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Keywords:

  • malignant melanoma;
  • brain metastases;
  • stereotactic radiosurgery;
  • biochemotherapy

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND.

Brain metastases are an alarming complication of advanced melanoma, frequently contributing to patient demise. The authors performed a retrospective analysis to determine whether the treatment of metastatic melanoma with biochemotherapy would result in similar outcomes if brain metastases were first controlled with aggressive, central nervous system (CNS)-directed treatment.

METHODS.

Seventy melanoma patients were treated with biochemotherapy for metastatic melanoma between 1999 and 2005. Of these, 20 patients had recently diagnosed brain metastases, whereas 50 did not. Brain metastases (if present) were treated with stereotactic radiosurgery ≥28 days prior to systemic therapy. All patients were treated with biochemotherapy consisting of either dacarbazine or temozolomide in combination with a 96-hour continuous intravenous infusion of interleukin-2 and subcutaneous interferon-α-2B. The primary endpoint was survival from the time of the initial diagnosis of metastatic disease.

RESULTS.

Median survival from the time of the diagnosis of metastatic melanoma was 15.8 months for patients with brain metastases and 11.1 months for those without CNS involvement (P = .26 by the log-rank test; P = .075 by the Gehan Wilcoxon test). Dacarbazine-based and temozolomide-based regimens appeared similar with regard to their effect on overall survival and CNS disease progression. A plateau in further brain recurrences was observed in patients who survived for > 20 months.

CONCLUSIONS.

Data from the current study suggest that the outcome of biochemotherapy is comparable in patients with and those without brain metastases, if brain metastases are controlled with multidisciplinary treatment. Prolonged survival can be achieved in approximately 15% of patients, regardless of whether or not brain metastases are present. Cancer 2007. © 2007 American Cancer Society.

The overall survival rate for patients with malignant melanoma has gradually improved over the last 25 years. Four decades ago, 60% of patients who were diagnosed with melanoma died as a result, compared with 11% currently.1 Early detection combined with improved surgical strategies have accounted for the majority of this improvement. In contrast, the prognosis of patients diagnosed with stage IV melanoma has remained grave. Median survival has not changed much over the last decade and remains between 6 months to 10 months overall.2, 3 This disturbing statistic is, in part, explained by a lack of active agents for the treatment of melanoma.4 In addition, frequent involvement of the central nervous system (CNS) by malignant melanoma adds substantially to mortality. Clinically apparent brain metastases develop in at least 18% to 46% of patients with stage IV disease.5, 6 Autopsy series report roughly twice this prevalence of brain metastases in patients dying of melanoma.6–9 Factors that may be associated with the development of brain metastases include male gender and mucosal or head and neck primary tumors, as well as deep or ulcerated lesions.10 The development of brain metastases often leads directly to the patient's death.9, 10

Identification of a solitary CNS metastasis from melanoma that is amenable to potentially curative surgical resection is relatively uncommon, and patients generally have been treated with whole-brain radiotherapy (WBRT). In larger series of melanoma patients with brain metastases, the median survival of those treated with WBRT has reportedly ranged from 3.6 months to 4.8 months.10–13 Fife et al. recently published treatment results from 686 patients with melanoma brain metastases who were treated between 1985 and 2000 by the Sydney Melanoma Unit.14 These investigators found a median survival of 8.7 months to 8.9 months in 205 patients treated with surgery with or without subsequent radiotherapy, whereas patients treated with WBRT (236 patients) had a median survival of 3.4 months and patients who received supportive care only (210 patients) had a median survival of only 2.1 months.

Due to the perception of a very poor prognosis, the majority of clinical trials currently exclude all patients with melanoma brain metastases. We and others have reported the successful treatment of brain metastases patients using stereotactic radiosurgery (SRS) or gamma-knife-based radiotherapy in small numbers of patients.15–18 Due to the suggestion of prolonged survival being achievable with SRS-based treatment of brain metastases, we have included all patients with systemic metastatic disease, including those with recently diagnosed brain metastases, in institutional treatment protocols. We performed a retrospective analysis of patients treated with biochemotherapy between 1999 and 2006 to analyze the impact of brain metastases on eventual treatment outcome.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient Selection

After institutional review board approval of this retrospective review, we used institutional records to identify 70 patients with American Joint Committee on Cancer (AJCC) stage IV melanoma who had been treated with biochemotherapy at the Huntsman Cancer Institute between October 1999 and March 2006. Clinical information obtained included age, gender, date of initial melanoma diagnosis, location of the primary lesion, date of extracranial disease recurrence, date of diagnosis of brain metastases, treatment of CNS disease, date of first cycle of biochemotherapy, number of cycles and type of biochemotherapy administered, best clinical response, and date of last clinical follow-up or death.

Clinical Management Strategy

Neurosurgery, WBRT, and SRS were employed in a multidisciplinary approach to manage 36 patients with CNS involvement from malignant melanoma (20 of whom had metastatic disease at presentation and 16 of whom developed metastases during or after biochemotherapy). Patients were not excluded from treatment based on the type of CNS involvement. One patient with meningeal melanoma in addition to brain parenchyma lesions was included as were all patients with brain metastases (range, 1–20 metastases). In the group of 20 patients with brain metastases at the time of initial presentation, treatment incorporated neurosurgery in 55%, WBRT in 55%, and SRS in 80% of patients. Two modalities were combined in 70% of patients and all 3 modalities were employed in 20% of patients. Sixteen patients without intracranial metastases from malignant melanoma later developed disease progression in the CNS. A similar treatment approach was employed to treat the 16 patients with delayed CNS disease progression (these patients are included in this report).

Use of Surgical Resection and WBRT

Neurosurgery was employed to treat single accessible cortical lesions and for tissue diagnosis (if necessary). SRS was used as the primary treatment modality if patients had ≤5 brain metastases. WBRT with or without an SRS boost to dominant lesions was employed in patients with more than 5 brain metastases. WBRT was delivered in standard fashion, employing a dose of 30 gray (Gy) in 10 fractions.

SRS Planning and Treatment

Patients were treated with a BrainLAB™ m3® micromultileaf collimator (BrainLAB AG, Feldkirchen, Germany) attached to a Clinac 21EX® (Varian, Salt Lake City, UT) or a Novalis® (BrainLAB AG) SRS unit. High-resolution magnetic resonance imaging (MRI) (2-mm T1-postgadolinium) images were used to define target volumes and risk structures after fusion to computed tomography (CT) scans obtained with a stereotactic localizer frame (BrainLAB AG). BrainSCAN® (BrainLAB AG) software was used to fuse the images and plan the SRS with dynamic conformal arc techniques. This allowed each lesion to be treated with a single isocenter, with total treatments times of < 1 hour for up to 5 metastases. The treatment dose was prescribed to the isodose line, which covered ≥95% of the target volume (range, 74–96%). Conformity indices were calculated for each lesion, as described by Nakamura et al.19 The planned radiotherapy dose was based on the maximum dimension of the metastasis as follows: < 2 cm, 22 Gy; 2 to 3 cm, 18 Gy; and ≥3cm, 15 Gy. Patients with lesions measuring > 4 cm were usually not considered for SRS.

Systemic Therapy

All patients with metastatic melanoma were considered for biochemotherapy. Reasons for nontreatment included personal preference or significant coronary artery disease. This accounted for only 4 potentially eligible patients. Two patients were treated for metastatic ocular melanoma with biochemotherapy and were excluded from this analysis. One additional patient was treated for high-risk, stage III melanoma in an adjuvant fashion and did not meet eligibility requirements for this analysis. No patients were found to have brain metastasis only (recursive partitioning analysis [RPA] class I).

We utilized 2 biochemotherapy regimens during the time of this study. Regimen 1 (1999–2002) was comprised of dacarbazine at a dose of 800 mg/m2 given intravenously (iv) on Day 1; interleukin-2 (IL-2) given at a dose of 9 million IU/m2/day as a 96-hour, continuous iv infusion; and interferon-α-2B (IFN-α-2B) at a dose of 5 million U/m2 given subcutaneously on Days 1 to 5, 8, 10, and 12. In Regimen 2 (2002–2005), dacarbazine was replaced by temozolomide at a dose of 150 mg/m2 orally on Days 1–4, combined with IL-2 and IFN-α-2B, as described above. This change was instituted due to the high frequency of brain metastases and the theoretic benefit of temozolomide penetration into the CNS. Objective response to biochemotherapy was assessed by CT scans after every second cycle of treatment in each patient, based on maximum unidimensional tumor measurements (including within the CNS).

Patients who had a ≥25% reduction in the sum of maximum unidimensional tumor measurements on radiographs were considered to have a partial response (both in the CNS and at extracranial sites). Disease progression was considered to be a > 20% increase in the sum of maximum unidimensional tumor measurements or from maximum treatment response. Patients with stable disease or an objective response were allowed to continue to receive treatment. Disease progression or intolerable toxicity led to the discontinuation of biochemotherapy. In patients without brain metastases, CNS imaging was performed at the time of the development of new neurologic symptoms or at disease progression. Patients with previously treated brain metastasis were followed approximately every 2 months with brain MRI scans, with the intent of employing additional treatment (eg, SRS or WBRT) to control CNS disease progression.

Statistical Analysis

The primary endpoint of this retrospective analysis was overall survival from the time of diagnosis of metastatic disease. Survival was defined as the time (in months) from the date of diagnosis of stage IV melanoma until death or last clinical follow-up. Survival from the date of the administration of the first cycle of biochemotherapy also was calculated. Comparisons of overall survival and the time to CNS treatment failure were analyzed using the Kaplan-Meier method20 and P values were calculated using the log-rank test21 and Gehan Wilcoxon test.22

Subset analyses were performed on 50 patients who were initially without CNS involvement based on time to CNS failure after biochemotherapy as well as based on the type of biochemotherapy regimen employed (dacarbazine-based or temozolomide-based). The effect of age, gender, Eastern Cooperative Oncology Group Zubrod performance status, lactate dehydrogenase (LDH), site of primary melanoma, time to extracranial metastatic disease progression, and type of treatment of CNS metastatic disease also were evaluated for their effect on overall survival using univariate and multivariate Cox analyses. The Fisher exact test was used for a comparison of dichotomous variables. Statistical significance was established at a probability level of < .05. All statistical analyses were performed using Statistica 6.0 software (StatSoft Inc, Tulsa, OK).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

We identified 70 patients with stage IV melanoma who were treated with biochemotherapy at the Huntsman Cancer Institute between October 1999 and September 2005. Of these, 20 patients were found to have brain metastases during initial staging and concurrently with extracranial metastases. An additional 50 patients were found to have had extracranial metastases only. Characteristics of these groups are shown (Table 1). The groups did not differ significantly, with the exception of AJCC stage (58% vs 100%; P = .0025). It should be noted that, by definition, brain metastases result in a stage IVC designation. There was a trend toward more organ involvement in patients with brain metastases: 90% of patients (18 of 20 patients) with brain involvement had ≥3 organs sites involved, whereas only 76% of patients (38 of 50 patients) without brain involvement had ≥3 organ sites involved. However, this difference did not prove to be statistically significant (P = .32 by the Fisher exact test). Zubrod performance status and LDH were used as indirect measures of tumor burden, and were found to be similar in both groups. All 20 patients with CNS involvement belonged to RPA class II. Thirteen patients were aged > 65 years.

Table 1. Characteristics of Patients Treated With Biochemotherapy
 No CNS metastasis (n = 50)Brain metastasis (n = 20)
  • CNS indicates central nervous system; LDH, lactate dehydrogenase; AJCC, American Joint Committee on Cancer.

  • *

    One patient had a Zubrod performance status of 3.

  • P = .0025.

Gender
 Male36 (72%)14 (70%)
 Female14 (28%)6 (30%)
Median age (range), y49.7 (24.1–75.8)47.8 (26.1–63)
Zubrod performance status
 0–134 (68%)13 (65%)
 216 (32%)*7 (35%)
Elevated LDH21 (42%)7 (35%)
AJCC Stage
 IVA7 (14%)0 (0%)
 IVB14 (28%)0 (0%)
 IVC29 (58%)20 (100%)
Time to onset of metastases (range), y3.7 (0–30)2.5 (0–13)
No. of organ sites involved
 12 (4%)0 (0%)
 28 (16%)2 (10%)
 32 (4%)0 (0%)
 >338 (76%)18 (90%)

The apparent response to biochemotherapy treatment noted in melanoma patients with or without treated brain metastases is shown in Table 2. The number of biochemotherapy cycles administered to the 2 groups was not statistically significantly different. Patients with brain metastases received a median of 3.4 = 2.7 (mean ± standard deviation) cycles of biochemotherapy versus 2.9 ± 1.4 cycles in patients without brain metastases. A comparison of response rates in both groups also was performed, comparing the sum of maximum unidimensional tumor measurements between scans. Patients with brain metastases had a 5% objective response rate versus a rate of 14% in patients without brain involvement. Results were also calculated to include patients who appeared to be obtaining a therapeutic benefit from treatment. This was necessary because some patients with brain metastases were found to have stable brain findings on MRI, even in the presence of objective responses at extracranial sites. Therapeutic benefit was calculated by adding patients with stable disease to those with objective responses. A total of 44% of patients with brain metastases had achieved a therapeutic benefit from biochemotherapy versus 42% in the group without brain metastasis.

Table 2. Response Rates and Therapeutic Benefit After 2 Cycles of Biochemotherapy
 No CNS metastasis (n = 50)Brain metastasis (n = 20)P
  1. CNS indicates central nervous system; PR, partial response; CR, complete response; SD, stable disease.

Biochemotherapy
 Dacarbazine-based14 (28%)3 (15%) 
 Temozolomide-based36 (72%)17 (85%) 
Cycles of biochemotherapy, mean (± standard deviation)2.9 (±1.4)3.4 (±2.7).42
Objective response rate (PR+CR)14%5%.42
Therapeutic benefit (PR+CR+SD)42%45%1.00

Overall survival from the time of diagnosis of stage IV malignant melanoma for both groups was analyzed (Fig. 1). Surprisingly, the median survival from the time of diagnosis in patients with brain metastases was 15.8 months, compared with 11.1 months for 50 patients without CNS involvement (P = .26 by the log-rank test; P = .075 by the Wilcoxon test). The 1-year and 2-year survival rates in patients with brain metastases were 65% and 15%, respectively, whereas patients without brain metastases had rates of 48% and 18%, respectively. Another unexpected finding was that none of the 20 patients with brain metastases died within first 6 months after diagnosis, despite the delay in the onset of biochemotherapy to allow for the treatment of the brain metastases and resolution of any treatment-related edema (Fig. 1). This markedly exceeded the expected median survival derived from WBRT treatment series. Analysis of survival measured from the date of the first administered cycle of biochemotherapy also was performed (Fig. 2). The median survival from the onset of biochemotherapy for 20 patients with brain metastases was 8.1 months and was 7.1 months for 50 patients without CNS involvement (P = .64 by the log-rank test; P = .54 by the Gehan Wilcoxon test). The majority of patients were subsequently able to receive second-line or third-line therapy after failure of biochemotherapy.

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Figure 1. Overall survival from the time of diagnosis of metastatic melanoma. A Kaplan-Meier survival plot based on brain metastases is shown. Censored observations are indicated by tick marks. The survival difference between patients with and those without brain metastases was not found to be statistically significant (P = .26 by the log-rank test; P = .075 by the Wilcoxon test).

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Figure 2. Overall survival from the time of the initiation of biochemotherapy.

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Of the 50 patients without brain metastases at the time of diagnosis of metastatic melanoma, 16 (32%) eventually developed CNS involvement as a site of treatment failure after biochemotherapy. Overall survival (12.5 months) for the 16 patients who eventually developed CNS progression during or after biochemotherapy did not differ significantly from that of the 34 patients who never had any brain metastases. On univariate analysis, gender was the only variable found to be predictive of CNS failure. Nine of 14 women (64%) developed brain recurrences compared with 7 of 36 men (19%) (P = .002). The gender-related difference remained significant on multivariate analysis (P = .016). The type of biochemotherapy (temozolomide vs dacarbazine) was not found to be significant on multivariate analysis (P = .35). There was no apparent difference with regard to time to CNS disease progression when comparing dacarbazine chemotherapy and temozolomide, although the sample size was small. The 1-year brain metastasis-free survival rate was nearly identical: 76.4% ± 12.1% for dacarbazine-based biochemotherapy and 76.6% ± 6.4% for temozolomide-based biochemotherapy. No statistical difference was apparent when comparing 4 of 14 patients (28.6%) who developed brain metastases after dacarbazine-based biochemotherapy with 12 of 36 patients (33.3%) treated with temozolomide-based biochemotherapy. There also did not appear to be a difference in overall survival when comparing the entire data set of all 70 patients based on the type of biochemotherapy (dacarbazine vs temozolomide). The median survival of 17 patients treated with dacarbazine-based biochemotherapy was 11.9 months versus 12.8 months for 53 patients treated with temozolomide-based biochemotherapy. In 4 patients, CNS disease recurrence was the only sign of treatment failure. All patients had ≤5 new lesions, and these patients underwent SRS-based treatment as salvage therapy, with the addition of surgery or WBRT in 3 of these patients. Of these 4 patients, 3 patients had been treated with dacarbazine-based biotherapy and 1 patient was treated with temozolomide-based biochemotherapy.

Only 1 of 20 patients with brain metastases at the time of diagnosis developed radiation necrosis and required surgical resection for control of symptoms. This patient had been treated with both SRS plus WBRT. One additional patient (of 16) who developed brain metastases after biochemotherapy required surgical resection of a necrotic CNS metastasis after SRS and WBRT of a brain metastasis that developed after biochemotherapy. No patient treated with SRS alone developed radiation necrosis in a brain metastasis that required surgical intervention.

The time to CNS failure after biochemotherapy also was analyzed in patients who were free of brain metastases at the onset of treatment (Fig. 3). This analysis demonstrated a surprising finding: there appeared to be a plateau in CNS disease recurrences after 13 months (temozolomide-based biochemotherapy) and 20 months (dacarbazine-based biochemotherapy) in patients who appeared to have the most durable extracranial responses to treatment.

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Figure 3. Central nervous system recurrence-free survival.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

To our knowledge, little consensus currently exists regarding standard therapy for those approximately 8000 patients diagnosed each year in the U.S. with metastatic melanoma.23 This most likely reflects the low level of activity of all available agents.24 The alkylating agent dacarbazine remains a standard of care in community practice, and is a frequent comparator for new regimens.25, 26 Temozolomide, a related oral imidazo-netetrazine, has better cerebrospinal fluid penetration.27, 28 Both dacarbazine and temozolomide are converted to the same active metabolite, MTIC, that is responsible for DNA O6 guanosine methylation.29 Both dacarbazine and temozolomide result in response rates of approximately 10% to 20%, with a median duration of 3 to 4 months.26, 28, 30 A small randomized trial comparing dacarbazine and temozolomide as initial chemotherapy of metastatic melanoma demonstrated similar response rates and survival.30 Initial reports of combination chemotherapy, such as the so-called “Dartmouth regimen” (dacarbazine, carmustine, cisplatin, and tamoxifen) suggested markedly improved response rates in small phase 2 trials.31 These encouraging results were not confirmed in phase 3 prospective randomized trials.32, 33 In fact, median survival after combination chemotherapy proved to be no better than that observed after dacarbazine treatment alone.34

IL-2 was approved by the U.S. Food and Drug administration (FDA) for the treatment of metastatic melanoma in 1998. High-dose iv bolus IL-2 treatment resulted in overall objective response rates of approximately 12% to 21%.35, 36 IL-2 was able to induce durable complete responses and prolonged survival in a small minority (approximately 5%) of patients with metastatic melanoma, albeit with high levels of toxicity.37, 38 Legha et al. subsequently pioneered a concept of “biochemotherapy” using cisplatin, vinblastine, and dacarbazine in combination with a 96-hour continuous iv infusion of IL-2 and subcutaneous IFN-α-2B (CVD biochemotherapy).39, 40 In early single-institution phase 2 trials, CVD biochemotherapy was claimed to have achieved response rates of 60%, with complete responses noted in up to 24%.41 Subsequent larger clinical trials could not replicate these high response rates. A randomized trial by Eton et al. suggested a 3-month improvement in progression-free survival with CVD biochemotherapy compared with CVD chemotherapy alone.42 An as-yet unpublished Intergroup study (E3695) was closed at interim analysis because a statistical difference with regard to CVD versus CVD biochemotherapy was unlikely.43 Unfortunately, only a small number of centers are currently able to administer this complex and relatively toxic inpatient regimen. Additional attempts to decrease the toxicity of biochemotherapy by administering subcutaneous, outpatient IL-2 also have not demonstrated a benefit for biochemotherapy versus chemotherapy alone.44–46

Melanoma is responsible for 10% of all brain metastases and ranks second highest in incidence proportion percentage for brain metastases from all solid tumors.47 Brain involvement leads directly to death in the majority of patients.9 CNS involvement occurs with such a high frequency in patients with metastatic melanoma that brain metastases must be expected and management strategies incorporated into the overall treatment plan. Therefore, we have taken an aggressive approach for the detection and treatment of brain metastases. If brain metastases are identified, patients are aggressively treated using an SRS-based paradigm. Our institutional experience in 44 patients with CNS metastases undergoing multidisciplinary treatment incorporating SRS between 1999 and 2004 found a median survival of 11.1 months.18 This prior report was restricted to patients receiving SRS at the Huntsman Cancer Institute and did not include patients treated at other institutions. Twenty patients of the 44 in the report were eventually treated with biochemotherapy. Seventeen patients from that study are included in the current analysis. Eleven were patients who were treated with SRS-based radiotherapy prior to the initiation of biochemotherapy. Six additional patients required SRS after CNS failure after biochemotherapy. Due to the protracted control of brain metastases obtained using this approach, we hypothesized that patients with appropriately treated brain metastases might have outcomes after biochemotherapy that are similar to those of patients without brain metastases.

The purpose of the current study was not to evaluate the effectiveness of this biochemotherapy regimen but rather to measure the impact of brain metastases on outcome in patients eligible for IL-2-based treatment. The results of the current study demonstrated that biochemotherapy resulted in a comparable outcome regardless of whether a patient was diagnosed with brain metastases. Overall survival was found to be similar in both groups, with the trend actually favoring the group of patients with CNS metastatic involvement. Objective responses were noted in 13% of patients in the current study (including both CNS and extracranial sites). Only 1 patient achieved a complete response (1.4%) and a second patient was converted to a complete response by surgical resection of a solitary residual site of disease. This objective response rate, although low, appears comparable to that reported in other previous biochemotherapy studies.48 The therapeutic benefit rate (incorporating patients with objective responses and stable disease) was calculated in our patients because it became apparent that prolonged disease stabilization was being observed in a number of them. This finding resulted because SRS-treated CNS lesions were frequently interpreted as being “stable” on MRI scans. Of note, the 20 patients with brain metastases had lower apparent objective response rates but a similar therapeutic benefit rate compared with patients without CNS metastases. It should be noted that 42% of 37 patients surviving > 12 months from the time of diagnosis of metastatic melanoma had stable disease as their best response to biochemotherapy, whereas only 3% achieved a complete response and 13% a partial response. Of the 12 patients alive over 24 months, 46% had stable disease as their best response to biochemotherapy, whereas only 8% achieved a complete response and 17% a partial response. The current study results raise concerns regarding the relevance of the endpoints used to judge the outcome of clinical trials in patients with brain metastases. Our data suggest that the percentage of patients alive at 1 or 2 years may be of significant value in interpreting the clinical benefit of melanoma treatment. It should be noted that nearly all of the current study patients were able to receive additional salvage treatment after disease progression after biochemotherapy, including clinical trials with chemotherapy and vaccines.

Improved CNS penetration of temozolomide has been postulated to decrease CNS melanoma recurrences.27, 28 The role of temozolomide in the treatment of established brain metastases is also not clear. A large phase 2 study of temozolomide as the primary treatment of brain metastases found a very low response rate and median progression-free survival of only 2 months.49 In studies of temozolomide in combination with WBRT, Antonadou et al. reported a high response rate (96%) for the combination of temozolomide with WBRT in a randomized phase 2 trial in brain metastases derived from a variety of cancers.50 Unfortunately, this did not translate into improved overall survival. Margolin et al. reported another phase 2 study of temozolomide plus WBRT that was restricted to melanoma patients with brain metastases. None of the patients in this study had received prior chemotherapy. Response rates were much lower, with only 1 patient of 31 achieving a complete response. The median overall survival was a disappointing 6 months (similar to historic controls).51 It also should be noted that CNS progression of melanoma is rarely independent of extracranial disease. Thus, patients with controlled CNS metastases may still die of their disease if the extracranial component is not treated effectively.

In the current study, 53 patients were treated with temozolomide-based biochemotherapy versus 17 patients who were treated with dacarbazine-based treatment. We performed an exploratory analysis of the 50 patients without brain metastases prior to biochemotherapy to evaluate the role of dacarbazine versus temozolomide. There was no significant difference noted with regard to overall survival. The 14 patients who received dacarbazine had a 28.6% incidence of new CNS metastases versus a 33.3% risk in the 36 patients who were treated using temozolomide-based biochemotherapy (difference not statistically significant). Thus, the results of the current study do not suggest that temozolomide-based biochemotherapy is superior to dacarbazine-based treatment for the prevention of new melanoma brain metastases, although only a small number of patients in the current study were treated with dacarbazine.

A comparison of the 16 patients who initially did not have brain metastases at the time of presentation but who subsequently developed them after biochemotherapy versus the 34 patients who never developed brain involvement demonstrated that female gender was the only variable associated with an increased risk of CNS disease progression. This finding was surprising and unexplained because female gender is generally regarded as a good prognostic factor in overall melanoma survival. Only 4 of these 16 patients developed disease recurrence with isolated CNS metastases without extracranial disease progression. It is interesting to note that 3 of these 4 patients had been treated with dacarbazine, compared with 1 patient who received temozolomide-based biochemotherapy. All patients were retreated using either SRS, surgery, or WBRT.

Another unexpected finding was a plateau in CNS disease recurrence approximately 13 to 20 months after both temozolomide-based or dacarbazine-based biochemotherapy. This finding suggests the hypothesis that metastatic reseeding of the brain from extracranial sources diminishes and becomes self-limited with effective systemic therapy if CNS disease is controlled with SRS-based therapy.

In conclusion, all currently available agents used to treat melanoma are, at best, minimally active. More effective disease remission-inducing agents are badly needed. Although biochemotherapy has demonstrated minimal impact on median progression-free survival rates, its value, similar to that of high-dose IL-2, is in the 5% to 10% of patients who achieve durable remission or stable disease with prolonged survival. A major hypothesis generated from the results of the current study is that patients with adequately treated brain metastases from melanoma can have overall survival rates that are equivalent to patients with metastatic disease without CNS involvement. To date, such patients have been excluded from clinical trials, which does not appear warranted. As with all small, single-institution retrospective analyses or phase 2 trials, the results of the current study should be interpreted with caution. Although we attempted to include all eligible patients in our treatment analysis, there may well be institution-related referral, screening, and treatment biases that are difficult to characterize. We present these promising results in the hope of encouraging verification of this treatment approach in multi-institution trials.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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