PROSPECTIVE RANDOMIZED CLINICAL

TRIALS IN ONCOLOGY 1055–3207/02 $15.00 + .00

RANDOMIZED CLINICAL
TRIALS IN MELANOMA
Kathryn Spanknebel, MD, Larissa Temple, MD, MSc,
Spiros Hiotis, MD, PhD, Alice Yeh, MD, and Daniel G. Coit, MD

The management of local, regional, and metastatic melanoma has

been the subject of at least 154 prospective randomized clinical trials
(RCT) published from 1975 to 2000 (Table 1). Among solid malignancies
primarily treated with surgical resection, few have been evaluated within
the context of the prospective RCT more thoroughly than melanoma. As
a result, 25 well-designed trials have defined the appropriate surgical
management of cutaneous melanoma (see Table 1) and guidelines recom-
mended by the results of such trials have been widely accepted in clin-
ical practice. A similar effort, reflected in 62 prospective RCTs, has been
put forth in the adjuvant setting in patients with high-risk or regional
metastatic disease (Tables 1 and 2). Likewise, efforts to improve the sur-
vival of patients with metastatic melanoma have led to 67 prospective
RCTs investigating the use of agents comprising three main areas of ther-
apy: systemic chemotherapy-based regimens, immunotherapy, and vac-
cine therapy (see Table 2). The surgical, systemic, and adjuvant treatment
of melanoma is thus distinguished by the impact of organized, coopera-
tive research and evidenced-based medicine.

SURGERY

Primary Melanoma

Until data from prospective RCTs were reported in the 1980s, ex-
tensive excisions for melanoma were standard therapy, mandating 5-cm
radial margins of excision, generally with split thickness skin grafting

From the Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York,
New York

SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA

VOLUME 11 • NUMBER 1 • JANUARY 2002 23

24 SPANKNEBEL et al

Table 1. RANDOMIZED CLINICAL TRIALS IN MELANOMA DISTRIBUTED BY PRINCIPAL

MODALITY OF TREATMENT STUDIED, EXTENT OF DISEASE, AND TRIAL RANK

Radiation
Surgery Chemotherapy Therapy Immunotherapy Other Total
Trials Trials Trials Trials Trials Trials

Tumor
Ia 4 0 0 2 0 6
Ib 7 7 1 7 5 27
Ic 0 3 0 3 1 7
Nodes
Ia 3 0 0 6 0 9
Ib 9 9 0 7 1 25
Ic 2 3 1 6 0 13
Metastasis
Ia 0 4 0 2 0 6
Ib 0 28 2 6 1 37
Ic 0 18 0 3 3 24
Total Trials 25 72 4 42 11 154

and were based on histopathologic studies of the cutaneous extent of in-

transit melanoma.12, 20 This was challenged when the World Health Orga-
nization (WHO) Melanoma Group initiated a well-designed clinical trial
randomizing patients with less than 2-mm-thick lesions to treatment with
either 1-cm or 3-cm wide local excision (WLE) margins. Results first re-
ported in 198829 and updated at a mean follow-up of 90 months in 199131
described no significant difference in overall or disease-free survival be-
tween the two groups. Four local recurrences occurred in patients who
underwent 1-cm WLE and had a primary melanoma more than 1 mm in
thickness. These results led investigators to conclude that 1-cm excision
margins were safe, particularly in patients with cutaneous melanoma of
1 mm thickness or less. This has become common surgical practice for thin
melanoma.
A second large, cooperative trial conducted by the Intergroup
Melanoma Committee, randomized patients with 1-mm to 4-mm-thick
cutaneous melanomas to WLE with either 2-cm or 4-cm margins. Balch
et al reported no significant difference in overall survival, local recurrence
rate, or rate of in-transit metastases between the two groups. The results
of this trial led the investigators to conclude that intermediate thickness
(1 mm to 4 mm) melanomas can be treated safely with 2-cm WLE margins,
thus frequently avoiding split-thickness skin graft.3 These data were
unchanged at the author’s most recently reported follow-up.1
The third important surgical trial to address margins of resection, or-
ganized by the Swedish Melanoma Study Group, randomized patients
with 0.8- to 2.0-mm-thick cutaneous melanomas to receive either 2-cm
or 5-cm WLE margins. No significant differences in survival, local recur-
rence, regional nodal recurrence, or distant metastases were observed be-
tween the two groups. The investigators thus concluded that 2-cm WLE
margins were adequate for the treatment of cutaneous melanomas of
0.8 mm to 2.0 mm thickness.22
 Table 2. DETAILED DISTRIBUTION OF NONSURGICAL PROSPECTIVE RANDOMIZED CLINICAL TRIALS IN MELANOMA
CONDUCTED IN PATIENTS WITH LOCAL, REGIONAL, AND METASTATIC DISEASE

Chemotherapy Chemotherapy Immunotherapy, Radiation

Chemotherapy Hormonal Immunotherapy Biologic, Therapy Other Total
Trials Trials Trials Vaccine Trials Trials Trials Trials

Tumor
Ia 0 0 0 2 0 0 2
Ib 2 0 5 7 1 5 20
Ic 1 0 2 3 0 1 7
Nodes
Ia 0 0 0 6 0 0 6
Ib 3 0 6 7 0 1 17
Ic 0 0 3 6 1 0 10
Metastases
Ia 1 2 1 2 0 0 6
Ib 15 3 10 6 2 1 37
Ic 8 0 10 3 0 3 24
Total Trials 30 5 37 42 4 11 129
25
26 SPANKNEBEL et al

Data from these evidence-based trials have resulted in clinical guide-

lines for surgical excision margins for melanoma based on the depth of
the primary lesion. For lesions less than 1 mm deep, a 1-cm margin is ade-
quate, while 2-cm margins are necessary for intermediate (1 mm to 4 mm)
lesions. There are no prospective RCTs evaluating resection margins for
deep (> 4 mm) primary lesions. There are also no trials addressing depth
of resection, specifically commenting on the value of taking muscular
fascia.

Regional Metastatic Melanoma

There have been four trials comparing elective lymph node dissec-
tion (ELND) versus observation in patients with cutaneous melanoma
and clinically negative lymph nodes. The WHO Melanoma Oncology
Group26–28 compared ELND versus observation in patients with primary
cutaneous extremity melanoma and clinically negative lymph nodes and
found no significant difference in survival between the two groups. A
second WHO trial examined the issue of ELND for patients with pri-
mary cutaneous melanoma of the trunk and found no significant dif-
ference in overall 5-year survival between treatment and observation
groups.5 The Intergroup Melanoma Surgical Program randomized pa-
tients with melanoma of the extremity, trunk, or head and neck to undergo
ELND versus nodal observation and found no difference in overall 5-year
survival.2 A recent update with 10- to 15-year survival data continued
to show no significant difference between the ELND versus observation
groups.1 There may, however, be subsets of patients with clinically nega-
tive lymph nodes who may benefit from ELND. Subgroup analyses from
the Intergroup Melanoma Surgical Program suggested that ELND might
be associated with an improved survival in patients with ulcerated and
intermediate depth (1 mm–4 mm) lesions and 60 years of age or less.1, 2
Additional subgroup analyses from the WHO Melanoma Oncology
Group trial demonstrated an improved survival for patients with occult
metastases undergoing ELND.5 These subgroup analyses suggested that
ELND might have a role in patients who harbor micrometastatic disease.
These trials were instrumental in defining the limited role of ELND. Intu-
itively, patients without micrometastatic disease could receive no benefit
from ELND. Thus, small differences associated with ELND would be dif-
ficult to demonstrate in groups with low incidence of nodal metastasis.
Perhaps these subgroups would have become the subjects of further
clinical trials had sentinel lymph node biopsy not supplanted selective
ELND. The technique of sentinel lymph node biopsy used to detect occult
nodal disease, followed by therapeutic lymph node dissection for patients
with involved sentinel lymph nodes, has been suggested as an optimal
treatment approach5 and is currently being evaluated in two prospective
RCTs, the Multicenter Selective Lymphadenectomy Trial19 and the Sun-
belt Melanoma Trial. Sentinel lymph node biopsy has become a standard
practice to evaluate the clinically negative, intermediate risk lymphatic
basin. Therapeutic lymphadenectomy remains common practice though
 RANDOMIZED CLINICAL TRIALS IN MELANOMA 27

it has not and likely will not be tested by RCT. The added value of deep
inguinal lymphadenectomy in patients with positive superficial inguinal
lymph nodes is similarly untested by RCT and is only applied selectively.
A number of studies have described the benefits of prophylactic, re-
gional hyperthermic isolated limb perfusion (ILP) for the treatment of
high-risk primary cutaneous melanoma of the extremity. Most reported
studies are small and underpowered, and have thus drawn severe crit-
icism. One large cooperative-group trial, however, including the WHO,
European Organization for Research and Treatment of Cancer (EORTC),
and the Southwest Oncology Group (SWOG), randomized 832 patients. In
this trial, patients with primary cutaneous extremity melanoma of 1.5 mm
thickness or greater were randomized to receive WLE alone versus WLE
plus ILP with melphalan and mild hyperthermia. With a median follow-
up period of 6.4 years, no significant difference in survival was observed
between the two groups. The investigators thus concluded that prophy-
lactic ILP for patients with high-risk primary melanoma of the extremity
was not beneficial, and did not recommend the addition of ILP to surgical
excision.16

ADJUVANT TREATMENT OF HIGH RISK MELANOMA

Systemic chemotherapeutic agents and combination chemoimmuno-

therapy, previously tested in patients with metastatic disease, have been
evaluated in the adjuvant setting, presuming an improved efficacy in pa-
tients with a smaller tumor burden. Results of these trials have been uni-
formly negative with no improvements in disease-free survival or overall
survival compared with controls. Likewise, nonspecific immunostimu-
lants such as Bacillus Calmette-Guerin (BCG), Corynebacterium parvum,
and levamisole have demonstrated no clear benefits in treatment groups
compared with controls. Nonetheless, several of these trials were large,
well-conducted studies with historic importance in that their negative re-
sults modified common practice and prompted the investigation of other
adjuvant modalities.

Immunotherapy

There are four published trials comparing high or low dose inter-
feron (IFN)-alpha 2b that have found no survival differences between
observation and treatment groups. The NCCTG trial 83-7052 compared
observation alone with high dose IFN-alpha 2b.8 No statistical improve-
ments in disease-free or overall survival were observed between treated
versus control groups. Patients admitted to this study, however, included
those with intermediate thickness melanoma and nearly 50% of patients
had unproven lymph node metastases that may in part account for the
differences in outcome between the two studies.8 Three important trials,
the WHO 16,4 the French Cooperative Group on Melanoma,11 and the
Austrian Melanoma Cooperative Group,21 compared low dose IFN-alpha
28 SPANKNEBEL et al

2b with observation alone. In two trials, the regional lymph nodes were
not staged11, 21 and the third trial focused entirely on recurrent nodal
disease.4 Low-dose IFN-alpha 2b improved relapse-free survival, but was
shown to have no impact on long-term survival.4, 11, 21 Subgroup analyses
in these three studies have demonstrated improved survival with low-
dose IFN-alpha 2b; however, these were secondary analyses and must be
cautiously interpreted.
The ECOG trial E1684 has been published recently and was notewor-
thy for being the first major trial to identify a positive effect from any ad-
juvant therapy.15 This trial formed the basis for the approval by the FDA
Oncologic Drug Advisory Committee of IFN-alpha 2b as the first adjuvant
treatment for patients with deep primary melanoma or regional lymph
node metastatic disease. This trial adopted a high-dose schedule of IFN-
alpha 2b along with its associated toxicity but demonstrated a statistically
significant disease-free and overall survival advantage for treated patients
compared with controls. A similar trial design created as the successor
to the prior trial was reported in 2000 and compared all three potential
regiments: observation alone, low-dose IFN-alpha 2b, and high-dose IFN-
alpha 2b in high-risk patients with deep primary or regional metastatic
melanoma. Investigators found an improved relapse-free survival but no
difference in overall survival. Authors concluded that the dose of IFN-
alpha 2 was not a factor impacting overall survival.14 Significant contro-
versy still surrounds the interpretation of these trials, but is an excellent
demonstration of the importance of confirmatory trials. In summary, five
prospective RCTs evaluating the adjuvant impact of IFN-alpha 2b demon-
strated improved relapse-free survival; however, a durable impact of ther-
apy on overall survival was not achieved consistently. Most of these pub-
lished trials recommend the adjuvant use of IFN-alpha 2b in the context of
a clinical trial.4, 11, 14, 15, 21

Vaccine Therapy

There are numerous melanoma vaccine studies34–36 but only two re-
ported prospective RCTs.17, 33 Both trials demonstrated that vaccines were
safe and well tolerated. In Livingston et al’s trial, patients who produced
antibodies after vaccination demonstrated a significant improvement in
survival and disease-free interval.17 Wallack et al identified improved sur-
vival in 44- to 57-year-old male patients with one to five positive lymph
nodes in subset analyses.31 In the primary analysis comparing all patients
treated with vaccine versus placebo, however, neither trial demonstrated
differences in disease-free or overall survival.17, 33 Data from these ran-
domized trials suggest that the vaccines used do not improve outcome
in patients with stage III melanoma; however, other available vaccines
may prove beneficial and are the subject of ongoing trials in the adjuvant
setting. The results of adjuvant ganglioside vaccination with GM2-KLH/
QS-21 therapy versus high-dose IFN-alpha 2b are being evaluated cur-
rently in the ECOG trial 1694.
 RANDOMIZED CLINICAL TRIALS IN MELANOMA 29

TREATMENT OF METASTATIC MELANOMA

A number of chemotherapeutic agents have demonstrated activity

in patients with metastatic disease including dacarbazine (DTIC), the
nitrosoureas, vinca alkaloids, platinum compounds, and the taxanes. Of
these, DTIC has been the standard agent to which all other therapies are
compared with overall response rates of 10% to 25% and rare, complete re-
missions lasting 3 to 6 months.18 Because of the limited number of agents
with activity in metastatic melanoma, and the fact that treatment of dis-
seminated disease is largely palliative, investigators have pursued addi-
tional agents seeking improved efficacy and limited toxicity.

Chemohormonal Therapy

Of the chemohormonal therapy trials, the Dartmouth regimen (cis-

platin, carmustine [BCNU], DTIC, and tamoxifen) has been the most
actively studied in prospective RCTs. Researchers attempted to further
improve on the results of DTIC therapy by combining agents active
against melanoma for a potential additive antitumor effect. These initial
reports led to several large, prospective RCTs evaluating the role of DTIC-
based combination chemotherapy with or without tamoxifen.6, 7, 10, 24, 32
Of these five trials, only one was positive.7 This was the first multi-
institutional trial to show improved response rates and median survival
with DTIC plus tamoxifen compared with DTIC alone. Subsequently an-
other trial was conducted by Chapman et al to clarify the role of the
Dartmouth regimen in the management of metastatic melanoma patients.
This was the largest multi-institutional trial of all the chemohormonal
therapy trials and was powered sufficiently to evaluate the efficacy of
the Dartmouth regimen versus DTIC alone. Investigators found that there
was no difference between treatment groups with respect to tumor re-
sponse, toxicity, or survival.6 Authors concluded that DTIC remains the
standard treatment for stage IV melanoma patients and this has been
adopted largely into present clinical management.

Systemic Chemotherapy

The Royal Marsden Hospital led a multicentered RCT of a novel oral

agent, temozolomide, versus standard intravenous DTIC in patients with
advanced melanoma.18 Temozolomide was shown previously to have ac-
ceptable bioavailability and the clinically important attribute of the abil-
ity to cross the blood–brain barrier, a clear advantage over DTIC. On
an intent-to-treat basis, temozolomide demonstrated equivalent results
compared with DTIC alone with respect to outcome measures of sur-
vival, progression-free survival, response rates, and toxicity. This impor-
tant study is the only RCT where the efficacy and safety of a single-
agent, oral therapy approached that of standard DTIC. This has prompted
30 SPANKNEBEL et al

further investigation of temozolomide in patients with CNS metastases in

multiagent biochemotherapy trials.

Systemic Biochemotherapy

Biochemotherapy defines treatment strategies that combine biologic

response modifiers, such as interleukin-2 (IL-2) and IFN-alpha, with
systemic chemotherapy. One of two large, prospective RCTs compar-
ing biochemotherapy with IL-2/IFN-alpha alone was conducted by the
EORTC Melanoma Cooperative Group and published in 1997.13 This
trial determined the contribution of cisplatin to IL-2/IFN-alpha versus
IL-2/IFN-alpha alone in patients with advanced melanoma. The addi-
tion of cisplatin demonstrated a 20% difference in response rates favoring
biochemotherapy; however, this did not translate to improved survival.
Authors suggested that the differences in response rates were related to
the additive effects of cisplatin to biotherapy. These results have prompted
an intergroup study with ECOG and SWOG investigating the role of cis-
platin, vinblastine, and dacarbazine (CVD) plus IL-2/IFN-alpha versus
CVD alone in metastatic melanoma patients9 with results pending.

Immunotherapy

Recombinant cytokines, particularly IL-2 and IFN-alpha, have been

tested extensively in melanoma patients within the context of prospective
immunotherapy RCTs (see Table 2). Interleukin-2 has been used in adop-
tive immunotherapy models with IFN-alpha and lymphokine-activated
killer (LAK cells) for metastatic disease in two RCTs. In the largest study
of stage IV melanoma patients, enrollment was stopped early with only
a 5% response rate noted in 44 patients.25 In a second RCT comparing
IL-2 versus IL-2/LAK cells, 54 of 181 patients had metastatic melanoma.23
There was no difference in response or survival in either study. Al-
though the trials are small, the use of IL-2 and LAK cells in patients with
metastatic melanoma have no demonstrated benefit with respect to pro-
gression of disease or survival.23, 25 Thus, although these trials are nega-
tive results, they represent important steps in the further understanding of
immunotherapy and have refocused research efforts to other IL-2–based
strategies.

LEVEL Ia EVIDENCE IN MELANOMA

Surgical Trials

1) Narrow Excision (1-cm Margin). A Safe Procedure for Thin Cutaneous

Melanoma.
Veronesi U, Cascinelli N. Arch Surg 126:438–441, 1991

Hypothesis: To determine the adequacy of 1-cm versus 3-cm excision mar-

gins for cutaneous melanomas of greater than 2 mm tumor thickness.
 RANDOMIZED CLINICAL TRIALS IN MELANOMA 31

% Change
# Patients Significance Identified
Randomized Study Groups Stratification Demonstrated in Trial
612 1 cm margins Histology None None
n = 305 Equivalent
> 3 cm margins
n = 307

Published Abstract: We analyzed the results at 8 years of an interna-

tional, randomized, prospective study carried out by the World Health Organi-
zation Melanoma Programme aimed at evaluating the efficacy of 1-cm margin
excision of primary melanomas not thicker than 2 mm. Data for 612 patients
were assessable; 305 were randomized to receive 1-cm margin excision and 307
to receive wide excision (margins of greater than or equal to 3 cm). The major
prognostic criteria were similar in the two groups. Breslow thickness was 0.99 mm
in the narrow excision group and 1.02 mm in the wide excision group. Disease-
free and overall survival rates (mean follow-up period, 90 months) were similar in
the two groups. Only four patients had a local recurrence as a first relapse. All un-
derwent narrow excision, and each had primary melanomas thicker than 1 mm.
Editor’s Summary and Comments: This study prospectively evaluated the
efficacy of surgical excision with 1-cm versus wide (>3 cm) margins for patients
with cutaneous melanoma of tumor depth less than or equal to 2.0 mm. No differ-
ence was observed in overall and disease-free survival among those who under-
went excision with 1-cm margins, when compared with those with wide (>3 cm)
margins. An anecdotal observation, all patients in the 1-cm excision margin group
who developed local recurrences (4/305) had primary tumors that were thicker
than 1 mm. Though not specifically studied, the 1-cm margin of excision has be-
come common practice for lesions less than 1 mm in thickness.

2) Local Recurrence in Malignant Melanoma: Long-Term Results of the

Multi-institutional Randomized Surgical Trial.
Karakousis CP, Balch CM, Urist MM, Ross MM, Smith TJ, Bartolucci AA. Ann
Surg Oncol 3:446–452, 1996

Hypothesis: Recurrence rates following wide local excisions of intermediate-

thickness melanoma are identical with 2-cm versus 4-cm margins.

% Change
# Patients Significance Identified
Randomized Study Groups Stratification Demonstrated in Trial
470 2 cm margin Histology None None
n = 238 Equivalent
4 cm margin
n = 232

Published Abstract: BACKGROUND: In the past, radical margins of excision

were prescribed for cutaneous melanoma based on preconceived notions rather
32 SPANKNEBEL et al

than on hard clinical evidence. METHODS: In a prospective study of 742 pa-

tients with intermediate-thickness melanoma (1–4 mm), 470 patients with trunk
or proximal extremity lesions were randomized into a 2- or 4-cm margin. Patients
with distal extremity or head and neck lesions (n = 272) received uniformly a
2-cm margin. RESULTS: The overall rate of local recurrence was 3.8%. This rate
in the randomized portion (n = 470) was 2.1% for the 2-cm margin and 2.6%
for the 4-cm margin ( P = 0.72). A progressive increase in local recurrence rates
was observed with thickness: 2.3% for lesions 1.0–2.0 mm, 4.2% for those 2.01–
3.0 mm, and 11.7% for those 3.01–4.0 mm thick (P = 0.001). Local recurrence oc-
curred in 1.5% of those without ulceration and in 10.6% of those with ulceration
of the primary lesion ( P = 0.001). The local recurrence rate was not significantly
affected by the margin of resection even among the thicker or ulcerated lesions.
It also was not affected significantly by the method of closure of the primary
site or management of the regional nodes, or the age or gender of the patients.
CONCLUSIONS: A 2-cm margin is as effective as a 4-cm margin in local control
and survival of intermediate-thickness melanomas. The local recurrence rate is
significantly affected by the thickness of the primary lesion and the presence or
not of ulceration.
Editor’s Summary and Comments: A follow-up study of the Intergroup
Melanoma Surgery Trial in which recurrence rates among those who underwent
2-cm versus 4-cm excision margins were compared. No difference was observed
between the two groups. Despite a significantly higher overall recurrence rate in
patients with ulcerated lesions, no difference was demonstrated between groups.
This study largely defines current practice in which 2-cm radial margins of exci-
sion are used for melanomas of more than 1 mm thickness.

3) Resection Margins of 2 versus 5 cm for Cutaneous Malignant Melanoma

with a Tumor Thickness of 0.8 to 2.0 mm: Randomized Study by the Swedish
Melanoma Study Group.
Ringborg U, Andersson R, Eldh J, Glaumann B, Hafstrom L, Jacobsson S,
Jonsson PE, Johansson H, Krysander L, Lagerlof B. Cancer 77:1809–1814, 1996

Hypothesis: To evaluate treatment results of malignant melanoma 0.8 to

2 mm in tumor thickness with resection margins of 2 cm or 5 cm.

% Change
# Patients Significance Identified
Randomized Study Groups Stratification Demonstrated in Trial
769 2-cm margin Histology None None
n = 373 Equivalent
5-cm margin
n = 396

Published Abstract: BACKGROUND: The traditional surgical treatment for

primary malignant melanoma has often been a wide excision with a margin of
about 5 cm. Since the risk of local recurrences is dependent on tumor thickness,
thin tumors (< 1 mm) have routinely been excised with a narrow margin. For thick
tumors, the optimal resection margin is controversial, and can be determined only
by prospective, randomized trials. METHODS: The Swedish Melanoma Study
Group performed a prospective, randomized multicenter study to evaluate an
 RANDOMIZED CLINICAL TRIALS IN MELANOMA 33

excision margin of 2 versus 5 cm for patients with cutaneous malignant mela-

noma with tumor thickness >0.8 and < or = 2.0 mm. The trial includes 769 pa-
tients. Patients with melanomas of the skin of the head, neck, hands, feet, or vulva
were not included in the trial. In the event of an excision biopsy for diagnosis,
radical surgery was completed within 6 weeks. The median follow-up time was
5.8 years for estimation of survival and 4.0 years for diagnosis of recurrent dis-
ease. RESULTS: No significant differences have been observed between the treat-
ment groups regarding local or regional recurrences or survival. CONCLUSIONS:
We recommend an excision with a margin of 2 cm for cutaneous malignant
melanoma with a tumor thickness > 0.8 and < or = 2.0 mm.
Editor’s Summary and Comments: There is no significant difference in sur-
vival or recurrence demonstrated among patients with 0.8-mm to 2.0-mm Breslow
thickness cutaneous melanoma who were treated with 2-cm versus 5-cm excision
margins. This properly conducted randomized, prospective study confirmed the
adequacy of 2-cm excision margins for intermediate cutaneous melanomas that
has been adopted widely as the standard of care.

4) Delayed Regional Lymph Node Dissection in Stage I Melanoma of the

Skin of the Lower Extremities.
Veronesi U, Adamus J, Bandiera DC, Brennhovd O, Caceres E, Cascinelli N,
Claudio F, Ikonopisov RL, Javorski VV, Kirov S, Kulakowski A, Lacour J,
Lejeune F, Mechl Z, Morabito A, Rode I, Sergeev S, van Slooten E, Szczygiel K,
Trapeznikov NN, Wagner RI. Cancer 49:2420–2430, 1982

Hypothesis: To determine the necessity for elective regional lymph node dis-
section in patients with cutaneous melanoma of the extremity.

% Change
# Patients Significance Identified
Randomized Study Groups Stratification Demonstrated in Trial
553 ELND None None None
n = 267
Delayed LND
n = 286

Published Abstract: Results of a prospective randomized clinical trial con-

ducted by the WHO Collaborating Centers for the Evaluation of Methods of Diag-
nosis and Treatment of Melanoma are reported. Five-hundred-fifty-three Stage I
patients whose limbs were affected entered the study; 267 were submitted to wide
excision and immediate node dissection and 286 had wide excision and node dis-
section at the time clinically positive nodes were detected. Survival curves of the
two treatment groups could be superimposed. No subsets of patients benefitted
from immediate node dissection. The authors conclude that delayed node dissec-
tion is as effective as the immediate dissection in Stage I melanoma of the extrem-
ities if the patient can be checked every three months. If the quarterly follow-up
is not guaranteed, immediate node dissection is advisable, at least for melanomas
thicker than 2 mm.
Editor’s Summary and Comments: This landmark trial conducted by the
WHO largely changed common practice of ELND for intermediate thickness
melanoma. This final report of the WHO trial on elective regional node dissection
34 SPANKNEBEL et al

definitely states that survival is equal among patients with cutaneous melanoma
who undergo close observation and node dissection as needed when compared
with patients that undergo immediate ELND.

5) Immediate or Delayed Dissection of Regional Nodes in Patients with

Melanoma of the Trunk: A Randomised Trial. WHO Melanoma Programme
[See comments].
Cascinelli N, Morabito A, Santinami M, MacKie RM, Belli F. Lancet 351:793–
796, 1998

Hypothesis: To evaluate the efficacy of immediate elective lymph node dis-

section in patients with intermediate thickness melanoma of the trunk.

% Change
# Patients Significance Identified
Randomized Study Groups Stratification Demonstrated in Trial
252 ELND Gender, site, None None
n = 122 histology
Observation
n = 118

Published Abstract: BACKGROUND: The use of elective regional node dis-

section in patients with cutaneous melanoma without any clinical evidence of
metastatic spread is still debated. Our aim was to evaluate the efficacy of imme-
diate node dissection in patients with melanoma of the trunk and without clinical
evidence of regional node and distant metastases. METHODS: An international
multicentre randomised trial was carried out by the WHO Melanoma Programme
from 1982 to 1989. The trial included only patients with a trunk melanoma 1.5 mm
or more in thickness. After wide excision of primary melanoma, patients were
randomised to either immediate regional node dissection or a regional node dis-
section delayed until appearance of regional-node metastases. FINDINGS: Of the
252 patients entered, 240 (95%) were eligible and evaluable for analysis. 122 of
these were randomised to immediate node dissection. 5-year survival observed
in patients who had delayed node dissection was 51.3% (95% CI 41.7–60.1) com-
pared with 61.7% (52.0–70.1) of patients who had immediate node dissection
( P = 0.09). 5-year survival rate in patients with occult regional node metastases
was 48.2% (28.0–65.8) and 26.6% (13.4–41.8, P = 0.04) in patients in whom the re-
gional node dissection was delayed until the time of appearance of regional node
metastases. Multivariate analysis showed that routine use of immediate node dis-
section had no impact on survival (hazard ratio 0.72, 95% CI 0.5–1.02), whilst
the status of regional nodes affected survival significantly (P = 0.007). The pa-
tients with regional nodes that became clinically and histologically positive dur-
ing follow-up had the poorest prognosis. INTERPRETATION: Node dissection
offers increased survival in patients with node metastases only. Sentinel node
biopsy may become a tool to identify patients with occult node metastases, who
could then undergo node dissection.
Editor’s Summary and Comments: This study randomized patients with
trunk melanomas of 1.5 mm thickness or greater. No overall difference in survival
was observed between patients who underwent immediate elective lymph node
dissection and patients managed with observation alone. A significant survival
benefit was observed among patients with occult nodal metastases who were
 RANDOMIZED CLINICAL TRIALS IN MELANOMA 35

managed with immediate regional lymph node dissection. This is a well-designed

and appropriately powered study to examine the benefit of ELND in patients
with trunk melanomas. As a result of these findings the investigators advocate
sentinel lymph node biopsy (SLNB) for patients with trunk melanomas greater
than 1.5 mm thickness. Patients with occult nodal disease should be identifiable
by SLN Bx and should then be offered regional lymph node dissection.

6) Long-Term Results of a Multi-Institutional Randomized Trial Com-

paring Prognostic Factors and Surgical Results for Intermediate Thickness
Melanomas (1.0 to 4.0 mm). Intergroup Melanoma Surgical Trial.
Balch CM, Soong S, Ross MI, Urist MM, Karakousis CP, Temple WJ, Mihm MC,
Barnhill RL, Jewell WR, Wanebo HJ, Harrison R. Ann Surg Oncol 7:87–97, 2000

Hypothesis: To determine whether elective regional lymph node dissection

confers a survival benefit to patients with intermediate thickness melanoma and
to identify patients at high risk for occult regional nodal metastases.

% Change
# Patients Significance Identified
Randomized Study Groups Stratification Demonstrated in Trial
740 ELND Age None None
n = 379 Histology
Observation
n = 361

Published Abstract: BACKGROUND: Ten- to 15-year survival results were

analyzed from a prospective multi-institutional randomized surgical trial that
involved 740 stages I and II melanoma patients with intermediate thickness
melanomas (1.0 to 4.0 mm) and compared elective (immediate) lymph node dis-
section (ELND) with clinical observation of the lymph nodes as well as prog-
nostic factors that independently predict outcomes. METHODS: Eligible patients
were stratified according to tumor thickness, anatomical site, and ulceration, and
then prerandomized to either ELND or nodal observation. By using Cox stepwise
multivariate regression analysis, the independent predictors of outcome were tu-
mor thickness (P < .001), the presence of tumor ulceration (P < .001), trunk site
( P = .003), and patient age more than 60 years (P = .01). RESULTS: Overall 10-year
survival was not significantly different for patients who received ELND or nodal
observation (77% vs. 73%; P = .12). Among the prospectively stratified subgroups
of patients, 10-year survival rates favored those patients with ELND, with a 30%
reduction in mortality rate for the 543 patients with nonulcerated melanomas
(84% vs. 77%; P = .03), a 30% reduction in mortality rate for the 446 patients with
tumor thickness of 1.0 to 2.0 mm (86% vs. 80%; P = .03), and a 27% reduction in
mortality rate for 385 patients with limb melanomas (84% vs. 78%; P = .05). Of
these subgroups, the presence or absence of ulceration should be the key factor for
making treatment recommendations with regard to ELND for patients with inter-
mediate thickness melanomas. CONCLUSIONS: These long-term survival rates
from patients treated at 77 institutions demonstrate that ulceration and tumor
thickness are dominant predictive factors that should be used in the staging of
stages I and II melanomas, and confer a survival advantage for these subgroups
of prospectively defined melanoma patients.
36 SPANKNEBEL et al

Editor’s Summary and Comments: A well-controlled study with long-term

follow-up evaluating ELND in patients with intermediate thickness melanoma of
the extremity, trunk, and head and neck. Overall 10-year survival was not sig-
nificantly different for patients who received ELND versus nodal observation.
Authors, however, have concluded that benefit is apparent to patients in select
subgroups noted by: (1) 30% reduction in mortality for patients with nonulcer-
ated melanomas; (2) 30% reduction in mortality for patients with tumor thickness
1.0 mm to 2.0 mm, and (3) 27% reduction in mortality for patients with extremity
melanomas. This subgroup analysis has drawn criticism from experts in the
field. The practice of ELND for the subgroups identified by the investigators has
not been accepted widely, despite the findings reported in this paper.

7) Prophylactic Isolated Limb Perfusion for Localized, High-Risk Limb

Melanoma: Results of a Multicenter Randomized Phase III Trial. European
Organization for Research and Treatment of Cancer Malignant Melanoma Co-
operative Group Protocol 18832, the World Health Organization Melanoma
Program Trial 15, and the North American Perfusion Group–Southwest Oncol-
ogy Group-8593.
Koops HS, Vaglini M, Suciu S, Kroon BB, Thompson JF, Gohl J, Eggermont
AM, Di Filippo F, Krementz ET, Ruiter D, Lejeune FJ. J Clin Oncol 16:2906–
2912, 1998

Hypothesis: To evaluate whether prophylactic isolated limb perfusion (ILP)

could prevent regional recurrence and influence survival in patients with primary
cutaneous melanoma of the extremity with greater than 1.5 mm thickness lesions.

% Change
# Patients Significance Identified
Randomized Study Groups Stratification Demonstrated in Trial

852 Perfusion Histology, None None

n = 430 Site, Gender
No Perfusion
n = 422

Published Abstract: PURPOSE: Patients with primary cutaneous mela-

noma ≥1.5 mm in thickness are at high risk of having regional micrometastases at
the time of initial surgical treatment. A phase III international study was designed
to evaluate whether prophylactic isolated limb perfusion (ILP) could prevent
regional recurrence and influence survival. PATIENTS AND METHODS: A total
of 832 assessable patients from 16 centers entered the study; 412 were randomized
to wide excision (WE) only and 420 to WE plus ILP with melphalan and mild
hyperthermia. Median age was 50 years, 68% of patients were female, 79% of
melanomas were located on a lower limb, and 47% had a thickness ≥3 mm.
RESULTS: Median follow-up duration is 6.4 years. There was a trend for a longer
disease-free interval (DFI) after ILP. The difference was significant for patients
who did not undergo elective lymph node dissection (ELND). The impact of ILP
was clearly on the occurrence—as first site of progression—of in-transit metas-
tases (ITM), which were reduced from 6.6% to 3.3%, and of regional lymph node
(RLN) metastases, with a reduction from 16.7% to 12.6%. There was no benefit
from ILP in terms of time to distant metastasis or survival. Side effects were
 RANDOMIZED CLINICAL TRIALS IN MELANOMA 37

higher after ILP, but transient in most patients. There were two amputations for
limb toxicity after ILP. CONCLUSION: Prophylactic ILP with melphalan cannot
be recommended as an adjunct to standard surgery in high-risk primary limb
melanoma.
Editor’s Summary and Comments: A large multi-institutional study of ILP
for patients with extremity melanoma. Patients with primary melanomas of the
limb 1.5 mm thickness or greater were randomized to receive wide local exci-
sion with or without immediate, prophylactic ILP. Some patients also received
regional lymph node dissection, but this was not offered in a controlled fashion.
No significant difference in survival was demonstrated nor was time to dis-
tant metastases. Some reduction in disease-free interval was observed among
subgroups of patients that received ILP, however this subgroup analysis was not
a predetermined outcome measure. A well-designed and very large study on the
benefit of prophylactic ILP for patients with primary melanoma of the extremity
greater than 1.5 mm thickness. This study clearly demonstrates that prophylactic
ILP is not beneficial and should not be recommended to patients with primary cu-
taneous melanoma of the extremity.

Systemic Therapy Trials

1) Treatment of Metastatic Malignant Melanoma with Dacarbazine Plus

Tamoxifen.
Cocconi G, Bella M, Calabresi F, Tonato M, Canaletti R, Boni C, Buzzi F, Ceci G,
Corgna E, Costa P. N Engl J Med 327:516–523, 1992

Hypothesis: Combination dacarbazine (DTIC) and tamoxifen improves re-

sponse and survival rates compared with DTIC alone in metastatic melanoma
patients.

% Change
# Patients Study Significance Identified
Randomized Groups Stratification Demonstrated in Trial
117 DTIC n = 55 Gender, age, Response rates 10% vs. 38% RR
DTIC + site Survival 30 vs. 69 weeks
tamoxifen median survival
n = 62

Published Abstract: BACKGROUND: Endocrine factors may affect the clin-

ical course of malignant melanoma and the response to the treatment of this
disease. The presence of estrogen receptors in melanomas has been suggested,
and occasional responses to antiestrogen therapy have been reported. METHODS
AND RESULTS: We randomly assigned 117 patients with metastatic malignant
melanoma to treatment with dacarbazine alone or dacarbazine in combination
with tamoxifen. The overall rate of response, measured objectively, was higher
(28 percent vs. 12 percent, P = 0.03) and survival was longer (median, 48 vs.
29 weeks, P = 0.02) among the patients who received dacarbazine plus tamox-
ifen than among those who received dacarbazine alone. Among women, both
the response rate (38 percent vs. 10 percent, P = 0.04) and the median survival
(69 vs. 30 weeks, P = 0.008) were better with dacarbazine plus tamoxifen than
with dacarbazine alone, whereas among men the differences were smaller and
not statistically significant. Among the patients given dacarbazine alone, there
38 SPANKNEBEL et al

were no significant differences between women and men in response rate (10 per-
cent vs. 13 percent) or survival (30 vs. 27 weeks), whereas among those given
dacarbazine plus tamoxifen, women had better outcomes, as indicated by both
response rate (38 percent vs. 19 percent, P = 0.15) and survival (69 vs. 31 weeks,
P = 0.02). When we analyzed the Quetelet body-mass index (the weight in kilo-
grams divided by the square of the height in meters) as an indirect indicator of the
levels of endogenous estrogens in postmenopausal women and in men, survival
was not affected by the body-mass index in the group given dacarbazine alone,
whereas in the group given dacarbazine plus tamoxifen, survival was longer
among patients whose Quetelet index was above the median value than among
those with a Quetelet index lower than the median value (60 vs. 26 weeks, P less
than 0.001). CONCLUSIONS: In the treatment of metastatic malignant melanoma,
dacarbazine plus tamoxifen is more effective than dacarbazine alone, as indicated
by both the response rate and the median survival; the difference in efficacy is
mainly among women.
Editor’s Summary and Comments: This randomized study compared the
efficacy of DTIC to DTIC + tamoxifen in patients with metastatic melanoma. Pa-
tient characteristics between the two arms were comparable. Authors noted three
main results: (1) DTIC + tamoxifen was more effective than DTIC alone with re-
spect to response rates and length of survival; (2) differences in treatment arms
were more distinct among women; (3) retrospective, subgroup analysis of those
patients who received DTIC + tamoxifen showed that men and postmenopausal
women with BMI greater than median value had better overall survival than
those with BMI less than median value. Longer survival is more likely for women
than men early in disease, but not once metastases occur. The authors conclude
that given the findings of the study, tamoxifen should now be considered stan-
dard therapy in patients with metastatic melanoma.

2) Phase III Multicenter Randomized Trial of the Dartmouth Regimen ver-

sus Dacarbazine in Patients with Metastatic Melanoma.
Chapman PB, Einhorn LH, Meyers ML, Saxman S, Destro AN, Panageas KS,
Begg CB, Agarwala SS, Schuchter LM, Ernstoff MS, Houghton AN, Kirk-
wood JM. Clin Oncol 17:2745–2751, 1999

Hypothesis: The use of tamoxifen, dacarbazine, cisplatin, carmustine (Dart-

mouth regimen) to improve the outcome of patients with advanced melanoma
compared to the use of dacarbazine alone (DTIC).

% Change
# Patients Significance Identified
Randomized Study Groups Stratification Demonstrated in Trial
240 Dartmouth Institution, None None
n = 119 sex, site
DTIC
n = 121

Published Abstract: PURPOSE: Several single-institution phase II trials

have reported that the Dartmouth regimen (dacarbazine, cisplatin, carmustine,
and tamoxifen) can induce major tumor responses in 40% to 50% of stage IV
melanoma patients. This study was designed to compare the overall survival
time, rate of objective tumor response, and toxicity of the Dartmouth regimen
 RANDOMIZED CLINICAL TRIALS IN MELANOMA 39

with standard dacarbazine treatment in stage IV melanoma patients. PATIENTS

AND METHODS: In this multicenter phase III trial, 240 patients with measur-
able stage IV melanoma were randomized to receive the Dartmouth regimen
(dacarbazine 220 mg/m2 and cisplatin 25 mg/m2 days 1 to 3, carmustine
150 mg/m2 day 1 every other cycle, and tamoxifen 10 mg orally bid) or dacar-
bazine 1,000 mg/m2 . Treatment was repeated every 3 weeks. Patients were ob-
served for tumor response, survival time, and toxicity. RESULTS: Median survival
time from randomization was 7 months; 25% of the patients survived ≥1 year.
There was no difference in survival time between the two treatment arms when
analyzed on an intent-to-treat basis or when only the 231 patients who were both
eligible and had received treatment were considered. Tumor response was as-
sessable in 226 patients. The response rate to dacarbazine was 10.2% compared
with 18.5% for the Dartmouth regimen (P = .09). Bone marrow suppression, nau-
sea/vomiting, and fatigue were significantly more common in the Dartmouth
arm. CONCLUSION: There was no difference in survival time and only a small,
statistically nonsignificant increase in tumor response for stage IV melanoma pa-
tients treated with the Dartmouth regimen compared with dacarbazine. Dacar-
bazine remains the reference standard treatment for stage IV melanoma.
Editor’s Summary and Comments: This trial included patients with stage IV
or stage III (N2) melanoma, although the majority of patients had advanced dis-
ease. There were no significant differences between overall survival, length of sur-
vival, or tumor response rates, regardless of the treatment or method of analysis
(intention to treat versus those completing therapy). This was a methodologically
well-designed trial, sufficiently powered to address the question.

3) Randomized Phase III Study of Temozolomide versus Dacarbazine in

the Treatment of Patients with Advanced Metastatic Malignant Melanoma.
Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, Gore
M, Aamdal S, Cebon J, Coates A, Dreno B, Henz M, Schadendorf D, Kapp A,
Weiss J, Fraass U, Statkevich P, Muller M, Thatcher N. J Clin Oncol 18:158–166,
2000

Hypothesis: The oral agent temozolomide is equivalent to intravenous DTIC

therapy in patients with advanced melanoma with respect to survival, response
rates, safety, and pharmacokinetics.

% Change
# Patients Significance Identified
Randomized Study Groups Stratification Demonstrated in Trial
305 Temozol Site of disease None None
n = 156 Sex
DTIC Performance
n = 149 Status

Published Abstract: PURPOSE: To compare, in 305 patients with advanced

metastatic melanoma, temozolomide and dacarbazine (DTIC) in terms of over-
all survival, progression-free survival (PFS), objective response, and safety, and
to assess health-related quality of life (QOL) and pharmacokinetics of both drugs
and their metabolite, 5-(3-methyltriazen-1-yl)imidazole-4-carboximide (MTIC).
PATIENTS AND METHODS: Patients were randomized to receive either oral
40 SPANKNEBEL et al

temozolomide at a starting dosage of 200 mg/m2 /d for 5 days every 28 days

or intravenous (IV) DTIC at a starting dosage of 250 mg/m2 /d for 5 days every
21 days. RESULTS: In the intent-to-treat population, median survival time was
7.7 months for patients treated with temozolomide and 6.4 months for those
treated with DTIC (hazards ratio, 1.18; 95% confidence interval [CI], 0.92 to 1.52).
Median PFS time was significantly longer in the temozolomide-treated group
(1.9 months) than in the DTIC-treated group (1.5 months) (P = .012; hazards
ratio, 1.37; 95% CI, 1.07 to 1.75). No major difference in drug safety was ob-
served. Temozolomide was well tolerated and produced a noncumulative, tran-
sient myelosuppression late in the 28-day cycle. The most common nonhemato-
logic toxicities were mild to moderate nausea and vomiting, which were easily
managed. Temozolomide therapy improved health-related QOL; more patients
showed improvement or maintenance of physical functioning at week 12. Sys-
temic exposure (area under the curve) to the parent drug and the active metabo-
lite, MTIC, was higher after treatment with oral temozolomide than after IV
administration of DTIC. CONCLUSION: Temozolomide demonstrates efficacy
equal to that of DTIC and is an oral alternative for patients with advanced
metastatic melanoma.
Editor’s Summary and Comments: A well designed multicentered random-
ized clinical trial comparing oral therapy with temozolomide versus standard in-
travenous DTIC therapy in patients with stage IV melanoma without CNS or oc-
cular involvement. When subgroups were analyzed on an intent-to-treat basis,
patients receiving temozolomide were shown to have an equivalent overall sur-
vival and a longer progression-free survival compared with DTIC treated con-
trols. Quality of life was not significantly different and the drug was well tol-
erated with equivalent systemic exposure to the parent active metabolite of the
drug. The authors concluded that the oral agent temozolomide should be consid-
ered an equivalent oral agent to DTIC therapy and should be considered for pa-
tients with CNS metastases.

4) Interferon Alfa-2a and Interleukin-2 with or without Cisplatin (CDDP)

in Metastatic Melanoma: A Randomized Trial of the European Organization for
Research and Treatment of Cancer Melanoma Cooperative Group.
Keilholz U, Goey SH, Punt CJ, Proebstle TM, Salzmann R, Scheibenbogen
C, Schadendorf D, Lienard D, Enk A, Dummer R, Hantich B, Geueke AM,
Eggermont AM. J Clin Oncol 15:2579–2588, 1997

Hypothesis: The addition of cisplatin (CDDP) to a regiment of interferon

(IFN) and interleukin-2 (IL-2) improves survival in metastatic melanoma patients.

% Change
# Patients Significance Identified
Randomized Study Groups Stratification Demonstrated in Trial
137 IL-2/IFN Institution, extent Survival: Response rate:
n = 66 of disease none 18% vs. 33%
IL-2/IFN + Response
CDDP rate: yes
n = 71

Published Abstract: PURPOSE: The combination of interferon alfa-2a (IFN-

alpha) and high-dose interleukin-2 (IL-2) is active in metastatic melanoma. The
addition of cisplatin (CDDP) has resulted in response rates greater than 50%. This
 RANDOMIZED CLINICAL TRIALS IN MELANOMA 41

study was performed to determine whether the addition of CDDP to a cytokine

treatment regimen with IFN-alpha and high-dose IL-2 influences survival of pa-
tients with metastatic melanoma. PATIENTS AND METHODS: Patients with ad-
vanced metastatic melanoma were randomly assigned to receive treatment with
IFN-alpha 10 × 106 U/m2 subcutaneously on days 1 through 5 and a high-dose in-
travenous decrescendo regimen of IL-2 on days 3 through 8 (18 mIU/m2 /6 hours,
18 mIU/m2 /12 hours, 18 mIU/m2 /24 hours, and 4.5 mIU/m2 /24 hours × 3)
without (arm A) or with (arm B) CDDP 100 mg/m2 on day 1. Treatment cycles
were repeated every 28 days to a maximum of four cycles. RESULTS: One hun-
dred thirty-eight patients with advanced metastatic melanoma, of whom 87% had
visceral metastases, were accrued for the trial. Both regimens were feasible in a
multicenter setting. The objective response rate was 18% without and 33% with
CDDP (P = .04). The progression-free survival was 53 days without and 92 days
with CDDP (P = .02, Wilcoxon; P = .09, log-rank). There was no statistically sig-
nificant difference in survival between treatment arms, with a median overall sur-
vival duration for all patients of 9 months. CONCLUSION: The addition of CDDP
to cytokine treatment with IFN-alpha and IL-2 does not influence survival of pa-
tients with advanced metastatic melanoma, despite a significant increase in re-
sponse rate and progression-free survival.
Editor’s Summary and Comments: A significant increased response rate was
found with the addition of CDDP (18% versus 33%) and there was an improved
progression-free survival (53 days versus 92 days) although no survival differ-
ences were found between groups.

5) Randomized Phase III Trial of Treatment with High-Dose Interleukin-

2 Either Alone or in Combination with Interferon Alfa-2a in Patients with
Advanced Melanoma.
Sparano JA, Fisher RI, Sunderland M, Margolin K, Ernest ML, Sznol M,
Atkins MB, Dutcher JP, Micetich KC, Weiss GR. J Clin Oncol 11:1969–1977, 1993

Hypothesis: High-dose IV interleukin-2 (IL-2) plus interferon alfa-2a (IFN-

alpha 2a) compared with high-dose IL-2 alone significantly enhances response
rate in treatment of patients with advanced melanoma.

% Change
# Patients Significance Identified
Randomized Study Groups Stratification Demonstrated in Trial
85 IL-2 Histology None None
n = 44 Site
IL-2/IF-alpha
n = 41

Published Abstract: PURPOSE: To compare the response rate, survival,

and toxicity of treatment with high-dose intravenous (IV) bolus interleukin-2
(IL-2) plus interferon alfa-2a (IFN-alpha) with high-dose IL-2 alone in patients
with advanced melanoma in a randomized phase III trial design. PATIENTS
AND METHODS: Eighty-five patients with advanced melanoma were randomly
assigned to receive IL-2 6 × 106 U/m2 per dose every 8 hours as tolerated for
a maximum of 14 doses on days 1 through 5 and 15 through 19, or IL-2 4.5 ×
106 U/m2 per dose, plus IFN-alpha 2 × 106 U/m2 using an identical schedule.
42 SPANKNEBEL et al

A planned interim analysis was performed after 85 patients were entered, which
forms the basis for this report. RESULTS: Partial response (PR) occurred in two
of 44 patients (5%; 95% confidence interval, 1% to 15%) receiving IL-2 alone, com-
pared with four of 41 patients (10%; 95% confidence interval, 3% to 23%) receiving
IL-2/IFN-alpha (P = .30). There were no complete responses (CRs). The median
duration of response was 11.5 months (range, 2.0 to 15.7+). There was no signif-
icant difference in the median survival duration for patients receiving IL-2 alone
(10.2 months) compared with patients receiving IL-2/IFN-alpha (9.7 months). The
median and mean number of doses of IL-2 were equivalent in both groups, as
was toxicity. There were three treatment-related deaths, two in the IL-2-alone arm
and one in the IL-2/IFN-alpha arm. The trial was terminated after the first interim
analysis based on predefined early-stopping rules, which included termination if
the response rate in the IL-2/IFN-alpha arm was less than 25%. CONCLUSION:
Using the preparation, dose, and schedule of IL-2 in our trial, IFN-alpha failed to
enhance significantly the response rate to high-dose IL-2 in the treatment of pa-
tients with advanced melanoma.
Editor’s Summary and Comments: Phase III trial comparing IL-2 plus IFN
alpha-2a versus IL-2 alone in advanced melanoma. Identical dosing, scheduling
and preparing of IL-2 plus IFN-alpha was as described by Rosenberg et al in
previous trial where they showed enhanced response. In the current study, there
was no significant difference in median survival for either groups. Complete re-
sponses were not seen in either group. Partial responses were not different. The
trial was stopped with only 30% of the projected accrual. Toxicity was not signifi-
cantly different; however greater than 20-fold increase in transaminase level was
seen more frequently in patients receiving the combined therapy. Response rate
seen with IL-2 alone is the lowest reported to date using the regimen described
(1%–15% versus 11%–23% in previous trials) despite no differences in study pop-
ulation, toxicity profile, and dosing.

6) Prospective Randomized Trial of High-Dose Interleukin-2 Alone or

in Conjunction with Lymphokine-Activated Killer Cells for the Treatment of
Patients with Advanced Cancer.
Rosenberg SA, Lotze MT, Yang JC, Topalian SL, Chang AE, Schwartzentruber
DJ, Aebersold P, Leitman S, Linehan WM, Seipp CA. J Natl Cancer Inst 85:622–
632, 1993

Hypothesis: The combination of lymphokine-activated killer (LAK) cells and

IL-2 improves outcome in patients with advanced cancer when compared with
IL-2 alone.

% Change
# Patients Significance Identified
Randomized Study Groups Stratification Demonstrated in Trial
181 IL-2 n = 90 Histology None None
LAK/IL-2
n = 91

Published Abstract: BACKGROUND: Treatment using interleukin-2 (IL-2)

alone or in conjunction with lymphokine-activated killer (LAK) cells has been
shown to mediate disease regression in selected patients with advanced cancer.
PURPOSE: This prospective randomized trial was designed to determine whether
 RANDOMIZED CLINICAL TRIALS IN MELANOMA 43

the administration of LAK cells in conjunction with high-dose IL-2 alters response
and survival rates, compared with those for IL-2 alone, in patients with advanced
cancer. METHODS: The 181 patients who had metastatic cancer that had failed
to respond to standard therapy or who had disease for which no effective ther-
apy existed received treatment with high-dose IL-2 alone or with LAK cells plus
IL-2. Both treatment groups were to receive the same dose of IL-2 administered
according to the same schedule. IL-2 doses were omitted depending on the tol-
erance of the patient. Of the 181 patients, 97 had renal cell cancer and 54 had
melanoma. RESULTS: Median potential follow-up was 63.2 months. There were
10 complete responses among the 85 assessable patients who received IL-2 plus
LAK cells, compared with four among the 79 who received IL-2 alone. There were
14 and 12 partial responses, respectively. Complete response continues in seven
patients at 50–66 months. The 36-month actuarial survival with IL-2 plus LAK
cells was 31%, compared with 17% with IL-2 alone (two-sided P value [P2] =
.089). A trend toward improved survival was seen for patients with melanoma
who received IL-2 plus LAK cells, compared with those who received IL-2 alone
(24-month survival: 32% versus 15%; 48-month survival: 18% versus 4%; P2 =
.064 [corrected]). None of 26 patients with melanoma who received IL-2 alone are
alive; five of 28 who received IL-2 plus LAK cells are alive, and three continue
in complete response. No difference in survival was seen in patients with renal
cell cancer in the two treatment groups. There were six treatment-related deaths
(3.3%); three were due to myocardial infarction. Other toxic effects resolved by
discontinuation of IL-2. Many toxic effects were related to increased vascular per-
meability induced by IL-2. CONCLUSIONS: Some patients with metastatic can-
cer have prolonged remission when they are treated with high-dose IL-2 alone or
in conjunction with LAK cells. Our results suggest a trend toward increased sur-
vival when IL-2 is given with LAK cells in patients with melanoma, but no trend
was observed for patients with renal cell cancer. IMPLICATIONS: As these stud-
ies continue, efforts are underway to develop improved immunotherapies using
tumor-infiltrating lymphocytes (TIL) and gene-modified TIL.
Editor’s Summary and Comments: These data do not demonstrate any real
survival benefit. In addition, the population is heterogenous and only patients
with melanoma were randomized. Its significance is in the use of immunotherapy
and contributions of this author.

7) Randomized, Surgical Adjuvant Clinical Trial of Recombinant Inter-

feron Alfa-2a in Selected Patients with Malignant Melanoma.
Creagan ET, Dalton RJ, Ahmann DL, Jung SH, Morton RF, Langdon RM, Jr.,
Kugler J, Rodrigue LJ. J Clin Oncol 13:2776–2783, 1995

Hypothesis: Interferon (IFN) used as an adjuvant therapy in stage I and II

melanoma patients improves outcome.

% Change
# Patients Significance Identified
Randomized Study Groups Stratification Demonstrated in Trial
232 IFN None None None
n = 132
Observation
n = 132
44 SPANKNEBEL et al

Published Abstract: PURPOSE: We conducted a randomized prospective

trial in selected patients with fully resected high-risk stage I and II malignant
melanoma. PATIENTS AND METHODS: Interferon alfa-2a (IFN alpha-2a) 20 ×
106 U/m2 was administered three times each week for 12 weeks by the in-
tramuscular route. Both the treatment group (n = 131) and the control group
(n = 131) were evenly balanced with regard to relevant prognostic discriminants.
RESULTS: The median disease-free survival (DFS) time was 2.4 years for the IFN
alpha-2a group and 2.0 years for the observation group (log-rank P = 0.19). The
median survival times were 6.6 years for IFN alpha-2a and 5.0 years for observa-
tion (log-rank P = .40). For stage I patients (n = 102), there was no apparent ther-
apeutic advantage from IFN alpha-2a therapy. The DFS for stage II patients was
a median of 10.8 months in the control group versus 17 months in the treatment
group. The overall survival time was 4.1 years for the treatment group versus
2.7 years for the control group. The differences in DFS for stage II patient were sig-
nificant in a Cox model. These results must be interpreted cautiously because of
subset analysis. A severe flu-like toxicity occurred in 44% of patients, 13% lost at
least 10% of their baseline weight, and 45% experienced a worsening of Eastern
Cooperative Oncology Group (ECOG) performance score. CONCLUSION: Our
findings indicate trends that suggest a possible benefit for selected patients with
high-risk malignant melanoma. The results will require further study in a larger
patient population for confirmation.
Editor’s Summary and Comments: No differences in recurrence rates were
demonstrated between groups; however there was a trend to improved survival.
Subset analyses suggested that patients with stage II disease may benefit from
IFN therapy.

8) Randomised Trial of Interferon Alpha-2a as Adjuvant Therapy in Re-

sected Primary Melanoma Thicker than 1.5 mm without Clinically Detectable
Node Metastases. French Cooperative Group on Melanoma.
Grob JJ, Dreno B, de la SP, Delaunay M, Cupissol D, Guillot B, Souteyrand
P, Sassolas B, Cesarini JP, Lionnet S, Lok C, Chastang C, Bonerandi JJ. Lancet
351:1905–1910, 1998

Hypothesis: Adjuvant treatment with low doses of IFN alpha-2a reduces re-
currence in patients with high-risk melanoma.

% Change
# Patients Study Significance Identified
Randomized Groups Stratification Demonstrated in Trial
499 IFN None Relapse-free 3-year relapse
n = 246 interval rate 33% vs.
Control 44%
n = 252

Published Abstract: BACKGROUND: Owing to the limited efficacy of ther-

apy on melanoma at the stage of distant metastases, a well-tolerated adjuvant
therapy is needed for patients with high-risk primary melanoma. Our hypothesis
 RANDOMIZED CLINICAL TRIALS IN MELANOMA 45

was that an adjuvant treatment with low doses of interferon-alpha could be effec-
tive in patients with localised melanoma. METHODS: After resection of a primary
cutaneous melanoma thicker than 1.5 mm, patients without clinically detectable
node metastases were randomly assigned to receive either 3 × 106 IU interferon
alpha-2a, three-times weekly for 18 months, or no treatment. The primary end-
point was the relapse-free interval. FINDINGS: 499 patients were enrolled, of
whom 489 were eligible. When used as part of a sequential procedure, interferon
alpha-2a was of significant benefit for relapse-free interval ( P = 0.038). A long-
term analysis, after a median follow-up of 5 years, showed a significant extension
of relapse-free interval ( P = 0.035) and a clear trend towards an increase in over-
all survival ( P = 0.059) in interferon alpha-2a–treated patients compared with
controls. There were 100 relapses and 59 deaths among the 244 interferon alpha-
2a–treated patients compared with 119 relapses and 76 deaths among the 245
controls. The estimated 3-year-relapse rates were 32% in the interferon alpha-2a
group and 44% in controls; the 3-year death rates were 15% and 21%, respec-
tively. Only 10% of patients experienced WHO grade 3 or 4 adverse events. Treat-
ment was compatible with normal daily life. INTERPRETATION: Adjuvant ther-
apy of high-risk melanoma with low doses of interferon alpha-2a for 18 months
is safe and is beneficial when started before clinically detectable node metastases
develop.
Editor’s Summary and Comments: This was a large study comparing low-
dose IFN alpha-2a with observation in patients with Breslow lesions greater than
1.5 mm without clinically palpable nodal disease. Relapse-free survival was sig-
nificantly extended; however, overall survival was not significantly improved at
5-year follow-up. Subgroup analyses demonstrated improved relapse-free sur-
vival with lower T stage; however, the primary outcome was not significantly dif-
ferent between the two groups.

9) Adjuvant Interferon Alfa-2a Treatment in Resected Primary Stage II Cu-

taneous Melanoma. Austrian Malignant Melanoma Cooperative Group.
Pehamberger H, Soyer HP, Steiner A, Kofler R, Binder M, Mischer P, Pachinger
W, Aubock J, Fritsch P, Kerl H, Wolff K. J Clin Oncol 16:1425–1429, 1998

Hypothesis: Adjuvant IFN alpha-2a decreases the number of recurrences and

improves disease-free survival in stage II melanoma.

% Change
# Patients Significance Identified
Randomized Study Groups Stratification Demonstrated in Trial
311 IFN 4 None Disease-free
n = 15 survival
Observation
n = 157

Published Abstract: PURPOSE: Patients with primary cutaneous melanoma

with a Breslow thickness ≥1.5 mm have only a 30% to 70% probability of sur-
vival after surgery, and no adjuvant therapy has so far improved this outcome.
Since interferon alfa-2a (IFN alpha-2a) exhibits antitumor activity in metastatic
46 SPANKNEBEL et al

melanoma, we investigated whether adjuvant IFN alpha-2a diminishes the occur-

rence of metastases and thus prolongs disease-free survival in melanoma patients
after excision of the primary tumor. PATIENTS AND METHODS: In a prospec-
tive randomized study, 311 melanoma patients with a Breslow thickness ≥1.5 mm
were assigned to either adjuvant IFN alpha-2a treatment (n = 154) or observa-
tion (n = 157) after excision of the primary tumor. IFN alpha-2a was given daily
at a dose of 3 mIU subcutaneously (s.c.) for 3 weeks (induction phase), after
which a dose of 3 mIU s.c. three times per week was given over 1 year (mainte-
nance phase). RESULTS: Prolonged disease-free survival was observed in patients
treated with IFN alpha-2a versus those who underwent surgery alone. This differ-
ence was significant (P = .02) for all patients enrolled onto the study (intention-
to-treat analysis) at a mean observation time of 41 months. Subgroup analysis
showed that Breslow tumor thickness had no influence on treatment results in
the groups of patients investigated. CONCLUSION: Adjuvant IFN alpha-2a treat-
ment diminishes the occurrence of metastases and thus prolongs disease-free sur-
vival in resected primary stage II cutaneous melanoma patients.
Editor’s Summary and Comments: Patients were treated with wide local ex-
cision with no lymph node dissection. Disease-free interval was significantly bet-
ter in patients treated with IFN alpha-2a; however, overall survival was not
improved.

10) Interferon Alfa-2b Adjuvant Therapy of High-Risk Resected Cuta-

neous Melanoma: The Eastern Cooperative Oncology Group Trial EST 1684.
Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH.
J Clin Oncol 14:7–17, 1996

Hypothesis: High-dose IFN alpha as an adjuvant therapy improves the out-

come of patients with T4 and N1 melanoma.

% Change
# Patients Study Significance Identified
Randomized Groups Stratification Demonstrated in Trial
287 IFN Stage Overall survival 2.8 versus
n = 137 3.8 years,
Observation P = 0.02,
n = 143 one sided

Published Abstract: PURPOSE: Interferon alfa-2b (IFN alpha-2b) exhibits an-

titumor activity in metastatic melanoma and on this basis has been evaluated
as an adjuvant therapy following surgery for deep primary (T4) or regionally
metastatic (N1) melanoma. METHODS: A randomized controlled study of IFN
alpha-2b (Schering-Plough, Kenilworth, NJ) administered at maximum-tolerated
doses of 20 MU/m2/d intravenously (i.v.) for 1 month and 10 MU/m2 three times
per week subcutaneously (SC) for 48 weeks versus observation, was conducted
by the Eastern Cooperative Oncology Group (ECOG) in 287 patients. RESULTS:
A significant prolongation of relapse-free survival (P = .0023, one-sided) and pro-
longation of overall survival (P = .0237, one-sided) was observed with IFN alpha-
2b therapy in this trial, which is now mature with a median follow-up time of
6.9 years. The impact of treatment on relapse rate is most pronounced early
during the treatment interval. The overall benefit of treatment in this trial was
 RANDOMIZED CLINICAL TRIALS IN MELANOMA 47

analyzed stratified by tumor burden and the presence or absence of microscopic

nonpalpable and palpable regional lymph node metastasis. The benefit of ther-
apy with IFN alpha-2b was greatest among node-positive strata. Toxicity of IFN
alpha-2b required dose modification in the majority of patients, but treatment at
> or = 80% of the scheduled dose was feasible in the majority of patients through
the IV phase of treatment, and for more than 3 months of SC maintenance ther-
apy. Discontinuation of treatment due to toxicity was infrequent after the fourth
month of therapy. CONCLUSION: IFN alpha-2b prolongs the relapse-free inter-
val and overall survival of high-risk resected melanoma patients. The increment
in median disease-free survival (from 1 to 1.7 years) and overall survival (from 2.8
to 3.8 years) that results from this therapy is associated with a 42% improvement
in the fraction of patients who are continuously disease-free after treatment with
IFN (from 26% to 37%) in comparison to observation. IFN alpha-2b is the first
agent to show a significant benefit in relapse-free and overall survival of high-risk
melanoma patients in a randomized controlled trial.
Editor’s Summary and Comments: The data showed an improved relapse-
free period and overall survival. This was even more marked in patients with N1
disease. Although this is a well-designed trial, the statistical significance of the re-
sults are based on one-sided tests. When using standard two-sided statistical tests
in the analysis of these data, the overall survival is not significantly different be-
tween groups.

11) High- and Low-Dose Interferon Alfa-2b in High-Risk Melanoma: First

Analysis of Intergroup Trial E1690/S9111/C9190.
Kirkwood JM, Ibrahim JG, Sondak VK, Richards J, Flaherty LE, Ernstoff MS,
Smith TJ, Rao U, Steele M, Blum RH. J Clin Oncol 18:2444–2458, 2000

Hypothesis: There is a dose response with IFN alpha-2b therapy when used
as adjuvant therapy in high-risk melanoma patients.

% Change
# Patients Significance Identified
Randomized Study Groups Stratification Demonstrated in Trial
642 High dose IFN Stage, None None
n = 215 number of
Low dose IFN nodes
n = 215
Observation
n = 212

Published Abstract: PURPOSE: Pivotal trial E1684 of adjuvant high-dose in-

terferon alfa-2b (IFN alpha-2b) therapy in high-risk melanoma patients demon-
strated a significant relapse-free and overall survival (RFS and OS) benefit
compared with observation (Obs). PATIENTS AND METHODS: A prospective,
randomized, three-arm, intergroup trial evaluated the efficacy of high-dose IFN
alpha-2b (HDI) for 1 year and low-dose IFN alpha-2b (LDI) for 2 years versus Obs
in high-risk (stage IIB and III) melanoma with RFS and OS end points. RESULTS:
A total of 642 patients were enrolled (608 patients eligible), of whom a majority
(75%) had nodal metastasis (50% had nodal recurrence). Unlike E1684, E1690
48 SPANKNEBEL et al

allowed entry of patients with T4 (>4 mm) deep primary tumors, regardless of
nodal dissection, and 25% of the patients entered onto this trial had deep pri-
mary tumors (compared with 11% in E1684). At 52 months’ median follow-up,
HDI demonstrated an RFS benefit exceeding that of LDI compared with Obs. The
5-year estimated RFS rates for the HDI, LDI, and Obs arms were 44%, 40%, and
35%, respectively. The hazards ratio for the intent-to-treat analysis of HDI versus
Obs was 1.28 (P(2) = .05); for LDI versus Obs, it was 1.19 (P(2) = .17). By Cox
analysis, the impact of HDI on RFS achieved significance (P(2) = .03). The RFS
benefit was equivalent for node-negative and node-positive patients. Neither HDI
nor LDI has demonstrated an OS benefit compared with Obs at this time. A ma-
jor improvement in the median OS of patients in the E1690 Obs arm was noted
in comparison with E1684 (6 years vs 2.8 years). An analysis of salvage therapy
for patients who relapsed on E1690 demonstrated that a significantly larger pro-
portion of patients in the Obs arm received IFN alpha–containing salvage ther-
apy compared with the HDI arm; this therapy was unavailable to patients during
E1684, and patients with undissected regional nodes were not included in E1684.
This study did not specify therapy at recurrence. Analysis of treatments received
at recurrence demonstrated significantly more frequent use of IFN alpha-2b at re-
lapse from Obs than from HDI, which may have confounded interpretation of the
survival benefit of assigned treatments in E1690. CONCLUSION: The results of
the intergroup E1690 trial demonstrate an RFS benefit of IFN alpha-2b that is
dose-dependent and significant for HDI by Cox multivariable analysis.
Editor’s Summary and Comments: Three-armed study demonstrating an
improvement in relapse-free survival but no survival benefit. Patients with deep
T lesions could participate in the study with or without a nodal dissection mak-
ing the groups somewhat more heterogeneous. The stratification, however, proba-
bly controlled for this potential confounder as demonstrated in the patient charac-
teristic table. An additional potential confounder may be that patients who failed
therapy (usually in the observation group) received IFN alpha-2b and may bias
the results against IFN. Interestingly, unlike E1684 (Kirkwood, 1996) there was no
survival benefit with high-dose IFN. In this trial there was a median of 52 month
follow-up, and subsequent reports are to be expected.

12) Improved Survival in Stage III Melanoma Patients with GM2 Antibod-
ies: A Randomized Trial of Adjuvant Vaccination with GM2 Ganglioside.
Livingston PO, Wong GY, Adluri S, Tao Y, Padavan M, Parente R, Hanlon C,
Calves MJ, Helling F, Ritter G. J Clin Oncol 12:1036–1044, 1994

Hypothesis: Induction with GM2 antibodies results in a survival benefit in

patients with stage III melanoma.

% Change
# Patients Significance Identified
Randomized Study Groups Stratification Demonstrated in Trial
122 bacille Calmette-Guerin None None None
(BCG)
n = 64
BCG/GM2 vaccine
n = 58
 RANDOMIZED CLINICAL TRIALS IN MELANOMA 49

Published Abstract: PURPOSE: To perform a double-blind randomized trial

with American Joint Commission on Cancer (AJCC) stage III melanoma patients
for the following reasons: (1) to confirm our previous finding that patients with
antibodies against the melanoma differentiation antigen GM2 have an improved
prognosis, and (2) to demonstrate clinical benefit from GM2 antibody induction.
PATIENTS AND METHODS: One hundred twenty-two patients with AJCC stage
III melanoma who were free of disease after surgery were randomized: 58 to re-
ceive treatment with the GM2/BCG vaccine, and 64 to receive treatment with
bacille Calmette-Guerin (BCG) alone. All patients were pretreated with low-dose
cyclophosphamide (Cy.) RESULTS: GM2 antibody was detected in 50 of 58 pa-
tients treated with GM2/BCG and seven of 64 patients treated with BCG alone.
With a minimum follow-up period of 51 months, there was a highly significant
increase in the disease-free interval (P = .004) and a 17% increase in overall sur-
vival (P = .02) in these 57 antibody-postive patients, confirming our earlier ex-
perience. Exclusion of all patients with preexisting GM2 antibodies (one in the
GM2/BCG group and five in the BCG group) from statistical analysis resulted
in a 23% increase in disease-free interval (P = .02) and a 14% increase in overall
survival (P = .15) at 51 months for patients treated with the GM2/BCG vaccine.
However, when all patients in the two treatment groups were compared as ran-
domized, these increases were 18% for disease-free interval and 11% for survival
in the GM2/BCG treatment group, with neither result showing statistical signif-
icance. CONCLUSION: (1) Vaccination with GM2/BCG induced immunoglobu-
lin M (IgM) antibodies in most patients. (2) GM2 antibody production was asso-
ciated with a prolonged disease-free interval and survival. (3) Comparison of the
two arms of this trial as randomized fails to show a statistically significant im-
provement in disease-free interval or survival for patients treated with GM2/BCG
vaccines.
Editor’s Summary and Comments: This was a well-designed and executed
RCT that demonstrated that GM2 ganglioside vaccination was a safe adjuvant
that was shown to have a biologic response. Improved disease-free interval and
overall survival were shown when stratified by patients who developed GM2 an-
tibodies. Nonetheless, overall and disease-free survivals were not improved.

13) Surgical Adjuvant Active Specific Immunotherapy for Patients with

Stage III Melanoma: The Final Analysis of Data from a Phase III, Randomized,
Double-Blind, Multicenter Vaccinia Melanoma Oncolysate Trial.
Wallack MK, Sivanandham M, Balch CM, Urist MM, Bland KI, Murray D,
Robinson WA, Flaherty L, Richards JM, Bartolucci AA, Rosen L. J Am Coll
Surgeons 187:69–77, 1998
Hypothesis: Vaccina melanoma oncolysate (VMO) improves disease-free and
overall survival.

% Change
# Patients Significance Identified
Randomized Study Groups Stratification Demonstrated in Trial
250 VMO vaccine Institution, None None
n = 104 stage
Placebo
n = 113
50 SPANKNEBEL et al

Published Abstract: BACKGROUND: A phase III, randomized, double-

blind, multicenter trial of active specific immunotherapy (ASI) using vaccinia
melanoma oncolysate (VMO) was performed in patients with stage III (American
Joint Commission on Cancer) melanoma to determine the efficacy of VMO to in-
crease the disease-free interval (DFI) or overall survival (OS) in these patients.
Two interim analyses of data from this trial were performed in May 1994 and
June 1995. Although the results from these analyses showed no statistically sig-
nificant improvement in DFI or OS in all patients using VMO, two subsets—
men aged 44–57 years with one to five positive nodes and all patients with clin-
ical stage I and pathologic stage II disease—showed an overall survival advan-
tage with VMO therapy. A final analysis of data from this trial was performed
in May 1996 and is reported here. The design of future melanoma vaccine trials
is discussed based on information learned from this first randomized, multicen-
ter trial of ASI therapy. STUDY DESIGN: A polyvalent VMO was prepared us-
ing melanoma cells derived from four melanoma cell lines and vaccinia vaccine
virus (V). Patients were accrued from 11 United States institutions and were ran-
domized by the Statistical Center at the University of Alabama, Birmingham. Two
hundred fifty patients were randomized to treatment with either VMO (1 U con-
taining 2 mg of total protein derived from 5 × 106 melanoma cells and 105.6 50%
tissue culture infectious dose of vaccinia virus) or control V (1 U containing 105.4
50% tissue culture infectious dose of vaccinia virus) once a week for 13 weeks
and then once every 2 weeks for a total of 12 months, or until recurrence. Pa-
tient data were collected by the Statistical Center and analyzed as of May 1996
for DFI and OS using Wilcoxon test and log-rank analysis. RESULTS: Two hun-
dred seventeen patients were found to be eligible according to the inclusion cri-
teria. Data from these patients were analyzed for DFI and OS after a median fol-
lowup of 46.3 months (50.2 months for VMO and 41.3 months for V). This final
analysis showed no statistically significant increase in either DFI ( P = 0.61) or OS
( P = 0.79) of patients treated with VMO (n = 104) compared with V (n = 113).
At 2-, 3-, and 5-year intervals, 47.8%, 43.8%, and 41.7% of patients treated with
VMO were disease-free, respectively, compared with 51.2%, 44.8%, and 40.4% of
patients treated with V. At the same intervals, 70.0%, 60.0%, and 48.6% of pa-
tients treated with VMO survived, compared with 65.4%, 55.6%, and 48.2% of pa-
tients treated with V. In a retrospective subset analysis, male patients aged 44–57
years (n = 20) with one to five positive nodes showed 18.9%, 26.82%, and 21.3%
improvement in survival at 2-, 3-, and 5-year intervals, respectively, after treat-
ment with VMO when compared with V (n = 18) ( P = 0.046). CONCLUSIONS:
This study was a randomized, multicenter, placebo-controlled evaluation of an ac-
tive specific immunotherapeutic agent to increase the DFI or OS of patients with
stage III melanoma in a surgical adjuvant setting. In this trial, ASI with VMO
when compared with V showed no difference in either DFI or OS. In a retrospec-
tive subset analysis, however, a subset of men with one to five positive nodes,
between the ages of 44 and 57 years, showed a survival advantage with VMO.
This results suggests that one must include a detailed subset analysis in the de-
sign of future trials of ASI for patients with American Joint Commission on Can-
cer stage III melanoma. An appropriate control arm also must be included in ASI
trials.
Editor’s Summary and Comments: This study has been reported at various
phases of maturation (Wallack, 1995, 1994, 1997). Essentially, the results at various
time points have been consistent with no significant differences noted between
the two groups in the primary analysis. A subgroup analysis of men 57 years of
age or younger with 1 to 5 positive lymph nodes, however, showed a 30% differ-
ence in survival at 4 years. Although the subset analysis is interesting, the data do
not support the use of vaccine melanoma oneolysate (VMO).
 RANDOMIZED CLINICAL TRIALS IN MELANOMA 51

References

1. Balch CM, Soong S, Ross MI, et al: Long-term results of a multi-institutional random-
ized trial comparing prognostic factors and surgical results for intermediate thickness
melanomas (1.0 to 4.0 mm). Intergroup Melanoma Surgical Trial. Ann Surg Oncol 7:87–
97, 2000
2. Balch CM, Soong SJ, Bartolucci AA, et al: Efficacy of an elective regional lymph node
dissection of 1 to 4 mm thick melanomas for patients 60 years of age and younger. Ann
Surg 224:255–263, 1996
3. Balch CM, Urist MM, Karakousis CP, et al: Efficacy of 2-cm surgical margins for
intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional random-
ized surgical trial. Ann Surg 218:262–267, 1993
4. Cascinelli N, Bufalino R, Morabito A, et al: Results of adjuvant interferon study in
WHO Melanoma Programme. Lancet 343:913–914, 1994
5. Cascinelli N, Morabito A, Santinami M, et al: Immediate or delayed dissection of
regional nodes in patients with melanoma of the trunk: A randomised trial. WHO
Melanoma Programme. Lancet 351:793–796, 1998
6. Chapman PB, Einhorn LH, Meyers ML, et al: Phase III multicenter randomized trial
of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma.
J Clin Oncol 17:2745–2751, 1999
7. Cocconi G, Bella M, Calabresi F, et al: Treatment of metastatic malignant melanoma
with dacarbazine plus tamoxifen. N Engl J Med 327:516–523, 1992
8. Creagan ET, Dalton RJ, Ahmann DL, et al: Randomized, surgical adjuvant clinical trial
of recombinant interferon alfa-2a in selected patients with malignant melanoma. J Clin
Oncol 13:2776–2783, 1995
9. Eton A, Legha S, Bedikian A: Phase III randomized trial of cisplatin, vinblastine and
dacarbazine (CVD) plus interleukin-2 (IL2) and interferon-alpha-2b (INF) versus CVD
in patients with metastatic melanoma. Proc Am Soc Clin Onc 2174, 2000
10. Ferri W, Agarwala SS, Gooding W, et al: A phase III randomized trial of dacar-
bazine and carboplatin with and without tamoxifen in the treatment of patients with
metastatic melanoma. Cancer 85:1979–1984, 1999
11. Grob JJ, Dreno B, de la SP, et al: Randomised trial of interferon alpha-2a as adju-
vant therapy in resected primary melanoma thicker than 1.5 mm without clinically de-
tectable node metastases. French Cooperative Group on Melanoma. Lancet 351:1905–
1910, 1998
12. Handley WS: The pathology of melanotic growths in relation to their operative treat-
ment. Lancet 1:927–935, 1907
13. Keilholz U, Goey SH, Punt CJ, et al: Interferon alfa-2a and interleukin-2 with or without
cisplatin in metastatic melanoma: A randomized trial of the European Organization for
Research and Treatment of Cancer Melanoma Cooperative Group. J Clin Oncol 15:2579–
2588, 1997
14. Kirkwood JM, Ibrahim JG, Sondak VK, et al: High- and low-dose interferon alfa-2b in
high-risk melanoma: First analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol
18:2444–2458, 2000
15. Kirkwood JM, Strawderman MH, Ernstoff MS, et al: Interferon alfa-2b adjuvant therapy
of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group
Trial EST 1684. J Clin Oncol 14:7–17, 1996
16. Koops HS, Vaglini M, Suciu S, et al: Prophylactic isolated limb perfusion for localized,
high-risk limb melanoma: Results of a multicenter randomized phase III trial. European
Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative
Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and
the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol
16:2906–2912, 1998
17. Livingston PO, Wong GY, Adluri S, et al: Improved survival in stage III melanoma
patients with GM2 antibodies: A randomized trial of adjuvant vaccination with GM2
ganglioside. J Clin Oncol 12:1036–1044, 1994
18. Middleton MR, Grob JJ, Aaronson N, et al: Randomized phase III study of temozolo-
mide versus dacarbazine in the treatment of patients with advanced metastatic malig-
nant melanoma. J Clin Oncol 18:158–166, 2000
52 SPANKNEBEL et al

19. Morton DL, Thompson JF, Essner R, et al: Validation of the accuracy of intraoperative
lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: A mul-
ticenter trial. Multicenter Selective Lymphadenectomy Trial Group. Ann Surg 230:453–
463, 1999
20. Olsen G: The malignant melanoma of the skin. New theories based on a study of 500
cases. Acta Chirurgica Scandinavica supplementum: 1–222, 1966
21. Pehamberger H, Soyer HP, Steiner A, et al: Adjuvant interferon alfa-2a treatment in re-
sected primary stage II cutaneous melanoma. Austrian Malignant Melanoma Coopera-
tive Group. J Clin Oncol 16:1425–1429, 1998
22. Ringborg U, Andersson R, Eldh J, et al: Resection margins of 2 versus 5 cm for cu-
taneous malignant melanoma with a tumor thickness of 0.8 to 2.0 mm: Randomized
study by the Swedish Melanoma Study Group. Cancer 77:1809–1814, 1996
23. Rosenberg SA, Lotze MT, Yang JC, et al: Prospective randomized trial of high-dose
interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the
treatment of patients with advanced cancer. J Natl Cancer Inst 85:622–632, 1993
24. Rusthoven JJ, Quirt IC, Iscoe NA, et al: Randomized, double-blind, placebo-controlled
trial comparing the response rates of carmustine, dacarbazine, and cisplatin with and
without tamoxifen in patients with metastatic melanoma. National Cancer Institute of
Canada Clinical Trials Group. J Clin Oncol 14:2083–2090, 1996
25. Sparano JA, Fisher RI, Sunderland M, et al: Randomized phase III trial of treatment
with high-dose interleukin-2 either alone or in combination with interferon alfa-2a in
patients with advanced melanoma. J Clin Oncol 11:1969–1977, 1993
26. Veronesi U, Adamus J, Bandiera DC, et al: Inefficacy of immediate node dissection in
stage I melanoma of the limbs. N Engl J Med 297:627–630, 1977
27. Veronesi U, Adamus J, Bandiera DC, et al: Stage I melanoma of the limbs. Immediate
versus delayed node dissection. Tumori 66:373–396, 1980
28. Veronesi U, Adamus J, Bandiera DC, et al: Delayed regional lymph node dissection in
stage I melanoma of the skin of the lower extremities. Cancer 49:2420–2430, 1982
29. Veronesi U, Cascinelli N, Adamus J, et al: Thin stage I primary cutaneous malignant
melanoma. Comparison of excision with margins of 1 or 3 cm. N Engl J Med 318:1159–
1162, 1988
30. Veronesi U, Cascinelli N: Narrow excision (1-cm margin): A safe procedure for thin cu-
taneous melanoma. Arch Surg 126:438–441, 1991
31. Verschraegen CF, Legha SS, Hersh EM, et al: Phase II study of vindesine and dacar-
bazine with or without non-specific stimulation of the immune system in patients with
metastatic melanoma. Eur J Cancer 29A:708–711, 1993
32. Wallack MK, Sivanandham M, Balch CM, et al: Surgical adjuvant active specific im-
munotherapy for patients with stage III melanoma: The final analysis of data from a
phase III, randomized, double-blind, multicenter vaccinia melanoma oncolysate trial.
J Am Coll Surg 187:69–77, 1998
33. Wallack MK, Sivanandham M, Balch CM, et al: A phase III randomized, double-blind
multiinstitutional trial of vaccinia melanoma oncolysate-active specific immunotherapy
for patients with stage II melanoma. Cancer 75:34–42, 1995
34. Wallack MK, Sivanandham M, Ditaranto K, et al: Increased survival of patients treated
with a vaccinia melanoma oncolysate vaccine: Second interim analysis of data from a
phase III, multi-institutional trial. Ann Surg 226:198–206, 1997
35. Wallack MK, Sivanandham M, Whooley B, et al: Favorable clinical responses in subsets
of patients from a randomized, multi-institutional melanoma vaccine trial. Ann Surg
Oncol 3:110–117, 1996

Address reprint requests to

Kathryn Spanknebel, MD
Department of Surgery
Memorial Sloan-Kettering Cancer Center
1275 York Avenue
New York, NY 10021

e-mail: spanknek@mskcc.org