Journal of Clinical Oncology, Vol 20, Issue 8
(April), 2002: 2045-2052
© 2002 American Society for Clinical Oncology
Sequential Biochemotherapy Versus Chemotherapy for Metastatic Melanoma: Results From a Phase III Randomized Trial
By Omar Eton,
Sewa S. Legha,
Agop Y. Bedikian,
J. Jack Lee,
Antonio C. Buzaid,
Cynthia Hodges,
Sigrid E. Ring,
Nicholas E. Papadopoulos,
Carl Plager,
Mary Jo East,
Feng Zhan,
Robert S. Benjamin
From the Departments Melanoma/Sarcoma and Biostatistics, The University of Texas M.D. Anderson Cancer Center, and St Luke’s Episcopal Hospital, Houston, TX, and Oncology Center of the Hospital Sirio-Libanes, São Paulo, Brazil.
Address reprint requests to Omar Eton, MD, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 430, Houston, TX 77030; email: oeton{at}mdanderson.org
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ABSTRACT
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PURPOSE: The addition of cytokines to chemotherapy has produced encouraging results in advanced melanoma. In this phase III trial, we compared the effects of chemotherapy (cisplatin, vinblastine, and dacarbazine [CVD]) with those of sequential biochemotherapy consisting of CVD plus interleukin-2 and interferon alfa-2b.
PATIENTS AND METHODS: Metastatic melanoma patients who had not previously received chemotherapy were stratified by prognostic factors and given chemotherapy or biochemotherapy. CVD consisted of dacarbazine (days 1 and 22) and cisplatin and vinblastine (days 1 to 4 and 22 to 25). Biochemotherapy involved CVD with vinblastine reduced 25% plus interleukin-2 by 24-hour continuous infusion (on days 5 to 8, 17 to 20, and 26 to 29) and interferon alfa-2b by subcutaneous injection (on days 5 to 9, 17 to 21, and 26 to 30). Response was assessed every 6 weeks.
RESULTS: Among 190 patients enrolled, 91 were assessable for biochemotherapy and 92 for chemotherapy. Ten percent of the patients were alive a median of 52 months from start of therapy. Response rates were 48% for biochemotherapy and 25% for chemotherapy (P = .001); six patients given biochemotherapy and two given chemotherapy had complete responses. Median time to progression (TTP) was 4.9 months for biochemotherapy and 2.4 months for chemotherapy (P = .008); median survival was 11.9 and 9.2 months, respectively (P = .06). The influence of treatment on TTP and survival was confirmed in multivariate analyses with other prognostic factors not included in the original stratification. Biochemotherapy produced substantially more constitutional, hemodynamic, and myelosuppressive toxic effects.
CONCLUSION: Cytokines substantially augment the antitumor activity of chemotherapy at the expense of considerable toxicity in patients with metastatic melanoma.
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INTRODUCTION
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MALIGNANT MELANOMA IS a solid tumor that is relatively resistant to systemic treatment and carries a poor prognosis at advanced stages.1 However, chemotherapy with one or more drugs can produce palliative clinical responses in some patients. For example, we and others found that a 5-day regimen consisting of cisplatin, vinblastine, and dacarbazine (CVD), administered at 3-week intervals, produced response rates of 20% to 30%, with the most noticeable responses in liver metastases.2 However, responses typically are not long lasting, and the complete response rates are less than 5%. Moreover, this combination chemotherapy regimen was no more effective than dacarbazine alone at prolonging survival.3
Cytokines such as interferons and interleukins also produce clinical responses in 10% to 20% of patients with metastatic melanoma.4,5 Interferon alfa-2b is approved for use in patients at high risk for recurrence after surgical resection of primary melanoma or lymph node metastases. Interleukin-2, also approved for use in advanced melanoma, produced durable complete remission rates of approximately 4%.5 However, the combination of interferon alfa-2b and interleukin-2 has not produced incremental gains in overall and complete response rates.6,7
The modest clinical effectiveness of chemotherapy and cytokine therapy given separately prompted evaluation of the two modalities given together (biochemotherapy or chemoimmunotherapy). We and others conducted a series of studies evaluating various combinations of chemotherapy with interleukin-2 and interferon alfa-2b in patients with advanced melanoma. Sequential and concurrent biochemotherapy produced overall response rates of 60% to 70% and complete response rates of 20% to 30%, which are considerable improvements over previous results. Coincident with this improved clinical effectiveness was a doubling in median time to progression (TTP) and a modest improvement in median overall survival duration over that of combination chemotherapy.8-10 Similarly encouraging results have also been reported by others.11,12
On the basis of these results, we began a phase III prospective, randomized trial in 1993 to compare the effects of sequential biochemotherapy with CVD plus interferon alfa-2b and interleukin-2 with those of chemotherapy with the same drugs on the clinical response, overall survival, and TTP for patients with advanced melanoma. Herein we report the results of this trial.
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PATIENTS AND METHODS
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Our previous experience treating patients with biochemotherapy allowed us to set less restrictive criteria for enrollment onto the current trial. Patients were eligible if they had advanced, inoperable nonchoroidal metastatic melanoma with indicator lesions, an Eastern Cooperative Oncology Group (ECOG) score of 0 to 3 (Karnofsky performance status of  40%), clinical and laboratory evidence of unimpaired function of major organs, and expected survival time of at least 8 weeks. Exclusion criteria were previous systemic chemotherapy, the presence of other significant illnesses or malignancies, and symptomatic brain metastases. After stratification for sex, ECOG performance status, and tumor characteristics (Table 1), eligible patients were randomly assigned to receive sequential biochemotherapy or chemotherapy as described below. Number and sites of metastases were recorded but were not included as stratification criteria (Table 1). The protocol for this single-institution study was approved by the institutional review board of The University of Texas M.D. Anderson Cancer Center, and all patients gave written informed consent to participate before enrollment in accordance with institutional and federal guidelines.
Treatment Plan
Each treatment course consisted of two 21-day cycles of chemotherapy given over a 6-week period. Patients in the biochemotherapy group were also given three cycles of interleukin-2 and interferon alfa-2b. Patients were evaluated for tumor response every 6 weeks; those with evidence of tumor reduction repeated the treatment. Patients in the biochemotherapy group could receive up to five cytokine cycles; no further biotherapy was planned beginning with the fifth cycle of chemotherapy because of severe dose-limiting toxic effects (eg, myelosuppression).8
Chemotherapy consisted of cisplatin at a dose of 20 mg/m2 of body-surface area given on days 1 to 4 and 22 to 25, vinblastine 2 mg/m2 on days 1 to 4 and 22 to 25, and dacarbazine 800 mg/m2 on days 1 and 22. Chemotherapy was given on an outpatient basis. Biochemotherapy involved the same chemotherapy regimen except the vinblastine dose was reduced to 1.5 mg/m2 plus interleukin-2 (Proleukin; Chiron Corporation, Emeryville, CA) given as a 24-hour continuous infusion of 9 million IU/m2 body-surface area on days 5 to 8, 17 to 20, and 26 to 29 and interferon alfa-2b (Intron-A; Schering-Plough, Madison, NJ) given at a dose of 5 MU/m2 body-surface area/d subcutaneously on days 5 to 9, 17 to 21, and 26 to 30. Except for the first chemotherapy cycle, biochemotherapy was administered while the patients were hospitalized at the M.D. Anderson Cancer Center. Differences between this protocol and that of our previous trials2,8 were that the chemotherapy was given over 4 days rather than 5, the vinblastine dose given to the biochemotherapy group was 25% lower than that given to the chemotherapy group, and the cytokines were supplied by different companies (those in previous trials were supplied by Hoffman-LaRoche, Nutley, NJ).
Other details of the treatment plan and management of toxic reactions are given elsewhere.2,8 We sought to maintain dose and schedule intensity. Chemotherapy doses were designed to achieve a nadir neutrophil count of 250 ± 150/mm3 per 3-week cycle. Use of dopamine (up to 5 to 7 µg/kg/min) was permitted during biotherapy; corticosteroid use was not permitted during either biotherapy or chemotherapy. Chemotherapy was started as soon as the absolute neutrophil count exceeded 1,000/mm3 and the platelet count exceeded 100,000/mm3; biotherapy was started when those values were 500/mm3 and 50,000/mm3, respectively. The cisplatin dose was withheld when the serum creatinine concentration exceeded 2 mg/dL, the interleukin-2 dose was withheld when the serum creatinine or bilirubin concentration exceeded 3 mg/dL, and the interferon alfa-2b dose was withheld when the platelet count dropped below 50,000/mm3.
Clinical Assessments
Tumors were evaluated by radiography, computed tomography, and photography at baseline and at 6-week intervals thereafter. A complete response was defined as the disappearance of any evidence of metastatic disease, and a partial response was defined as a reduction of more than 50% in the sum of the products of the largest perpendicular diameters of metastatic lesions. Responses had to persist for at least 4 weeks; given the scanning intervals in this study, this requirement effectively became 6 weeks.
Statistical Analysis
The major end point was response rate; secondary end points were TTP and overall survival. Survival curves were calculated with the Kaplan-Meier method13 and compared with two-sided Gehan-Wilcoxon and log-rank tests.14 With a two-sided 5% significance level, this study was designed to distinguish a complete response rate of 5% versus 20% using the continuity correction  2 test15 with 80% power. For the survival end point, the study was designed to have 70% power to detect a 50% improvement in median survival time (from 9 to 13.5 months). Ninety assessable patients per treatment group were required to achieve these statistical end points. Univariate and multivariate stepwise logistic regression analyses and Cox regressions were performed with the SAS System (SAS Institute Inc, Cary, NC) to identify prognostic factors for response and survival.
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RESULTS
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Patients
Between October 1993 and May 1999, 190 patients were enrolled onto the study. Five of these patients were ineligible because of choroidal melanoma, coexisting lymphoma, previous chemotherapy, numerous uncontrolled brain metastases, or severe underlying cardiac disease (diagnosed on the first treatment day); one patient died before treatment began, and one patient refused treatment after randomization. Hence, 183 patients were assessable for response, with a median follow-up of 52 months among the long-term survivors (range, 27 to 87 months). The results presented below were analyzed in August 2001.
The trial was balanced for age, sex, previous adjuvant interferon therapy, performance status, disease stage, and baseline serum lactate dehydrogenase levels (Table 1). Only 16 patients (9%) had an ECOG performance score of 2 or 3, and 16 patients (9%) had received interferon previously. Only 21 patients (11%) had inoperable regional (stage III) disease; the remaining patients had advanced (stage IV) melanoma. Because the sites of metastases were not included as stratification criteria, a modest imbalance that favorably impacted the biochemotherapy arm was detected in the number of visceral organs involved with metastases, as listed in Table 1.
Intensity of Chemotherapy and Biotherapy Doses
We measured dose-intensity (percentage of planned doses given) in three different ways. The first was as a function of planned doses of chemotherapy or biotherapy during the first 6 weeks for all patients. The second was as a function of drug for all cycles administered. The third was by total dose of each chemotherapy drug given to the biochemotherapy group as a percentage of the doses given to the chemotherapy-only group. Dose-intensity for the chemotherapeutic drugs was at least 96% in both treatment groups, and it was at least 92% for biotherapy (Table 2).
Patients in the biochemotherapy group received 346 cycles of chemotherapy (mean ± SD, 3.8 ± 1.9 cycles; median, four cycles); 38% of patients received one or two cycles, 26% received three or four cycles, and 35% received five or six cycles. Patients in the chemotherapy group received 328 chemotherapy cycles (mean ± SD, 3.6 ± 2.1 cycles; median, two cycles); 51% of patients received one or two cycles, 16% received three or four cycles, and 33% received five or more cycles. Although the mean numbers of chemotherapy cycles given per patient did not differ between the two groups (P = .25, two-sided t test), patients in the biochemotherapy group received a median of two more chemotherapy cycles than did those in the chemotherapy group because just over 50% of patients on the chemotherapy arm (51%) had progressed after cycle 2. As for the cycles of biotherapy (interleukin-2 plus interferon alfa-2b) given, the biochemotherapy group received 412 cycles of biotherapy for a mean and median of six cycles per patient; 13% of patients received one or two cycles, 30% received three or four cycles, and 57% received five or six cycles.
Clinical Responses
Biochemotherapy produced a major response rate of 48% (95% confidence interval [CI], 38% to 59%), which is nearly twice that produced by chemotherapy alone (25%; 95% CI, 17% to 35%; P = .001, two-sided 2 test). The differential rate of response was consistent across prognostic groups, and the highest frequency of response was in patients with soft tissue metastases (skin, subcutaneous, lymph node), lung metastases, or both (Table 3). The complete response rate in the biochemotherapy group was only 7% (95% CI, 2% to 14%); the complete response rate in the chemotherapy group was 2% (95% CI, 0.2% to 8%; P = .14, two-sided 2 test). Of the six patients who showed a complete response after biochemotherapy, three were alive. Among those three, only two have remained free of disease, one at 75 months and the other at 48 months after completing treatment. The four complete responders with progressive disease had tumor progression within 15 months of finishing treatment with the first site of metastasis being the brain in all four patients; in two of these patients, the brain was the only site of recurrence. The two complete responses in the chemotherapy group lasted 19 and 21 months, and both patients were alive 27 and 58 months from start of treatment, respectively, and neither had evidence of brain metastases.
Among all 183 assessable patients, no difference was found in the prevalence of brain metastases before enrollment (12% in the biochemotherapy group and 15% in the chemotherapy group, P = .54) or after treatment (45% in the biochemotherapy group and 50% in the chemotherapy group, P = .70, two-sided 2 test). The overall incidence of brain metastases at the time of this report was 52% in the biochemotherapy group and 58% in the chemotherapy group (P = .42).
TTP
Biochemotherapy doubled the median TTP from 2.4 to 4.9 months (P = .008, two-sided log-rank test) (Fig 1A). The low incidence of long-term progression-free disease in either treatment group probably reflects the low complete-response rate in both groups. Also, among those patients who had a complete or a partial response, median TTP was no different between the two treatment groups (7.4 months for the 44 patients in the biochemotherapy group and 8 months for the 23 patients in the chemotherapy group, P = .77) (Fig 1B). Patients whose disease did not respond had median TTPs of 1.9 months (biochemotherapy group) and 1.5 months (chemotherapy group) (P = .16). In Fig 1B, we must emphasize that twice the number of responders made up the more favorable Kaplan-Meier curve for biochemotherapy than for chemotherapy.
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Fig 1. Kaplan-Meier estimates of TTP in the two treatment groups. (A) all patients; (B) patients who showed complete or partial response, A, and patients who did not show a major response, B. Abbreviations: CVD-Bio, biochemotherapy; CVD, chemotherapy; CR, complete response; PR, partial response.
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Survival
Fifty-one percent of the patients who were treated with chemotherapy alone were subsequently crossed over to receive interleukin-2 and interferon alfa-2b after progression of disease. Nevertheless, enrollment in biochemotherapy improved median survival time by 29%, or approximately 3 months, over that of chemotherapy (11.9 v 9.2 months, see Fig 2A). Thirteen patients in the biochemotherapy group (14.3%) were still alive with median follow-up of 66 or more months, as were six patients in the chemotherapy group (6.5%) for a median of 52 or more months (P = .03, two-sided Wilcoxon test; P = .06, two-sided log-rank test). Among those who had a complete or partial response to therapy, median survival time was 18.7 months for the biochemotherapy group (n = 44) and 15.4 months for the chemotherapy group (n = 23) (P = .99) (Fig 2B). Among patients whose disease did not respond to therapy, median survival was 8.4 months for the biochemotherapy group and 8.1 months for the chemotherapy group (P = .52). In Fig 2B, we must emphasize that twice the number of responders made up the more favorable Kaplan-Meier survival curve for biochemotherapy than for chemotherapy.
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Fig 2. Kaplan-Meier estimates of overall survival in the two treatment groups. (A) all patients; (B) patients who showed complete or partial response, A, and patients who did not show a major response, B. Abbreviations: CVD-Bio, biochemotherapy; CVD, chemotherapy; CR, complete response; PR, partial response.
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Prognostic Factors Analysis
We then evaluated the potential effect of prognostic factors known to have influenced survival in a similar patient population.1 Our univariate analysis identified the number of involved visceral organs as influencing response, TTP, and overall survival (Table 4). Number of involved visceral organs was not a stratification factor in this study and was not perfectly balanced between the two arms (Table 1). We therefore performed multiple covariate logistic regression analyses wherein treatment arm was included as a potential prognostic factor.
Treatment arm and number of involved visceral organs significantly influenced response (treatment arm: hazard ratio, 3.0 [95% CI, 1.5 to 5.9; P = .002, Wald test]; number of involved visceral organs [zero, one, or two]: hazard ratio, 2.1 [95% CI, 1.1 to 4.2; P = .03, Wald test]).
Factors adversely influencing TTP in univariate analysis were an ECOG performance score of 2 or 3, enrollment onto the CVD arm, increased number of involved visceral organs, the presence of brain metastases, and a high baseline serum lactate dehydrogenase level (Table 4). In a Cox model for TTP that incorporated the most potent prognostic factors, including the number of involved visceral organs, treatment arm remained a significant contributor to TTP (P = .006) (Table 5).
Factors adversely influencing survival in univariate analysis were an ECOG performance score of 2 or 3, a high serum lactate dehydrogenase level, increased number of involved visceral organs, advanced disease stage, the presence of brain metastases, and enrollment onto the CVD arm (Table 4). In a Cox model for overall survival that incorporated the most potent prognostic factors, including number of involved visceral organs, treatment remained an important contributor to survival within sample size constraints (P = .07) (Table 5).
Toxic Effects
Four treatment-related deaths occurred. Three were in the chemotherapy group, and one was in the biochemotherapy group (Table 6). Causes included neutropenic sepsis, which occurred after five courses of chemotherapy when the patient was at home, and treatment complications (ie, infection, renal failure, and bleeding) in the presence of extensive metastatic disease. The frequency of grade 3 or 4 toxic effects was considerably higher in the biochemotherapy group than in the chemotherapy group (Tables 6 and 7), a finding consistent with previous reports. Nevertheless, nearly all of the toxic effects associated with biochemotherapy were expected, reversible with cessation of treatment, and readily managed on an inpatient ward.8 Ninety percent of the patients were given dopamine (2 to 7 µg/kg/min) to help manage the hypotension and prerenal azotemia associated with interleukin-2. Toxic effects from the chemotherapy were managed in the outpatient setting.2 Only three patients in the biochemotherapy group and one patient in the chemotherapy group required supportive care in an intensive care unit at any time during treatment.
Biochemotherapy was associated with twice as many episodes of grade 3 or 4 thrombocytopenia and anemia as chemotherapy, which resulted in six times as many platelet transfusions and twice as many blood transfusions as were given to the chemotherapy group (Table 7). Thrombocytopenia (platelet count < 50,000/mm3) frequently resulted in abrogation of day 5 interferon alfa-2b, thereby reducing the dose-intensity of the interferon alfa-2b administered (Table 2). Because thrombocytopenia was the primary dose-limiting effect, granulocyte colony-stimulating factor was rarely used to assist in neutrophil recovery. The incidence of neutropenic fever was the same in both treatment groups (49% and 46%); however, twice as many incidents of catheter-related sepsis took place in the biochemotherapy group (29%) as in the chemotherapy group (13%).
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DISCUSSION
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The prognosis of patients with metastatic melanoma remains poor.16 In this prospective, randomized trial, we compared the effects of chemotherapy with CVD with those of chemotherapy plus biotherapy with interleukin-2 and interferon alfa-2b in patients with metastatic nonchoroidal melanoma. This study was remarkable for its broad inclusion criteria, its adherence to dose and schedule intensity at the expense of considerable toxicity and cost, and the continuity of investigators at a single tertiary-care institution that is uniquely configured to optimally treat metastatic melanoma with biochemotherapy. We found that sequential biochemotherapy replicated our earlier findings in terms of having significant effects on all three clinical targets, including a near doubling of response rate and median TTP, as well as improved median overall survival time. Nevertheless, the complete response rate for the tested regimen (7%) was considerably less than expected from our previous reports, in part because the eligibility criteria were less selective, permitting, for example, patients with poor performance status, multiple visceral organ disease involvement, and controlled brain metastases to be enrolled. The response rate by prognostic subgroup is listed in Table 3. Also, this trial permitted accrual of patients who were previously treated with interferon in the high-risk adjuvant setting, a practice that has since become widespread based on Food and Drug Administration guidelines. No conclusion can be made regarding the effect of previous interferon therapy on the durable response rate to biochemotherapy because fewer than a dozen patients (9%) received such therapy in either arm. This assessment is confirmed for response, TTP, and survival as shown by the univariate analyses (Table 4). There are other potential causes for the decrease in observed complete response rate that can be considered but not confirmed such as the change in the interleuken-2 and interferon alfa-2b preparations and the decrease in the dose of vinblastine in this trial compared with our previous phase II trials.
By not replicating the previously reported higher response rates of 20% to 30%, the observed low incidence of long-term progression-free disease in this trial is not unexpected. On a positive note, however, although the TTP curves by response overlap in Fig 1B, there are twice as many cases making up the favorable response curve for biochemotherapy than for chemotherapy. This same analysis applies to the survival curves in Fig 2B.
The finding that biochemotherapy produced a higher overall survival rate than did chemotherapy, as confirmed in a multifactorial analysis of prognostic factors, is especially noteworthy because this effect was detected despite the fact that 51% of the patients who were treated with chemotherapy alone were subsequently crossed over to receive interleukin-2 and interferon alfa-2b. Furthermore, as encouraging as biochemotherapy’s clinical results were for advanced melanoma, the absolute results could have been more impressive had enrollment been more selective because the greatest clinical impact was seen in patients with good performance status, soft tissue and/or lung metastases only, and no evidence of brain metastases.
In a similar phase III trial, Rosenberg et al17 at the National Cancer Institute (NCI) compared the effects of cisplatin, dacarbazine, and tamoxifen against those of the same chemotherapy followed by interleukin-2 and interferon alfa-2b. This was less-intensive chemotherapy with more-intensive interleukin-2 dosing than in the current trial. The NCI study was prematurely closed and enrolled 46% fewer patients compared with our study. Also, only 75% of the planned chemotherapy cycles were given to the chemoimmunotherapy group in the NCI study. Despite these differences, the response rates in the NCI and the current study were comparable. However, the survival curves in the NCI study favored the chemotherapy group, and they were in a manner previously unreported for combination chemotherapy.17 These survival results were unexpected, as were our own results from an earlier even more weakly powered randomized phase II trial, which shows a favorable survival trend for patients receiving biochemotherapy as tested herein over the same regimen with the biotherapy preceding the chemotherapy.8,9 These results underscore the importance of designing appropriately powered randomized trials that should also achieve relative dose equivalence in drugs common to both treatment arms.
One such trial, for which the results are eagerly anticipated, is the Intergroup E-3695 trial, in which the ECOG and Southwest Oncology Group will compare a modified version of a concurrent biochemotherapy regimen with chemotherapy with CVD.18,19 Concurrent biochemotherapy, developed at M.D. Anderson Cancer Center by Legha et al,10 is easier to administer and better tolerated than sequential biochemotherapy and has recently been shown to produce response and survival rates that are competitive with those of sequential biochemotherapy. Accrual for the Intergroup E-3695 trial is expected to be complete in 2001.
In summary, the results from this clinical trial confirm that cytokines substantially augment the clinical activity of chemotherapy in the treatment of metastatic melanoma, a solid tumor that historically has been resistant to chemotherapy. Combination systemic therapy has finally yielded clinical activity that exceeds the activity of any single component. The importance of this advance is tempered by its considerable toxicity and overall modest impact (median TTP and overall survival time were each improved by less than 3 months). Nevertheless, the positive results support continued clinical and mechanistic development of biochemotherapy as a response induction regimen in clinical trials. Such trials should carefully examine the dose and schedule of the drugs used so that biochemotherapy can be made more tolerable and cost-effective without compromising its clinical effectiveness. Additional strategies are required for response consolidation and maintenance and for management of brain metastases.
No mechanistic studies have explained the enhanced clinical activity observed with biochemotherapy, in part because such studies have often targeted host-specific factors as measured in the peripheral blood rather than tumor-specific factors as measured in the metastases. Responding soft tissue lesions that were biopsied early in the course of treatment are often devoid of inflammatory infiltrate (unpublished observation). With the emergence of new technologies, future studies must focus on describing the pathologic and molecular events that differentiate responding from nonresponding metastases. Serial biopsy specimens of soft tissue metastases can be readily obtained in patients with metastatic melanoma. Moreover, with half the patients responding to biochemotherapy, there is finally an opportunity to use bioinformatics to identify critical tumor-related factors that predict response to treatment.
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ACKNOWLEDGMENTS
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Supported in part by the Chiron Corp, Emeryville, CA.
We thank Sewa Legha for developing biochemotherapy, Donna Gerber, Ana Kempfer, Susan McIntyre, and the nurses and social workers for support of the patients, and Christine Wogan for editorial assistance.
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Submitted September 7, 2001;
accepted January 3, 2002.
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TOP
ABSTRACT
INTRODUCTION
