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Clinical Trials |
2B in Patients with Metastatic Melanoma1
Department of Medicine, Division of Hematology/Oncology [M. B. A., J. A. G., D. F. M., L. T., J. W. M.] and the Biometrics Center [R. A. P.], Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, and Division of Hematology/Oncology, University of Illinois at Chicago, Chicago, Illinois 60612 [J. A. S., P. S.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Experimental Design: Patients received cisplatin, vinblastine, and temozolomide (20 mg/m2 cisplatin and 1.2 mg/m2 vinblastine i.v., days 1–4; 150 mg/m2 p.o. temozolomide, days 1–4) concurrent with interleukin 2 (9 MIU/m2/day) by continuous i.v. infusion on days 1–4 and IFN-
(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 also provided. Tumor staging included torso computed tomography scans and brain magnetic resonance imaging pretreatment, after cycle 4 and then every 3 months for 2 years. Torso computed tomography scans were also performed after cycle 2.
Results: A total of 147 treatment cycles were administered to 48 patients. No patients had received prior chemotherapy or interleukin 2; however, 19 (40%) had received prior adjuvant IFN-. Significant toxicities included 2 deaths from cardiac events (pericarditis al tamponade and posttreatment myocardial infarction with associated ventricular arrhythmia) and 3 gastrointestinal serious adverse events (pancreatitis, appendicitis, and upper GI bleed). No other nonhematological grade 4 toxicities were observed. Tumor responses were seen in 22 of 47 evaluable patients (relative risk, 47%) with 7 complete responses (15%). Response durations ranged from 1 to 29+ months with 1 currently ongoing. Median survival was 7.5 months. The CNS was the initial site of progression in 2 responding patients. An additional 6 responding patients developed CNS progression within 3 months of systemic progression. Initial CNS progression was significantly less frequent what was seen with the prior DTIC-based biochemotherapy regimen (2 of 22 versus 12 of 19; P = 0.001).
Conclusion: This regimen appears to be active and reasonably well tolerated in patients with metastatic melanoma. Although the substitution of temozolomide for DTIC reduced the incidence of initial CNS progression, this effect did not appear to result in an improved overall outcome.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2b showed that the biochemotherapy combination produced a doubling of the response rate and time to progression and a 3-month prolongation in median survival (6)
. Although both a National Cancer Institute Surgery Branch Trial comparing cisplatin, DTIC, and tamoxifen ± high-dose IL-2 and IFN- and an European Organization for Research and Treatment of Cancer trial comparing IL-2 and IFN- ± cisplatin also produced higher response rates for the biochemotherapy arms, no overall survival benefit was observed in either study (7
, 8)
. The determination of the overall value of biochemotherapy must await the completion of the Intergroup Phase III trial comparing concurrently administered CVD and IL-2 and IFN to CVD alone (9)
.
Despite high response rates with biochemotherapy, the response durations have been disappointing, perhaps explaining the equivocal impact of biochemotherapy therapy on overall survival in the three Phase III studies reported to date. Although 10–20% of responses to biochemotherapy may last >2 years, the median duration of response in most studies has been 
6 months (2
, 10 , 11)
. Furthermore, there appears to be a high rate of initial CNS progression in responding patients (10
, 12)
. For example, in a pilot trial of concurrent biochemotherapy, we reported that 11 of 19 major responders had the CNS as their initial site of relapse (13)
. Subsequent to this report, an additional patient exhibited an isolated CNS relapse 44 months after achieving a durable systemic response.4
Although occasionally such patients can be salvaged with local therapy to the CNS, the median survival after CNS relapse is only about 3–4 months (14)
. Successful approaches to preventing CNS relapse in patients exhibiting a major response to biochemotherapy might significantly enhance the duration of tumor responses and prolong overall survival.
Temozolomide is an analogue of DTIC that has the potential advantages of being p.o. absorbed and crossing relatively well into the CNS (15) . This ability to penetrate the CNS prompted the investigation of temozolomide therapy for primary brain tumors eventually leading to Food and Drug Administration approval of temozolomide for the treatment of patients with refractory anaplastic astrocytomas (16) . Temozolomide has also been shown to be active in patients with melanoma with responses observed in both systemic and CNS disease (17 , 18) . A Phase III European trial comparing temozolomide to DTIC in patients with metastatic melanoma showed the two agents to have equivalent antitumor activity (19) . Although most of these patients did not have routine CNS assessment after systemic progression, an analysis of a subset of patients so followed suggested that the incidence of CNS metastasis was less for the group of patients who had received temozolomide (20) . Therefore, in an effort to prevent initial CNS relapse and thereby enhance the quality and durabililty of responses to biochemotherapy, we performed a Phase II trial of a standard concurrent biochemotherapy regimen in which temozolomide had been substituted for DTIC.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1.5 mg/dl, serum creatinine <1.5 mg/dl, or calculated creatinine clearance 
75 ml/min. Patients were required to have an FEV1 of >2.0 liters or 75% of that predicted for height and age. Patients who were >50 years of age or with a history of cardiac disease (congestive heart failure, symptoms of coronary artery disease, serious cardiac arrhythmias, or prior myocardial infarction on electrocardiogram) were required to have a normal cardiac stress test. Screening tests for HIV antibody were required to be negative. Patients with active brain metastases were excluded. Patients with a history of brain metastasis had to be at least 2 months removed from definitive therapy, have been off corticosteroids, and have no evidence of disease progression or residual edema on pretreatment brain MRI. In addition, patients with other medical conditions requiring systemic corticosteroids, organ allografts, contraindications to the use of vasopressor agents, active infections requiring antibiotic therapy, a history of second malignancy other than nonmelanoma skin cancer, or carcinoma in situ or stage I carcinoma of the cervix were also excluded. Patients who received prior cytotoxic chemotherapy or IL-2 therapy were also 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 in this protocol. The protocol was approved by the Human Investigational Review Boards at both the Beth Israel Deaconess Medical Center and the University of Illinois at Chicago, and voluntary written informed consent was obtained from every patient.
Treatment Plan.
The dose and schedule for this treatment regimen are described in Table 1
. Patients were admitted to the hospital for the first 5 days of each treatment cycle and were treated with daily i.v. CVT in combination with IL-2 (Proleukin; Chiron) and IFN-2b (Intron; Schering). Therapy was administered on a regular oncology ward with available specialized patient monitoring. Patients were required to discontinue any antihypertensive therapy 24 h before beginning each treatment cycle. Before each inpatient treatment course, patients underwent placement of a triple lumen central venous catheter. This catheter was typically removed at the end of the first week of each treatment cycle. Patients received 250 mg of Keflex p.o. twice/day from day 1 to day 14 and 5 µg/kg/day granulocyte-colony stimulating factor (Neupogen; Amgen) s.c. on days 6–15 (or until absolute neutrophil count exceeded 10,000/dl) in an effort to prevent either catheter- or neutropenia-related infection. Thirty-two mg of Ondansetron i.v. or 1–2 mg of granisetron were administered 30 min before temozolomide and cisplatin administration on days 1–4 and continued on days 5–6 in an effort to control nausea and vomiting. One mg of Lorazepam i.v. or p.o. every 6 h and vigorous i.v. hydration were also provided. i.v. hydration and antiemetics were continued for 2–4 days after discharge in patients with persistent nausea and vomiting. Acetaminophen (650 mg every 4 h) was given to reduce febrile reactions, 150 mg of ranitidine p.o. every 12 h were given to prevent gastrointestinal bleeding, 25–50 mg of hydroxyzine hydrochloride p.o. every 6 h or 25 mg of diphenhydramine p.o. every 6 h were given for pruritus, and 25–50 mg of meperidine i.v. every 3 h was given for chills and rigors. Antidiarrheal agents and anxiolytics were administered as needed.
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Hypotension.
Vital signs were monitored every 4 h for stable patients receiving IL-2. Patients experiencing a fall in SBP <90 mm Hg received a 250-ml normal saline fluid bolus over 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 held 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 of age with no history of cardiac disease or hypertension) regardless of response to fluid boluses, IL-2 infusion was interrupted, and IFN administration was held. 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 of age with no history of cardiac disease or hypertension), dopamine was started at 2 µg/kg/min and 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 once the SBP was >90 mm Hg off of all vasopressor agents. 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 >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 once their blood pressure recovered. CVT were also held until the patient’s SBP recovered to >90 mm Hg without vasopressor support. If blood pressure failed to recover within 6 h of the scheduled time of CVT and IFN administration, therapy was omitted for that day.
Nephrotoxicity.
Patients had a serum creatinine checked before cisplatin administration on days 1–4. If serum creatinine was >1.6 mg/dl, cisplatin was held, 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 >1.6 mg/dl, cisplatin was held for that day. If creatinine remained greater than 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, temozolomide, 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 <1.5 mg/dl.
Hematological Toxicity.
Successive cycles of therapy were delayed if necessary until the WBC count and platelet count returned to the levels required for protocol eligibility. If the next cycle was delayed >2 weeks, the patient was taken off 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 temozolomide 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 developed hematological toxicity as described above, despite a 50% dose reduction in vinblastine and temozolomide, had further treatment held. Patients experiencing grade 3 or greater hematological toxicity during week 2 IFN therapy (days 8, 10, or 12) had IFN held for the remainder of the week. IFN was then administered at full dose in subsequent cycles.
Nausea and Vomiting.
Patients whose hospital discharge was delayed because of persistent nausea and vomiting or who experienced grade 3 nausea and vomiting after discharge had their IFN doses for week two withheld and had 25% dose reductions in both cisplatin and temozolomide in subsequent treatment cycles.
Neurotoxicity.
Patients underwent a thorough neurological exam before each cycle of therapy. If a patient developed a grade 2 peripheral neuropathy, cisplatin administration was discontinued. Patients experiencing grade 2 neuropsychiatric or neurocortical toxicity during therapy had IL-2 and IFN held 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.
Systemic tumor measurements were obtained after the second and fourth cycles of therapy and compared with those obtained within 2 weeks of initiating treatment. Follow-up scans were obtained 6 weeks and 3 months after completion of cycle 4 and every 3 months thereafter. Head MRI scans were obtained at the completion of cycle 4 and then every 3 months for the next 2 years.
Standard tumor 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 measurable lesions for at least two determinations, separated by a minimum of 4 weeks, with no new lesions or progression of existing lesions; a minor response was defined as >25% but <50% decrease in the sums of the areas of all 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 May 1, 2002.
Statistical Methods.
An initial study sample size of 30 patients was chosen with the anticipation that this would result in 10–15 major responders. When fewer than anticipated major responses were observed in the first 30 patients, the accrual goal was extended to 45 evaluable patients. The risk of CNS progression with CVD + IL-2/IFN biochemotherapy was assumed to be at least 50%. This study design implies that if 1 or fewer of at least 10 responding patients experienced an initial CNS progression, then one could be 95% certain that the true incidence of CNS progression among major responders was <40%. Fisher’s Exact test was used to compare the rate of initial CNS progression with the temozolomide-containing regimen to the historical data from patients who received CVD + IL-2/IFN.
Actuarial estimates of survival and response duration were calculated according to the method of Kaplan and Meier (21) . The association of patient characteristics (performance status, gender, prior IFN therapy, and AJCC stage) with treatment response was tested using Fisher’s exact test. All of the statistical analyses were performed using SAS version 6.12 software package. Data were updated and analyzed as of May 1, 2002.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Of the 48 patients, 26 had an ECOG performance status of 0, and 22 had a performance status of 1; 32 patients were men and 16 were women; and the median age was 53 years (range, 23–70 years). No patient had received prior chemotherapy or IL-2 therapy; however, 19 patients (40%) had received prior adjuvant IFN- therapy, and 8 (17%) had received another immune therapy before enrolling on this protocol. Table 2
also shows the distribution of enrolled patients by AJCC staging criteria (22)
and number of metastatic sites. Of note, 65% of patients were classified as stage M1c (visceral metastases beyond lung and/or elevated serum lactate dehydrogenase), and 41% of patients had more than two sites of metastases. Two patients had a history of CNS metastasis.
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. Four patients received only 1 cycle of therapy because of death while enrolled in the study (n = 1), appendicitis (n = 1), and early disease progression (n = 2), respectively. Thirty patients (62.5%) received more than two cycles of therapy. Dose modifications were necessary in <10% of treatment cycles and were generally related to hypotension (IL-2 and IFN), neutropenia (temozolomide and vinblastine), and nausea/vomiting (temozolomide and cisplatin).
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. The most common significant toxicities were hypotension (10% of patients; 3% of cycles), nausea and vomiting (21% of patients; 9% of cycles), and thrombocytopenia (44% of patients; 18% of cycles). Cardiac toxicity, primarily atrial fibrillation, was seen in 6 patients. Grade 4 neutropenia occurred in only 6 patients and 4% of the treatment cycles, and only 1 patient had a documented infection.
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2-week-old myocardial infarction and no residual melanoma. Three patients also experienced severe gastrointestinal toxicities. One patient developed pancreatitis after cycle 4 of therapy, another patient developed an upper GI bleed attributable to a Mallory Weiss tear after the first cycle of therapy, and the third patient developed an acute appendicitis on day 3 of therapy. All patients recovered completely from these events. The latter two patients went on to receive more biochemotherapy (one off protocol) without additional difficulty.
Response and Survival Data.
Of the 48 patients who received therapy, 47 patients were evaluable for response. One patient (the patient who developed appendicitis during the first cycle of therapy) was taken off protocol. Although this patient exhibited a response to an initial cycle of this therapy and subsequent IL-2 and DTIC-based biochemotherapy, because he received off-protocol therapy he was not considered evaluable for response to the treatment in this protocol. All patients are evaluable for survival.
Tumor response data are displayed in Table 5
. Tumor responses were seen in 22 patients (47%) with a median duration of 6 months (range, 1–29+ months). Seven patients (15%) had a complete response to therapy, and 15 patients (32%) had a partial response. One response is ongoing at >29 months. Response duration and progression-free survival curves are shown in Figs. 1
and 2
. Median overall survival was 7.5 months (Fig. 3)
, with 7 patients remaining alive at a median follow-up of 27 months (range, 21–42 months).
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. As anticipated, response rate, progression-free survival, and overall survival were better for the M1a patient population, although this reached statistical significance only for response rate. None of these outcomes appeared to correlate with gender, PS, or prior IFN use. Of note, 6 of 7 patients alive at last analysis had not received prior IFN therapy.
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. This difference was statistically significant (P = 0.001). Six additional responding patients developed CNS progression within 3 months of systemic progression. These data suggest with 95% certainty that the initial CNS progression rate with temozolomide-based biochemotherapy is <26%. Overall, CNS progression was documented in 36% (8 of 22) of responding and 31% (8 of 26) of nonresponding patients. Among the 8 responders on this study with documented CNS progression, the 2 with the CNS as initial site of progression were stage M1b (lung and lymph node metastases), whereas the other 6 who relapsed in the CNS within 3 months of systemic progression all had visceral metastases (M1c) at the time of presentation. Of the two patients with a history of treated CNS metastases, neither responded to temozolomide biochemotherapy; 1 progressed in lung and bone, whereas the other relapsed in the CNS subsequent to disease progression in the lung and soft tissue.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Initial CNS progression was significantly less common in patients treated with this temozolomide-containing biochemotherapy regimen relative to our prior experience with DTIC-based biochemotherapy. Only two instances of initial CNS progression were observed in 22 responding patients, compared with 12 in 19 patients treated with the DTIC-based regimen (P = 0.001). Six additional temozolomide-treated patients relapsed in the CNS within 3 months of systemic disease progression. Although these data show a significant reduction in the rate of initial CNS progression, response durations were disappointingly short, and median survival was only 7.5 months. Because survival is typically short in patients who relapse after responses to biochemotherapy, it is not surprising that overall survival was poor in this study, because the systemic relapse rate was high, despite the low rate of initial CNS relapse. Seven patients are currently alive at a median follow-up of 27 months. Six of these patients had not received prior IFN, suggesting that cross-resistance related to prior IFN exposure may limit long-term survival.
In the previously published pilot trial of DTIC-biochemotherapy, initial CNS relapses were unexpectedly high in responding patients, although CNS imaging was not performed at regular intervals after the completion of therapy, as was done in this current study. In the DTIC-biochemotherapy trial, follow-up ended after relapse, and therefore, there is no information regarding the frequency and timing of systemic relapses occurring after initial CNS progression. Likewise, there is no information from that study regarding the frequency and timing of CNS relapses occurring after initial systemic progression. Nevertheless, although the median response duration in the temozolomide-biochemotherapy and DTIC-biochemotherapy trials was similar (6 months versus 7 months, respectively), temozolomide treatment did appear to favor the outgrowth of systemic metastases before CNS metastases, whereas DTIC had the opposite effect. Alternatively, the quality of the systemic responses in the temozolomide biochemotherapy study may have been sufficiently inferior as to enable systemic relapse to occur before CNS relapse could be manifest, even by routine head MRI. This assumption is supported by the observation that in the temozolomide biochemotherapy, none of the 10 responding patients with M1c disease (greater systemic tumor burden) relapsed initially in the CNS, although 6 relapsed in the CNS after initial systemic progression. In contrast to the prior trial of DTIC-biochemotherapy (13) , 7 of the 10 responders with M1c disease relapsed initially in the CNS. Whatever the explanation, these data suggest that temozolomide may have altered the pattern of relapse in patients who responded to biochemotherapy.
Other approaches must be considered to overcome the early resistance and rapid disease progression that appear to limit the effectiveness of biochemotherapy treatments. Options currently under investigation include maintenance regimens involving outpatient injections of low-dose IL-2 and granulocyte/macrophage-colony stimulating factor alternating with intermittent pulses of high-dose IL-2. With this approach, the median time to progression was extended to 10.7 months, and several patients were converted either from stable disease to PR or from PR to CR (23) . If maintenance therapy appears to maintain the durability of systemic responses to biochemotherapy, then perhaps the inclusion of temozolomide in such a treatment regimen may have additional impact by reducing the frequency of late, isolated CNS progression.
In addition, recent studies have begun to test biochemotherapy in the high-risk adjuvant setting in an attempt to reduce both the incidence of CNS relapse and the immune resistance associated with either advanced disease state or prior IFN therapy. An Intergroup protocol comparing three cycles of biochemotherapy to a year of standard high-dose IFN- in patients after resection of regional nodal recurrence has been initiated recently. Once again, if late CNS relapse compromises the benefit of biochemotherapy relative to high-dose IFN alone in this study, then substitution of temozolomide for DTIC might overcome this problem. Nonetheless, at present, there appears to be no added value attributable to the ability of temozolomide to reduce the frequency of isolated CNS progression in melanoma patients responding to biochemotherapy.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This study was supported by grants from Amgen, Chiron, and Schering Plough. 
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. E-mail: matkins{at}caregroup.harvard.edu
3 The abbreviations used are: IL, interleukin; DTIC, dacarbazine; CVD, cisplatin, vinblastine, and DTIC; CVT, cisplatin, vinblastine, and oral temozolomide; CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; MRI, magnetic resonance imaging; SBP, systolic blood pressure; CR, complete response; PR, partial response; AJCC, American Joint Committee on Cancer; GI, gastrointestinal; PS, performance status.
4 M. B. Atkins, unpublished information.
Received 11/21/01; revised 6/ 3/02; accepted 6/ 5/02.
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