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Clinical Trials |
-2B in Patients with Metastatic Melanoma1
Department of Medicine, Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(5
MU/m2/day) on days 1–5, 8, 10, and 12. Prophylactic
antibiotics and a maximum of four cycles were administered. Routine
granulocyte colony-stimulating factor and aggressive antiemetics were
initiated after patients 7 and 14, respectively. Forty-four patients
were enrolled in this study. No patients had received prior
chemotherapy or interleukin 2; however, 23 (53%) had received prior
IFN-, mostly in the adjuvant setting. A total of 131 treatment
cycles was administered. Significant toxicities requiring dose
modification included: hypotension requiring pressors (15 episodes in
11 patients), grades 3/4 vomiting (12 episodes in 15 cycles; 5 episodes
in 12 patients (6 episodes in 9 cycles after initiation of the modified
antiemetic regimen), transient renal insufficiency (5 episodes
in 5 patients), grade 4 thrombocytopenia (24 episodes, 1 associated
with bleeding), neutropenia with or without fever (15 instances, only
11 in 112 cycles after routine use of granulocyte colony-stimulating
factor), and catheter-related bacteremia (2 patients). Five (16%) of
30 patients who were treated after the last protocol modification
experienced what we defined as unacceptable toxicity for a cooperative
group setting. Responses were seen in 19 of 40 evaluable patients
(relative risk, 48%) with 8 complete responses (20%). The median
response duration was 7 months (range, 1–17+ months) with one
currently ongoing. The central nervous system was the initial site of
relapse in 11 responding patients. The median survival duration was 11
months (range, 2–31 months). This modified, concurrent biochemotherapy
regimen is active and tolerable for use in a cooperative group setting.
Central nervous system relapse, however, remains a concern for
responders. This regimen is being compared with CVD in a Phase III
Intergroup Trial (Eastern Cooperative Oncology Group/Southwest Oncology
Group 3695). |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Immunotherapy, specifically IL-2 and/or IFN-, has also shown
activity in metastatic melanoma (9
, 10)
. High-dose bolus
IL-2 alone has produced responses in 15–20% of patients, with 5–10%
of patients achieving durable complete remissions (11)
.
Similar response rates have been seen with single-agent IFN-, but
the quality and durability of these responses have, in general, been
inferior to those reported with high-dose bolus IL-2 (12)
.
In an attempt to improve the response rate of patients treated with immunotherapy and the durability of response seen with combination chemotherapy, several investigators have combined cytotoxic chemotherapy with IL-2-based immunotherapy for the treatment of patients with metastatic melanoma. Composite results in nearly 400 patients who received cisplatin and IL-2-based biochemotherapy combinations have revealed a response rate of approximately 50%, with 10% of patients achieving a durable CR (13, 14, 15, 16, 17) . These results have suggested a potential advantage of biochemotherapy over chemotherapy alone; however, they were achieved in single-institution, Phase II trials and have yet to be reproduced in a randomized Phase III trial of biochemotherapy versus chemotherapy. Unfortunately, most of the regimens used in these studies were too toxic and complicated to be evaluated by cooperative groups unaccustomed to high-dose IL-2-based regimens.
The concurrent biochemotherapy regimen developed at the MDACC was seen
as an exception to these more toxic approaches (17)
. In
this regimen, CVD is administered concurrently with IFN--2a and
continuous infusion IL-2 over a 5-day period. This combination produced
responses in 34 (11 complete, 23 partial) of 53 patients (response
rate, 64%). Five patients (9%) remained disease free at >4 years.
Although significant side effects were still observed, including
neutropenic fever (64%), bacteremia (49%), and hypotension (39%), we
believed that by providing enhanced supportive care and developing a
strict, conservative approach to the management of hypotension and
other toxicities, these side effects could be kept to a tolerable
level. We now report the results of a pilot Phase II trial of this
modified, concurrent biochemotherapy regimen in patients with
metastatic melanoma.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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75% of predicted for height and age, and no history
of congestive heart failure, serious cardiac arrhythmias, angina, or
prior myocardial infarction. Patients who were >40 years of age or who
had a history of cardiac disease were required to have a normal cardiac
stress test. Screening tests for hepatitis B surface antigen and HIV
antibody were required to be negative. Patients with active brain
metastases on head CT scan, medical conditions requiring systemic
corticosteroids, organ allografts, contraindications to the use of
pressor agents, active infections requiring antibiotic therapy, a
history of second malignancy other than nonmelanoma skin cancer,
carcinoma in situ, or stage I carcinoma of the cervix were
excluded. Patients who had received prior chemotherapy or IL-2 therapy
were excluded. Prior immunotherapy with agents other than IL-2 in the
adjuvant or metastatic setting was allowed, but this had to be
completed 4 weeks before entry to the protocol. The protocol was
approved by the Human Investigational Review Boards at both New England
Medical Center and Beth Israel Deaconess Medical Center. Voluntary
written informed consent was obtained from every patient.
Treatment Plan.
The dose and schedule of this modified, concurrent biochemotherapy
regimen are described in Table 1
.
Patients were admitted to the hospital for the first 6 days of each
treatment cycle and were treated with CVD in combination with IL-2
(Proleukin, Chiron, Emeryville, CA) and IFN (Intron A, Schering Plow,
Kenilworth, NJ). Therapy was administered on a regular oncology ward
without any specialized patient monitoring. Patients were required to
discontinue any antihypertensive therapy 24 h before beginning
each treatment cycle. Before each course of therapy, patients underwent
placement of a central venous catheter, which was then removed at the
end of the first week of each cycle. Patients received ciprofloxacin
250 mg or Keflex 250 mg p.o. twice per day from day 1 to day 14 in an
effort to prevent catheter-related infection. The administration of
granulocyte colony-stimulating factor (5 µg/kg/day) on days 7 through
16 was made routine after patient number 7 and an aggressive approach
to antiemetic therapy (ondansteron 32 mg i.v. every day, Ativan 1 mg
i.v./p.o. every 6 h) was instituted after patient number 14.
Acetaminophen (650 mg every 4 h) to was given to reduce febrile
reactions, ranitidine (150 mg) p.o. every 12 h was given to
prevent gastrointestinal bleeding; hydroxyzine hydrochloride (25–50 mg
p.o. every 6 h) or diphenhydramine (25 mg p.o. every 6 h) was
given for pruritis, and meperidine (25–50 mg i.v. every 3 h) for
chills and rigors. Antidiarrheal agents and anxiolytics were given as
needed.
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. These
changes included the use of prophylactic antibiotics (ciprofloxacin or
Keflex) for days 1–14 and the removal of central lines after each
inpatient cycle. The dose of vinblastine was reduced to 4.8
mg/m2 per cycle. Granulocyte colony-stimulating
factor (5 µg/kg/day) and antiemetic therapy (ondansteron 32 mg i.v.
every day, Ativan 1 mg i.v./p.o. every 6 h) was administered as
described above. A maximum of four rather than six treatment cycles was
given. Strict, conservative, and explicit dose modification criteria
were developed for the management of hypotension, renal insufficiency,
hematological toxicity, and CNS toxicity.
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Hypotension.
Vital signs were monitored every 4 h for stable patients receiving
IL-2. Patients experiencing a fall in SBP to <90 mm Hg received a
bolus of 250 ml of normal saline fluid for >15 min. This was repeated
once for recurrent hypotension. If the SBP did not increase to >90 mm
Hg despite fluids, then IL-2 infusion was interrupted, and other
therapy was withheld until the SBP increased to >90 mm Hg, at which
time IL-2 and IFN were restarted at 50% of the baseline dose. If the
SBP fell to <85 mm Hg (80 mm Hg for patients <40 years old with no
history of cardiac disease or hypertension) regardless of response to
fluid boluses, IL-2 infusion was interrupted, and IFN administration
was withheld. Both agents were restarted at 50% of their original
doses when the SBP increased to >90 mm Hg. If the SBP remained <85 mm
Hg (80 mm Hg for patients <40 years old with no history of cardiac
disease or hypertension), dopamine was started at 2 µg/kg/min and was
increased up to a maximum of 6 µg/kg/min to keep SBP >90 mm Hg. IL-2
and IFN were restarted at 50% of their original doses when the SBP was
>90 mm Hg, with no pressors. Patients who did not respond sufficiently
to dopamine received Neo-Synephrine beginning at 0.2 µg/kg/min and
increased as necessary to keep SBP at >90 mm Hg. Patients requiring
both dopamine and Neo-Synephrine for blood pressure support did not
receive additional IL-2 therapy during that cycle but received IFN at
50% dose reduction when the blood pressure recovered. Cisplatin and
vinblastine also were withheld until the patient’s SBP was >90 mm Hg
without blood pressure support. If blood pressure failed to recover
within 6 h of the scheduled time of cisplatin, vinblastine,
and IFN administration, therapy was omitted for that day.
Nephrotoxicity.
Patients had a serum creatinine checked before cisplatin administration
on days 1 through 4. If serum creatinine was >1.6 mg/dl, cisplatin was
withheld, and a 500-ml normal saline fluid bolus was administered. If
the serum creatinine improved to 
1.6 mg/dl within 4 h, scheduled
cisplatin chemotherapy was administered. If creatinine remained at
>1.6 mg/dl on that day or subsequent days, cisplatin was withheld. If
creatinine remained >2.0 mg/dl despite fluid boluses, further
cisplatin during that cycle was withheld. Missed doses of cisplatin
were not replaced. Patients remained on vinblastine, IL-2, and IFN
unless grade 3 nephrotoxicity (creatinine >3.0 mg/dl) developed.
Subsequent cycles included full-dose cisplatin as long as the
creatinine returned to 1.6 mg/dl.
Hematological Toxicity.
Successive cycles of therapy were delayed if necessary until the WBC
count and platelet count returned to the levels required to begin
treatment. If the next cycle was delayed >2 weeks, the patient was
removed from the study. Patients experiencing grade 4 hematological
toxicity, grade 3 neutropenia with fever, or grade 3 thrombocytopenia
with bleeding had a 25% dose reduction of vinblastine and DTIC
on subsequent cycles. Patients with recurrent hematological toxicity,
as described above, despite dose reduction had a second 25% dose
reduction in subsequent cycles. Patients who, despite a 50% dose
reduction in vinblastine and DTIC, developed hematological toxicity as
described above were removed from the study. Patients experiencing
grade 3 hematological toxicity during week 2 of IFN therapy (days 8,
10, or 12) had IFN withheld for the remainder of the week. IFN was then
administered at full dose in subsequent cycles.
Neurotoxicity.
Patients underwent a thorough neurological exam before each cycle of
therapy. If a patient developed a peripheral neuropathy of grade 2 or
higher, cisplatin administration was discontinued. Patients
experiencing grade 2 neuropsychiatric or neurocortical toxicity during
therapy had IL-2 and IFN withheld until toxicity returned to grade
1. IL-2 and IFN were then restarted at a 50% dose reduction for
the remainder of therapy.
Response Criteria.
Tumor measurements were obtained after the second cycle of therapy and
compared with those obtained within 2 weeks of initiating treatment.
Standard response criteria were used. CR was defined as the complete
disappearance of all clinical and radiographic evidence of malignant
disease for at least two determinations separated by a minimum of 4
weeks; PR was defined as a >50% decrease in the sum of the products
of the perpendicular diameters of all of the measurable lesions for at
least two determinations separated by a minimum of 4 weeks, with no new
lesions or progression of existing lesions; minor response was defined
as >25% but <50% decrease in the sums of the areas of all of the
lesions on at least two determinations separated by a minimum of 4
weeks; progressive disease was defined as a >25% increase in the sum
of the areas of all lesions or the appearance of any new lesion.
Response durations were measured from the date of PR or CR and were
updated through April 1, 1999.
Statistical Methods.
The initial study sample size (30) was chosen to determine with
reasonable confidence (80%) whether this regimen was associated with
<30% incidence of unacceptable toxicity (i.e., hypotension
requiring pressors or any toxicity requiring readmission) during the
first two treatment cycles. If >7 patients developed significant
toxicity during this period, the regimen would have been declared
unacceptably toxic for use in a cooperative group setting and would
have been modified or reevaluated. After 14 patients were treated, the
protocol was modified in an attempt to reduce the incidence of
hematological and gastrointestinal toxicity. The sample size was then
increased to include 44 patients or 30 patients beyond the last
protocol modification. Only the last 30 patients were analyzed for
purposes of this safety end point.
Actuarial estimates of survival were calculated according to the method of Kaplan and Meier (18) . The association of patient characteristics (i.e., performance status, gender, prior therapy, number of sites of disease, and sites of metastasis) with treatment response was tested using Fisher’s exact test. All of the P values reported are two-sided. All of the statistical analyses were performed using SAS version 6.12 software package. Data were updated and analyzed as of April 1, 1999.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Of the 44 patients, 26 had an ECOG
performance status of 0, and 18 had a performance status of 1; 25
patients were men and 19 were women, and the median age was 45 years
(range, 19–71 years). Thirty-three patients (75%) had received
therapy in addition to surgery before entering this protocol, including
eight patients (18%) who had received local radiation therapy and 29
(66%) who had received systemic therapy. Twenty-three (53%) of 44
patients had received IFN in the adjuvant setting; however, no patient
had received prior chemotherapy or IL-2 therapy. Sixteen (36%) of 44
patients had more than two sites of metastatic disease, and 18 (41%)
patients had liver and/or bone metastases.
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. Thirty-nine patients (89%)
received at least two cycles of therapy, and 25 (57%) received more
than two cycles of therapy. Common reasons for dose modification
included hypotension (IL-2 and IFN), neutropenia and thrombocytopenia
(DTIC and vinblastine), and nausea/vomiting (cisplatin).
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. The most common significant
toxicities were myelosuppression and nausea/vomiting. Grade 4
neutropenia occurred in five (71%) of the first seven patients. After
the protocol was amended to include the routine administration of
G-CSF, 8 (22%) of 37 patients developed grade 4 neutropenia, and
neutropenic fever developed in 1 (0.8%) of 118 subsequent cycles of
therapy. Grade 3 or 4 nausea/vomiting occurred in 12 patients (27%)
and during 15 (11%) treatment cycles. After the initiation of the
modified antiemetic regimen, severe nausea/vomiting was seen in 5
patients (17%) and during 6 (6%) treatment cycles. Central venous
catheter-related bacteremia was documented in 2 patients. Grade 4
thrombocytopenia occurred in 19 patients (43%) and during 24 (18%)
cycles, but only one episode was associated with bleeding (tongue
bleeding, which resolved with platelet transfusion).
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Fifteen patients (34%) required readmission to the hospital or a delay
in discharge during 17 treatment cycles (13%). The majority of these
readmissions or delays in discharge were for neutropenia and fever or
dehydration secondary to nausea/vomiting. Toxicity observed in the last
30 patients is displayed in Table 6
.
After the routine use of G-CSF and the modified antiemetic regimen, 7
patients (23%) required readmission or a delay in discharge. This
involved 8 (8%) treatment cycles.
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). Eight patients (20%) had a CR to
therapy and 11 patients (28%) had a PR. One response is ongoing at 28
months. The CNS was the initial site of relapse for 11 of the 19
responding patients, including 4 of 8 complete responders.
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. The response rate to this
biochemotherapy did not correlate with ECOG performance status
(P = 0.2), gender (P = 0.75), prior
therapy (P = 0.7), prior IFN therapy (P = 1.0), prior radiation therapy (P = 1.0), number of
disease sites (P = 0.4), or presence of visceral
metastasis (P = 1.0).
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).The median survival of patients who
achieved a CR was 16.5 months (range, 6–31 months). Nineteen patients
survived longer than 12 months. Six patients remain alive at a median
of 21 months, one patient is disease-free, and five are alive with
disease.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This modified, concurrent biochemotherapy regimen seems to maintain antitumor activity. The objective response rate (CR + PR) of 48% and the CR rate of 20% are consistent with the results observed with other biochemotherapy regimens (13, 14, 15, 16, 17) . Responses were seen in all of the disease sites and with equal frequency in patients who had received prior IFN therapy in the adjuvant setting. In contrast to other systemic treatments in melanoma, patient response did not correlate with patient performance status, gender, prior therapy, number of disease sites, or specific disease sites.
The durability of responses and the percentage of durable CRs was disappointingly low. The median response duration was 7 months, with only one patient long-term disease-free. This disappointing result was, in large part, attributable to a high frequency of CNS relapse. Of the 19 patients who responded to therapy, 11 relapsed initially in the CNS. Eight of these 11 patients relapsed within 8 months of their initial response. Similar, although less dramatic, problems with CNS relapse have been seen by other investigators in patients responding to IL-2-based therapy (15 , 22) . Because the agents in this concurrent biochemotherapy protocol do not penetrate into the CNS, these CNS relapses likely stem from progression of metastatic disease that was below the level of detection of the pretreatment head CT scan. Perhaps the general poor prognosis of this patient population (82% with visceral disease and 75% with more than one site of metastasis) contributed to this high frequency of CNS involvement before treatment.
As systemic therapy for metastatic disease improves, isolated CNS relapse is likely to become a more prevalent obstacle. Clearly, new approaches need to be developed for controlling or preventing CNS metastases. Temozolomide, an analogue of DTIC that is well absorbed p.o. and is able to penetrate into the CNS, and fotemustine, a chloroethyl nitrosourea that rapidly crosses the blood-brain barrier, are two agents that could be included in biochemotherapy regimens that may potentially reduce this problem (23 , 24) . Alternatively, prophylactic CNS radiation could be used after biochemotherapy in major responders to prevent CNS metastases from developing. Another alternative might be to consider biochemotherapy administration in the high-risk adjuvant setting in which the likelihood of CNS seeding may be lower.
Other factors may have contributed to the short response duration and limited durable CR rate in this population. One factor is the high frequency of prior IFN exposure in this cohort. This adjuvant therapy may have fostered the development of a population of metastatic cells that were resistant to the immunomodulatory component of the therapy, resulting in clinical progression shortly after treatment ceased. Another factor is the duration of therapy. The MDACC concurrent biochemotherapy regimen treated patients for six cycles. In this trial. treatment was limited to four cycles of therapy in an attempt to decrease the incidence of cumulative toxicity (i.e., neurotoxicity, hematological toxicity, fatigue, and weight loss) that was seen in the MDACC trial (17) . However, if an immunomodulatory mechanism is responsible for the improved response rates seen with biochemotherapy relative to chemotherapy alone, it is unlikely that two more cycles of therapy would be necessary to trigger it.
Despite impressive response rates in this study and other
single-institution Phase II trials, there is currently no definitive
evidence that biochemotherapy provides a clear advantage over
chemotherapy alone in the treatment of metastatic melanoma. Recently,
several randomized Phase III investigations of biochemotherapy have
been initiated. The National Cancer Institute Surgery Branch has
compared the combination of cisplatin, DTIC, and tamoxifen, plus
high-dose IL-2 and IFN- to cisplatin, DTIC, and tamoxifen alone
(25)
. They reported that the response rate on the
biochemotherapy arm (44%) was higher than the chemotherapy-alone arm
(27%), but this improved antitumor activity did not translate into an
improved CR rate, number of durable CRs, or overall survival. The
European Organization for Research and Treatment of Cancer Melanoma
Group has recently completed a randomized Phase III trial that compared
biotherapy-alone (IL-2 and IFN) with biotherapy and cisplatin
chemotherapy in metastatic melanoma (26)
. They concluded
that both regimens were feasible in multicenter setting. Although the
response rate (33 versus 18%; P = 0.04) and
progression-free survival duration (92 versus 53 days;
P = 0.02) were significantly higher for the combination
arm, there was no difference in either overall survival or percentage
of patients remaining progression-free. These data raise concerns about
the true benefit of biochemotherapy and underscore the need to study
this question in large, multicenter, randomized Phase III trials. The
implementation of such a trial has been hampered by the lack of a
regimen suitable for testing in a cooperative group setting. The
development of this modified concurrent biochemotherapy regimen has
made it feasible to mount such a Phase III trial. This regimen is now
being compared with CVD alone in a Phase III trial (E3695) within the
ECOG and Southwest Oncology Group.
Depite the lack of a clear overall survival benefit in Phase III trials to date, all of the studies suggest that biochemotherapy can produce improved objective response rates, relative to chemotherapy or immunotherapy alone. These data suggest potential synergistic interactions between chemotherapy and immunotherapy components of these regimens. The proposed mechanisms of this potential synergy include cytokine enhancement of cisplatin-related DNA damage and cytotoxic chemotherapy-induced enhancement of melanoma antigen presentation, among others. Evidence supporting these various mechanisms are emerging from preclinical investigations and correlative laboratory studies conducted in conjunction with ongoing clinical trials (27, 28, 29, 30) . Understanding such mechanisms may not only lead to improved treatments for melanoma but also expand the therapeutic options for patients with other cisplatin- or IL-2-sensitive malignancies.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by a grant from Chiron and
Schering Plough, NIH Training Grant T32-CA094929 (to D. F. M.), and
Grant MOI RR00054 at New England Medical Center and Grant MOI RR 01032
at Beth Israel Deaconess Medical Center from the Division of Research
Resources, NIH. 
2 To whom requests for reprints should be
addressed, at Department of Medicine, Division of Hematology/Oncology,
Beth Israel Deaconess Medical Center, East Campus, Kirstein 158,
Boston, MA 02215; Phone: (617) 667-1930; Fax: (617) 975-8030; E-mail: matkins{at}caregroup.harvard.edu
3 The abbreviations used are: DTIC, dacarbazine;
IL, interleukin; MDAAC, M. D. Anderson Cancer Center; ECOG, Eastern
Cooperative Oncology Group; CT, computed tomography; CNS, central
nervous system; SBP, systolic blood pressure; CVD, cisplatin,
vinblastine, and DTIC; CR, complete response; PR, partial response;
FEV1, forced expiratory volume in 1 s.
Received 1/ 3/00; revised 3/ 7/00; accepted 3/ 8/00.
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