the previously cited advantages.
Recently, Nathan et al observed five clinical
responses (one CR and four PRs), with a global RR
of 24%, using paclitaxel (225 mg/m2 in a 3-hour
IV infusion every 3 weeks) and tamoxifen (40
mg/d orally) in 21 patients previously treated with
the Dartmouth chemotherapeutic regimen.52
On the basis of the demonstrated synergy in
vitro, Retsas et al treated 15 metastatic melanoma
patients with either vinorelbine 30 mg/m2 (maxi-
434
mum dose, 50 mg) followed 24 hours later by
paclitaxel 120 mg/m2 infused over 3 hours or using
a reverse sequence (paclitaxel3vinorelbine) as
first-line therapy.53,54 They observed three major
responses: one CR lasting 13 months and two PRs
lasting 7 and 6 months, respectively, all in patients
treated with the vinorelbine3paclitaxel sequence.
Other investigators used vinorelbine (30 mg/m2
IV weekly for 13 weeks, and then every 2 weeks up
to disease progression) in association with tamox-
ifen (20 mg/d), and observed six PRs (three of
which persisted ⱖ12 months) among 30 evaluable
patients, eight of whom were pretreated.55
In general, randomized trials have demonstrated
that combination chemotherapy yields slightly
higher RRs than single agents but at the cost of
increased toxicity and without additional real clin-
ical benefits.
FTMU was tested in several studies, and usually
showed an increased efficacy, without any signifi-
cant increase in toxicity. FTMU was combined
with DTIC, using two main schedules: alternating
or sequential administration. Patients (N ⫽ 103)
were treated with a combination of FTMU and
DTIC56 using the following schedule: induction
treatment—FTMU 100 mg/m2 IV days 1 and 8,
DTIC 250 mg/m2 IV days 15 to 18; 5 weeks of rest;
then maintenance treatment—FTMU 100 mg/m2
IV day 1 and DTIC 250 mg/m2 IV days 2 to 5. The
results were encouraging, with a 27% overall RR,
26% brain RR, 17% CR rate, and a median re-
sponse duration of 21.5 weeks. Hematologic and
gastrointestinal toxicities were both decreased
compared to FTMU given as a single agent (only
two weekly injections of FTMU, rather than
three).
Similar results were obtained at Salpêtrièr Hos-
pital of Paris with a combination of FTMU, DTIC,
and vindesine.57 Patients (N ⫽ 41) received the
following regimen: induction with FTMU 100
mg/m2 IV days 1 and 8, DTIC 250 mg/m2 days 15
and 16, and vindesine 2 mg/m2 IV days 15 and 16;
5 weeks of rest; then maintenance with the same
regimen every 4 weeks. The overall RR was 32%
with 15% CRs. It is worth noting that tumor
reduction allowed a surgical excision in two cases.
Grades 3 and 4 neutropenia and thrombocytope-
nia were present in 27% and 34% of patients,
respectively.
In sequential schedules, DTIC was administered
3 to 4 hours before FTMU, in an attempt to
BAJETTA ET AL
achieve a synergistic effect by depleting O6-alkyl-
transferase, the enzyme responsible for the resis-
tance to nitrosourea. Despite convincing clinical
efficacy, this schedule was compromised by unex-
pected fatal lung toxicity.58-60 To avoid this life-
threatening pulmonary side effect, an adjusted se-
quential regimen with lower doses of DTIC was
used in 63 patients. They were treated every 4
weeks with DTIC 200 mg/m2 IV followed 24 hours
later by FTMU at a dosage of 100 mg/m2 IV. This
regimen was well tolerated (14% grades 3 and 4
neutropenia and thrombocytopenia) but had little
efficacy (RR, 11%).61
The combination of FTMU and IFN-␣ seems to
improve the response duration and the CR rate. In
a multicenter study,62 50 patients were treated as
follows: induction with IFN-␣ 10 MIU/d subcuta-
neously (SC), three times per week and FTMU
100 mg/m2 IV on days 8, 15, and 22; a rest of 5
weeks; followed by maintenance with IFN-␣ 10
MIU/d SC on days 1, 3, and 5 and FTMU 100
mg/m2 IV on day 8, every 4 weeks. The median
duration of response reached 34 weeks with an
overall RR of 28% (8% CR rate). Acute toxicity
was mainly hematologic (grade 3 and 4 neutrope-
nia and thrombocytopenia in 30% and 22% of
patients, respectively). Likewise, 43 patients were
treated with FTMU 100 mg/m2 IV on day 1, DTIC
250 mg/m2 IV on days 2 to 5, every 3 weeks, and
IFN-␣ 3 MIU/d intramuscularly, three times per
week. A 40% RR was observed (9% CR rate), with
a median response duration of 24 weeks.63
In a subsequent study, 60 patients received
FTMU 100 mg/m2 IV on day 1, DTIC 300 mg/m2
IV on days 2 to 4, and cisplatin 25 mg/m2 IV on
days 3 and 4, each every 3 weeks, and IFN-␣ 3
MIU/d intramuscularly, three times weekly.64 The
median duration of response reached 36 weeks,
with an overall RR of 38% and a CR rate of 18%.
The role of tamoxifen in combination with
FTMU remains uncertain, as it seems that the
addition of tamoxifen increases the side effects
more than the RR. A combination of FTMU 100
mg/m2 IV and cisplatin 100 mg/m2 IV every 4
weeks preceded by tamoxifen 160 mg daily for 7
days from the second course onward was used in 66
patients. This schedule cannot be recommended
due to the number of potentially serious side ef-
fects (thrombocytopenia, renal toxicity, ototoxic-
ity, deep venous thrombosis), and its very low RR
(22.7%).65
CHEMOTHERAPY IN MELANOMA
A 4-week induction cycle combining FTMU
100 mg/m2 IV on days 1 and 8, DTIC 220 mg/m2
IV on days 1 to 3 and days 28 to 30, and cisplatin
25 mg/m2 IV on days 1 to 3 and days 28 to 30, with
continuous daily treatment with tamoxifen 20 mg,
obtained the same RR (10% without CR) and
more serious hematologic toxicity with a total of
42% grade 3 and 4 neutropenia and thrombocyto-
penia.66 Therefore, until positive results are ob-
tained, tamoxifen should not be used in combina-
tion with FTMU, as with other compounds, in the
treatment of metastatic melanoma.
IMMUNOTHERAPY
IFN and IL-2
The natural history of melanoma suggests a pos-
sible modulating role of the immune system of the
host. Since the 1970s to 1980s, there have been
multiple publications regarding the use of immu-
nostimulating agents (such as BCG, Corynebacte-
rium parvum, Poly A-Poly U, MeR) both systemi-
cally and locally administered.
Among the biologic response modifiers, the cy-
tokines, IFN-␣ and IL-2, have been the most stud-
ied molecules in the treatment of solid and hema-
tologic neoplasias. Initially, such agents were
evaluated alone, and more recently, in association
with chemotherapy.67-71
The antineoplastic activity of IFN-␣ results
from four possible mechanisms: (1) a cytostatic
effect; (2) a prodifferentiating action on trans-
formed cells; (3) antiangiogenic activity; or (4)
immunomodulating activity. This last activity is
especially due to the induction of expression of
major histocompatability complex (MHC) mole-
cules and some tumor-associated antigens, thus
increasing the recognition of tumor cells by the
immune system of the host. Then, IFN-␣ increases
the activity of natural killer cells and the macro-
phage activation.
Globally, about 15% of patients treated with
IFN-␣ obtained a tumor regression, with 5% of
CRs characterized by a duration of several months
and, in some cases, even longer.72 The main side
effect is a flu-like syndrome characterized by fever,
chills, myalgias, and headache. Using higher dos-
ages, pancytopenia, altered liver function, and
neuropsychiatric symptoms were observed. The
hyperpyrexia is generally well controlled using
paracetamol or, in case of paracetamol-resistant
435
fever, naproxen, and the symptoms tend to reduce
over time with continuing treatment.
The dosages and the routes of administration
vary, so that the available data do not allow defi-
nition of the best schedule. The correlation of a
specific dose with a specific antineoplastic effect is
difficult.
A meta-analysis from Huncharek et al, examin-
ing data derived from randomized controlled trials
comparing single-agent DTIC with combination
chemo/immunotherapy, indicated that the associ-
ation DTIC and IFN-␣ is more active than stan-
dard DTIC monotherapy in metastatic melano-
ma.73 Nevertheless, further randomized clinical
trials are necessary to confirm these results. In our
experience as well, the addition of IFN-␣ to
DTIC, even if it prolonged response duration, had
no effect on RR or survival.74
IL-2 (originally termed T-cell growth factor), a
cytokine produced by human T-helper lympho-
cytes, has an indirect antitumor activity by induc-
ing the expansion of lymphocytes following acti-
vation by specific antigens and stimulating the
production of other cytokines. In high doses, it
induces lymphokine-activated killer (LAK) cells
from natural killer (NK) cell precursors, which are
able to lyse tumor cells that fail to express MHC
class I molecules.75-78
In high-dose IV regimens, IL-2 is administered
at 600,000 to 720,000 IU/kg every 8 hours up to a
maximum of 15 doses. This is administered in two
cycles of up to 5 days with a 10- to 14-day period
of rest, depending on the recovery time of the
patients up to grade 0 to 1 toxicity. The adminis-
tration of high-dose recombinant IL-2 yields a
16% to 17% objective RR rate, 6% to 7% of which
are CRs.79-82 Follow-up data indicate that about
half of the CRs are durable, with some patients
disease-free 15 years after therapy. In general, the
median response duration in responsive patients is
at least 59 months. After ⱖ30 months, none of the
responding patients developed disease progression.
Relapse after IL-2–induced remission usually oc-
curs within 1 to 2 years (97% in partial responders,
but only 41% in complete responders).
When using such an agent, the most frequent
side effect is represented by a flu-like syndrome,
while the dose-limiting toxicity is capillary leak
syndrome or capillary hyperpermeability syndrome
with a consequent risk of pulmonary edema or
kidney failure, cardiac dysfunction, and hypoten-
436 BAJETTA ET AL

Table 4. Studies of Biochemotherapy

No. of Evaluable
Study Regimen Patients % PRs % CRs % RR

Blair, 199190 CDDP/DTIC/IL-2 28 25 18 43

Demchak, 199191 CDDP/IL-2 27 26 11 37
Hamblin, 199192 CDDP/DTIC/IL-2/IFN-␣ 12 58 25 83
Richards, 199293 Dartmouth/IL-2/IFN-␣ 74 40 15 55
Flaherty, 199394 CDDP/DTIC/IL-2 32 26 16 41
Atkins, 199495 CDDP/DTIC/TAM/IL-2 38 34 8 42
Dorval, 199996 CDDP/IL-2 ⫾ IFN-␣ 101 21/10 4/6 25/16
Antoine, 199797 CDDP/IL-2/IFN-␣ 127 39 10 49
Rosenberg, 199998 CDDP/DTIC/TAM ⫾ IL-2/IFN-␣ 102 10/19 4/3 27/44
Keilholz, 199999 DTIC/CDDP/IFN-␣ ⫾ IL-2 118 23/17 5/5 28/22
Legha, 1998100 CDDP/VBL/DTIC/IFN-␣/IL-2 53 43 21 64
Richards, 1999101 CDDP/DTIC/BCNU/IL-2/IFN-␣ 83 31 14 55
Proebstle, 1998102 CDDP/DTIC/IFN-␣/IL-2 42 24 0 24
O’Day, 1999103 CVD/IL2/IFN-␣ 35 37 20 57
Chapman, 2001104 CDDP/DTIC/VBL/IL-2/IFN-␣ 61 25 5 29

Abbreviations: CDDP, cisplatin; DTIC, dacarbazine; IL-2, interleukin-2; IFN-␣, interferon-alpha; TAM, tamoxifen; VBL, vinblastine; CVD,
cisplatin, vinca alkaloid, dacarbazine.

sion, rather than myelotoxicity. The mortality rate
is 1%, but could be reduced to 0.1% with more
accurate selection of patients.83
The association of IL-2 with other cytokines or
with the infusion of LAK cells/tumor-infiltrating
lymphocytes did not enhance response or survival.
Factors predictive for IL-2 response are the pres-
ence of metastases only to subcutaneous/cutaneous
sites, lymphocytosis immediately after the begin-
ning of treatment, and long-term immunologic
side effects, especially vitiligo .84
Tagliaferri et al, using a daily low-dose subcuta-
neous IL-2 alternate-week administration, did not
observe significant clinical responses in melanoma
patients, whereas responses were seen in renal and
gastrointestinal cancer patients.85
Clinical trials using subcutaneous IL-2 adminis-
tration in association with chemotherapy ⫾ IFN-␣
are ongoing in order to ameliorate the global ther-
apeutic index, especially in terms of toxicity, based
on the interesting data collected in renal cancer
either in the adjuvant or in the metastatic setting.
A phase I clinical trial using subcutaneous IL-2
and bryostatin-1 is currently ongoing at the NCI/
Massey Cancer Center.86 Bryostatin-1 is a biologic
agent that interacts with and activates protein-
kinase C with a consequent induction of differen-
tiation of tumor cells and regulation of their
growth. It also increases T- and B-cell activation
and LAK cell activity, and stimulates IL-2 receptor
expression on CD4⫹ and CD8⫹ lymphocytes,
other cytokine (tumor necrosis factor-alpha [TNF-
␣], IL-6) release, and neutrophil phagocytic activ-
ity and degranulation.87,88
A number of phase II/III clinical trials used IL-2
in association with peptide vaccines [gp100 (209-
217), or TRP-2 (180-188)], as an immunologic
adjuvant, in order to expand T lymphocytes acti-
vated by the vaccine.89
BIOCHEMOTHERAPY
Several studies regarding biochemotherapy, us-
ing different regimens, have been published since
199190-104 (Tables 4 and 5).
Our experience at the Salpêtrière Hospital with
chemoimmunotherapy began in December 1990.
Since then, 129 patients have received a combi-
nation of cisplatin, recombinant IL-2 (West’s
schedule) as a continuous infusion, and IFN-␣
given subcutaneously, in three consecutive trials.97
We treated 94 patients with the first schedule
(PI2), a combination of cisplatin 100 mg/m2 IV on
day 0, IL-2 18 MIU/m2/d on days 3 to 6 and days
17 to 21, and IFN-␣ 9 MIU subcutaneously three
times per week throughout the cycle, two cycles
every 28 days. Patients with an antitumor response
and good tolerance received maintenance treat-
ment (IL-2 on days 3 to 6 and days 17 to 21, and
CHEMOTHERAPY IN MELANOMA 437

Table 5. Cisplatin-Based Chemotherapy With Subcutaneous IL-2

No. of Evaluable
Study Regimen Patients % PRs % CRs % RR

Atzpodien109 DTIC/CBDCA/IL-2/IFN-␣ 40 27.5 7.5 35

Atzpodien109 CDBT/IL-2/IFN-␣ 27 44 11 55
Bernengo110 CDDP/TAM/IL-2/IFN-␣ 36 33 14 47.2
Dreno111 CDDP/IL-2/IFN-␣ 28 25 7.2 32.2
Dillman112 CDDP/DTIC/BCNU/IL-2/IFN-␣ 30 24 10 34
Andres113 CDDP/IFN-␣/IL-2 33 20 10 30
Kamanabrou114 CDDP/DTIC/BCNU/IL-2/IFN-␣ 109 27.5 11 38.5
McDermott115 CVD/IL-2/IFN-␣ 21 43 0 43
Thompson116 Dartmouth/IL-2/IFN-␣ 53 23 19 42
Stark117 Dartmouth/IL-2/IFN-␣ 19 21 5 26

Abbreviations: DTIC, dacarbazine; CBDCA, carboplatin; IL-2, interleukin-2; IFN-␣, interferon-alpha; CDBT, cisplatin, dacarbazine, carmustine,
tamoxifen; CDDP, cisplatin; TAM, tamoxifen; BCNU, carmustine; CVD, cisplatin, vinca alkaloid, dacarbazine.

IFN-␣, three times per week for 2 weeks). Each
cycle was repeated every 5 weeks for a maximum of
four cycles. In the second study (PI2/TAM), 24
patients received the same induction treatment
combined with tamoxifen (160 mg/d from day -5
to day ⫹5). In the third schedule (PI2/3w), the
second period of IL-2 (which was not directly
sequential to cisplatin in PI2) was omitted and
IL-2 was administered from day 3 to day 7. Eleven
patients received this cycle, repeated every 3
weeks for a maximum of four cycles.
For all three of the studies (127 evaluable pa-
tients), the overall RR was 49%, with a 10% CR
rate. RRs were higher for skin, soft tissue, and
lymph node metastases compared with visceral
sites. It is worth noting that 7% of treated patients
have had a long-term (⬎3 years) remission.
The side effects included flu-like syndrome, cap-
illary leak syndrome, neuropsychiatric distur-
bances, and myelotoxicity. However, grade 4 tox-
icity was rare and reversible with discontinuation
of therapy.
Compared with immunotherapy alone, bioche-
motherapy seems to provide higher RRs. Random-
ized trials are rare. Dorval et al compared a com-
bination of cisplatin, IL-2, and IFN-␣ in 101
patients and showed no statistical advantages for
the three-drug schedule in terms of RR and me-
dian duration of response.96 In an EORTC study
comparing the combination of IL-2 plus IFN-␣
with or without cisplatin, the addition of cisplatin
doubled the RR from 18% to 35% and increased
the progression-free survival from 53 days to 92
days without any statistical differences in terms of
survival.105
In a randomized trial on 102 patients that com-
pared the combination of high-dose bolus IV IL-2,
subcutaneous IFN-␣, and DTIC/cisplatin/tamox-
ifen with the three– cytotoxic drug regimen alone,
Rosenberg et al found no statistical differences in
terms of RR and survival. However, this study was
prematurely interrupted at an interim analysis. Al-
though the difference in terms of survival rates was
not significant, survival was better for those pa-
tients receiving chemotherapy alone.98
Meta-analyses have demonstrated an improve-
ment in outcome achieved with the use of chemo-
immunotherapies. The analysis by Allen and Ep-
stein showed that regimens including IFN-␣/IL-2
achieved an 11-month survival rate, compared
with 8.6 months using chemotherapy alone.106 In
the Eurocetus meta-analysis, chemotherapy com-
bined with IL-2– based immunotherapy added 2.5
months to the median survival.107
In conclusion, well-designed and well-conducted
large phase III trials are still needed to confirm def-
initely that chemoimmunotherapy is better than
chemotherapy or immunotherapy alone.
Several studies have been reported using differ-
ent schedules of cisplatin-based biochemotherapy.
Due to the heterogeneity of these trials, it is dif-
ficult to assess the real efficacy of this therapy and
the best manner of administration (combination v
monochemotherapy, bolus or continuous IV IL-2,
clinical benefit of IFN-␣ and/or tamoxifen). How-
ever, the RR seems to be higher when the cispla-
438
tin-containing chemotherapy regimen is given be-
fore the immunotherapy or concurrently.108 The
results of subcutaneous regimens combining IL-2
and IFN-␣ seem slightly lower than those
achieved with IL-2 IV, but are associated with a
better toxicity profile109-117 (Tables 4 and 5)
The study of Eton et al (CVD v CVD ⫹ IV
continuous infusion IL-2 ⫹ subcutaneous IFN-
␣2b) on 183 evaluable patients was the first to
demonstrate a statistically significant advantage of
biochemotherapy over chemotherapy alone in
terms of RR (48% v 25%), CR rate (7% v 2%),
and median TTP (4.9 v 2.4 months). A modest but
statistically significant increase in median overall
survival (11.9 v 9.2 months) was observed.118
An Italian multicenter phase III trial using cis-
platin/DTIC-containing chemotherapy ⫾ BCNU
versus the same regimen plus low-dose subcutane-
ous IL-2 (4.5 MIU on days 3 to 5 and 8 to 12) and
subcutaneous IFN-␣2b (3 MIU three times per
week) was performed on 176 patients.119 The RR
was 20.2% versus 25.3%, without a significant
improvement in TTP or survival.
We are performing an Italian multicenter phase
III clinical trial comparing chemotherapy alone
(CVD regimen) with biochemotherapy (the same
regimen of chemotherapy plus IL-2 subcutaneously
administered at a dosage of 9 MIU/d for 5 consec-
utive days for 2 weeks and IFN-␣2b 5 MIU/m2/d for
5 consecutive days, each cycle having a duration of
21 days). Another large phase III trial on 482
patients comparing the previously mentioned reg-
imen of Eton et al (CVD) versus CVD ⫹ IV
IL-2 ⫹ subcutaneous IFN is ongoing in the
United States (ECOG trial 3695). No data are
available at this time. These two trials will prob-
ably provide a definite answer concerning the pos-
sible superiority of the biochemotherapeutic ap-
proach.
OTHER CYTOKINES
IL-12 is a heterodimeric cytokine produced by
antigen-presenting cells (monocytes/macrophages
and dendritic cells) and B lymphocytes.120 It has a
number of interesting immunologic and biologic
activities: increase in NK cell lytic activity; acti-
vation of cytotoxic T lymphocytes (CTLs); mito-
genic activity for preactivated T and NK cells;
induction of LAK activity, independently of IL-2;
induction of IFN-␥, IL-15, and IL-18 secretion by
activated T and NK cells; promotion of the
BAJETTA ET AL
TH03 TH1 switch; antiangiogenic activity (via
IFN-␥ and interferon-inducible protein-10
[IP-10]).
The rationale underlying such a therapy is that
this cytokine represents a positive immunologic
factor that has a longer elimination half-life if
compared to that of IL-2 (up to 10.3 hours when
used IV and 10 hours when used subcutaneously),
with a consequent more flexible dose schedul-
ing.121,122 The IL-12-induced increase in NK lytic
activity is not inhibited by IL-4 and the side effects
are fewer; in particular, the problem of the vascu-
lar leak syndrome does not exist.
In a pilot clinical trial performed at INT in
previously treated metastatic melanoma patients,
we used a fixed dose of 0.5 ␮g/kg of IL-12 admin-
istered subcutaneously on days 1, 8, and 15 for two
identical 28-day cycles, up to four cycles in case of
objective response or SD.122
We observed two PRs at the soft tissue and
superficial lymph node level, with a median dura-
tion of 14 weeks; one mixed response with a CR of
hepatic lesions and subcutaneous progression was
also observed. These responses occurred quickly,
immediately following two administrations of the
first cycle, with SD or progressive disease in the
second part of treatment. This therapy was well
tolerated: flu-like syndrome was present in all pa-
tients with grade 1/2 fever, fatigue and arthromy-
algias; transient increases in transaminases and
triglyceridemia; and grade 1 reduction in DLCO in
two patients. All patients developed lymphopenia
with an inversion of CD4/CD8 ratio and a reduc-
tion of CD16⫹ cells, 24 hours after the first injec-
tion. Furthermore, an increase in IFN-␥ levels
within 24 hours after the first IL-12 injection was
also observed; and an increase in serum IL-10
levels in most of patients during the second cycle
and a decrease in urinary levels of basic fibroblast
growth factor (bFGF) in two of three responding
patients represent interesting data.
Putting together all of the collected pharmaco-
kinetic and pharmacodynamic data, including the
reduction in serum IL-12 levels at the end of the
two cycles of treatment, we would like to under-
line that an adaptive response probably appears in
the late phase of treatment. This adaptive response
could not be explained on the basis of an antibody
response to the injected cytokine because no anti–
IL-12 antibodies were detected in any of the pa-
tients. This could be due to a rebalance between
CHEMOTHERAPY IN MELANOMA
the TH1 subset (releasing IL-2/IFN-␥/TNF-␣) in-
volved in cell-mediated immunity and the TH2
subset (releasing IL-4/IL-5/IL-6/IL-10) involved in
humoral immunity; this is supported by the in-
crease in IL-10 levels in the second part of treat-
ment in most of the treated patients.
Nevertheless, the original hypothesis that IL-10
may be considered a downregulator of cell-medi-
ated immunity has been partially contradicted by
successive results.123 In fact, the administration of
high IL-10 doses to mice bearing established tu-
mors (including melanoma) led to tumor rejec-
tion, an effect that was abrogated by sublethal
irradiation.124 Furthermore, the injection of IL-10
can suppress both experimental and spontaneous
metastases in mice bearing murine or human mel-
anomas, by means of an NK-cell– dependent pro-
cess.125 On the basis of this evidence, the induc-
tion of IL-10 in the patients of this study may be
considered as a contribution to the antitumor ef-
fects of IL-12, rather than simply as a negative
feedback mechanism induced by recombinant hu-
man IL-12 administration. Another possible ex-
planation could be that the initial IL-12 injections
led to an upregulation of the high-affinity IL-12
receptors, thereby inducing major IL-12 removal
from the bloodstream; this according to the kinetic
characteristics of the molecule (enhanced suppres-
sion of serum IL-12 levels after later injections).
Therefore, the primary objective of successive
IL-12– based clinical trials is to overcome this
adaptive response in order to obtain a chronic
TH1-like immune activation involving IFN-␥ pro-
duction.
New trials that are ongoing or in development
will examine IL-12 plus IFN-␣ in patients with
metastatic kidney cancer or melanoma (NCI/
Cleveland Clinic Cancer Center)126; and IL-12
plus IL-2 in gene therapy or via systemic admin-
istration or in mixed setting. Other phase I trials
will attempt to modulate and better define recom-
binant human IL-12 schedules.
NEW CHEMOTHERAPEUTIC AGENTS
Methylating agents attack DNA at multiple
sites, although most of their cytotoxic activity is
due to the formation of methyl adducts at the O6
position of guanine. The presence of these adducts
results in a futile recycling of the mismatch repair
pathway, leading to DNA strand breaks and apo-
439
ptotic cell death. An intact mismatch repair sys-
tem is required to achieve their cytotoxic effect.
Repair of adducts by the DNA protein AGT
impairs the cytotoxic action of the alkylating
agents and mediates a major resistance pathway to
these drugs. BG and its analogs are potent AGT-
inactivating agents, able to deplete AGT to unde-
tectable levels. AGT-depleting agents in combi-
nation with methylating and chloroethylating
agents are now in clinical testing and may result in
greater clinical efficacy in metastatic melanoma.
BG in association with carmustine in treating
patients bearing unresectable locally recurrent or
metastatic melanoma is currently under study
(NCI, University of Chicago Cancer Research
Center).127 New clinical trials using CCI-779,
E7070, flavopiridol, pyrazoloacridine, and 9-nitro-
camptothecin are ongoing.
The mammalian target of rapamycin (mTOR) is
a central regulator of G1 cell cycle protein synthe-
sis that precedes commitment to normal cellular
replication.128 A clinical trial sponsored by the
NCI (Beckman Research Institute) using an
mTOR inhibitor (CCI-779) is currently recruiting
metastatic melanoma patients.129
E7070 exerts its antitumor effects by disturbing
the cell cycle at multiple points, including both
the G1/S and the G2/M transitions. The EORTC
Melanoma Cooperative Group is performing a
phase II clinical trial using E7070 administered IV
over 1 hour, repeated every 3 weeks until disease
progression or unacceptable toxicity.130
The protein kinase family represents a relatively
new target for anticancer therapy. Cyclin-depen-
dent kinases (CDKs) control cell division by
checking the different phases. The regulation of
CDKs is altered in a number of tumor types, so
that chemical modulators of CDKs interfering
with aberrant tumor CDK activity (such as fla-
vopiridol) are currently used in phase II clinical
trials in metastatic melanoma patients.131
Pyrazoloacridine, a synthetic DNA binding
agent that preferentially inhibits ribonucleic acid
rather than DNA synthesis, is active against hy-
poxic and noncycling tumor cells and has substan-
tial in vitro activity against a broad range of hu-
man solid tumors.132 A recent trial with such a
drug in metastatic melanoma is ongoing in the
United States.133
440
ANTIANGIOGENIC TREATMENT
A crucial step for the continuous growth of
primary tumors to reach a clinically or radiologi-
cally detectable mass, other than for the develop-
ment of metastases, is represented by the induction
and branching of a neovascularization (ie, angio-
genesis). In fact, when a tumor mass increases
beyond 0.5 mm in diameter the simple diffusion of
O2/CO2 and nutrients becomes insufficient to en-
sure tumor growth. Proliferation of vascular endo-
thelial cells and creation of a vascular net are
necessary.
The onset of angiogenesis involves an alteration
in the balance between proangiogenic and antian-
giogenic molecules. In this delicate balance, tumor
cells and endothelial cells influence each other
reciprocally in a paracrine pattern, the first pro-
ducing angiogenic molecules (such as vascular en-
dothelial growth factor [VEGF]/vascular perme-
ability factor [VPF] or bFGF) and the second
releasing tumor growth factors (such as epidermal
growth factor [EGF], platelet-derived growth fac-
tor [PDGF], insulin-like growth factor [IGF]-I/II,
IL-6).134
Thalidomide, or ␣-phthalimodoglutarimide, was
synthesized in the 1950s and used initially as a
sedative hypnotic. Following the discovery of limb
defects and deformities of internal organs in in-
fants born to mothers who consumed it during
pregnancy, thalidomide was withdrawn from the
market. Thalidomide has pleiotropic effects, in-
cluding downregulation of anti–TNF-␣ activity
and immunomodulation, changes in adhesion
molecules, and an antiangiogenic effect. This last
activity seems to be determined by the inhibition
or downregulation of integrin subunits, which in-
hibits or slows endothelial cell migration.135
Thalidomide has been approved by the Food
and Drug Administration for the treatment of er-
ythema nodosum leprosum, an inflammatory man-
ifestation of leprosy, and is now in clinical trials to
assess its efficacy in patients with a variety of
malignancies. As the major toxicities are somno-
lence, constipation, neurologic symptoms, and fa-
tigue, it may be an ideal drug to combine with
other traditional chemotherapeutic regimens.
Kudva et al, using thalidomide alone, observed a
CR of scalp lesions (judged to be in-transit metas-
tases).136 Phase II clinical trials using thalidomide
BAJETTA ET AL
and DTIC or TMZ are ongoing in metastatic mel-
anoma patients.137,138
Another phase II study is also in progress using
an association of two antiangiogenic agents, tha-
lidomide and SU5416.139 SU5416 is a synthetic,
specific VEGF receptor antagonist, that inhibits
the tyrosine kinase activity of the intracellular
domain of the Flk-1 (KDR) receptor for VEGF.140
In xenograft models, such an agent shows a wide
range of antitumor activity, with more efficacy in
slower growing tumors. In a phase I trial in pa-
tients bearing advanced, refractory tumors,
SU5416 induced stabilizations of disease for more
than 6 months.141 The authors used a twice-
weekly dosing schedule and the maximum toler-
ated dose was identified as 245 mg/m2, with a
favorable pharmacokinetic pattern (dose-depen-
dent clearance and extensive tissue penetration).
Toxicity was acceptable. A phase II clinical trial
using SU5416 is ongoing in previously treated
metastatic melanoma patients (NCI/University of
Chicago Cancer Research Center).142
CONCLUSION
The available weapons against metastatic mel-
anoma yield poor results in terms of response du-
ration and survival. The only agent capable of
inducing durable CRs is actually IL-2, but the
overall RR is very low and the toxicity is such that
treatment in an intensive care unit is required to
guarantee the patient’s life. Waiting for more sig-
nificant results using biologic therapies, such as
gene therapy, vaccines, or antiangiogenic agents,
the association of singly active agents and bioche-
motherapy seems to offer advantages over either
chemotherapy or immunotherapy alone. In fact, in
the future we should consider combining agents
with different biologic and biochemical bases,
where chemotherapy could continue to play a role.
In this last sense, the increasing knowledge of the
tumor biology could facilitate the selection of pa-
tients who could benefit from the several different
therapies now available.
ACKNOWLEDGMENT
We would like to acknowledge Caterina Somenzi for her
editorial assistance.
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