Japanese Journal of Clinical Oncology Advance Access originally published online on August 24, 2005
Japanese Journal of Clinical Oncology 2005 35(9):507-513; doi:10.1093/jjco/hyi141
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© 2005 Foundation for Promotion of Cancer Research
Complete Remission of Brain Metastases in Three Patients with Stage IV Melanoma Treated with BOLD and G-CSF
1 Department of Dermatology, University of Catanzaro, Magna Graecia, 2 Department of Dermatology, University of Rome, La Sapienza and 3 Department of Radiology, General Medicine I, University of Rome, La Sapienza, Italy
For reprints and all correspondence: Ugo Bottoni, Department of Dermatology, University of Catanzaro, Magna Graecia, Via Sinopoli, 9, 88100 Catanzaro, Italy. E-mail: ugobottoni{at}unicz.it
Received April 13, 2005; accepted June 19, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: Brain metastases are the most life-threatening among the secondary localizations of melanoma for their unresponsiveness to the surgical, radiotherapeutic and/or chemotherapeutic treatments.
Methods: Accidentally, we observed a complete response (CR) in a patient undergoing chemotherapy with bleomycin, vincristine or Oncovin, CCNU or lomustine, dacarbazine (BOLD) regimen for metastatic melanoma including brain metastases, who was also treated with G-CSF to manage a concomitant leukopenia. After this observation, seven more patients with stage IV melanoma with brain metastases were treated with BOLD regimen repeated every 6 weeks with administration of G-CSF in the intervals.
Results: Three patients presented CR (37.5%). Two patients stopped the treatment after two courses for evident progressive disease (25%). The other three patients showed stable disease (SD: 37.5%). Median duration of SD was 24 weeks. Among the eight patients, six (75%) achieved clinical benefit. Median time to progression was 8.5 months (range 0–74+ months). Median survival was 12.5 months (range 4–74+ months). Two patients are still alive and disease-free after 74 and 57 months, respectively.
Conclusion: We believe that the brilliant CR, the long duration of the disease-free intervals and the long survival in at least three of eight patients should encourage further research on BOLD with G-CSF for the treatment of advanced melanoma.
Key Words: brain metastases • melanoma • polychemotherapy • G-CSF • BOLD
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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The management of melanoma is an important medical issue. For patients with thin melanomas (
1 mm according to Breslow thickness) the 5 year survival is estimated to be from 89.9 to 100% (1). Therefore, early diagnosis and surgical removal can achieve complete cure. On the contrary, when the disease is advanced with metastases to internal organs, the 5 year survival is <10% (1) and the median overall survival has recently been evaluated to be between 2.2 and 3.5 months (2–4). Among the different sites of visceral metastases from melanoma, those localized to the brain are the most life-threatening for their unresponsiveness to the surgical, radiotherapeutic and/or chemotherapeutic treatments (4).
Accidentally, 6 years ago we observed a complete remission of metastatic melanoma with brain localizations in a patient undergoing chemotherapy with BOLD regimen who was also treated with G-CSF to manage a concomitant leukopenia. The remission persisted for more than 5 years. Based on this observation, we decided to treat other patients with metastatic melanoma using the combination of BOLD and G-CSF.
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PATIENTS AND METHODS |
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PATIENTS
We consecutively enrolled adult patients (>18 years old) referred to the Department of Dermatology, University of Rome, La Sapienza for histologically confirmed non-ocular melanoma, with disseminated metastases including brain localizations. Patients who met the following eligibility criteria were included: WHO performance status of 0 or 1; adequate hepatic function measured as serum bilirubin <1.5x upper limit of normal (ULN), serum ALT and serum AST <3x ULN; renal function (serum creatinine <1.5x ULN); and hematologic values assessed as absolute neutrophil count (ANC) >1500 cells/µl, hemoglobin >10 g/dl and platelet count >100 000/µl. Steroids were permitted as long as the dose was stable for at least 7 days before enrollment. Previous therapy was permitted but patients were ineligible if they had received prior immunotherapy, biological therapy or chemotherapy within 4 weeks.
The following data were registered: gender, age, site of primary melanoma, Breslow thickness, site(s) of metastases and WHO performance status.
All patients were treated with BOLD regimen (5). The therapy included bleomycin (B) at 15 mg intravenously on days 1 and 4, vincristine or Oncovin (O) at 1 mg/m2 intravenously on days 1 and 5, CCNU or lomustine (L) at 80 mg/m2 p.o. on day 1 and dacarbazine (DTIC) (D) 200 mg/m2 intravenously on days 1 through 5. We repeated the treatment every 6 weeks (instead of 4 weeks) and in the intervals we administered recombinant human G-CSF (rhG-CSF) (filgrastim). The drug was administered at the dosage of 5 µg/kg/day subcutis three times a week for 6 weeks during the intervals between the courses of chemotherapy.
TOXICITY AND RESPONSE ASSESSMENT
Toxicities were graded according to the National Cancer Institute's Common Toxicity Criteria (6). Patients were monitored for toxicity on day 1 of each treatment cycle, with a complete history, physical examination and a laboratory assessment including complete blood count (CBC), serum chemistry and urinalysis. In addition, CBC was performed on day 22 of each treatment cycle.
Gd-MRI and systemic computed tomography (CT) scans were performed at baseline and at the completion of every two cycles of treatment to assess response in brain metastases and extracranial sites of disease. After two courses of treatment, we controlled the clinical response according to Response Evaluation Criteria in Solid Tumors guidelines (7). We considered complete response (CR) as disappearance of all lesions; partial response (PR) as at least a 30% decrease in the sum of the longest diameter (LD) of lesions, taking as reference the baseline sum of LD; progressive disease (PD) as at least a 20% increase in the sum of the LD of lesions, taking as reference the smallest sum of LD recorded since the treatment started or the appearance of one or more new lesions; stable disease (SD) as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of LD since the treatment started.
DOSE MODIFICATIONS
Dose modifications were required in the presence of significant hematologic or non-hematologic adverse events. For patients with an ANC of less than 1500 cells/µl (grade 2) or a platelet count of less than 100 000/µl (grade 1), BOLD administration was delayed for 3 weeks until recovery to an ANC of >1500 cells/µl and platelet count of >100 000/µl. If after 3 weeks patients' ANCs remained less than 1500 cells/µl or their platelet counts remained less than 100 000/µl, they were discontinued from study treatment. For patients with non-hematologic grade 3 and 4 toxicities, BOLD dose was withheld until the toxicity resolved to no greater than grade 2, and then BOLD was restarted at the same dose level or a reduced dose at the investigator's discretion.
OBJECTIVES OF THE STUDY
The primary objective was to evaluate the response rate. Secondary objectives were to assess the median duration of responses, time to progression (TTP) and overall survival.
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RESULTS |
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PATIENT CHARACTERISTICS
A total of eight patients with metastatic melanoma who also presented brain metastases were enrolled between January 1998 and December 2000. Baseline characteristics of the patients and diseases are shown in Table 1. Six patients were males and two females. Median age was 62 years (range 36–70). In three subjects the site of primary tumor was unknown, whereas in others the primary cutaneous melanoma was localized on the back (two patients), on the foot (two patients) and on the left temporal region (one patient). The Breslow thickness in all patients with known primary tumor was >4 mm, except for one subject (patient #7) that presented a cutaneous melanoma of 3.5 mm thick.
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At the moment of our observation all patients presented brain metastases but no one was symptomatic. Brain metastases in patient #1 were multiple and widespread, the largest measuring 5 mm; patients #2 and #3 had a single secondary lesion of 15 mm; patient #4 had two metastases, the largest measuring 5 mm; patient #5 had a single secondary lesion of 38 mm; patient #6 had secondary lesion of 2 mm; patient #7 had three metastases, the largest measuring 15 mm; patient #8 had two metastases, the largest measuring 20 mm. Other sites of metastases were liver and lymph nodes in patient #1, bone, skin and lymph nodes in #4, lymph nodes in #5 and skin in #7. In all patients' performance status (PS WHO) was 1. Patients #1 and #2 had been previously treated with human recombinant interferon
2b. Patient #1 had been treated at the dosage of 3 MU for three times a week for 2 months, but therapy was discontinued 3 months before our consultation for PD. Patient #2 had previously been treated with long-term high dose interferon- adjuvant treatment according to the scheme of Kirkwood et al. (8), but after the first 2 weeks of treatment he refused to continue it. Patient #6 was treated 2 years before our observation with DTIC 200 mg/m2 intravenously for 5 days every 28 days for 6 cycles. He had also undergone surgical removal of a huge right perirenal metastasis and a brain metastasis, 24 and 6 months earlier, respectively. All other patients were naïve for antitumoral treatment. The median time from diagnosis of melanoma to development of brain metastases was 11 months. The median number of brain lesions was 2 (range, 1–6). Five of eight patients (62.5%) had at least two brain metastases.
RESPONSE
Objective response is presented in Table 2. Three of eight patients (37.5%) presented CR: patients #1, #4 and #6. After the first two courses, two patients (25%) discontinued treatment for evident PD, whereas three patients (37.5%) showed SD; and therefore, continued undergoing further courses of BOLD chemotherapy. Median duration of SD was four cycles (range 4–5 cycles). Therefore, among these patients six (75%) achieved clinical benefit. The median duration of response for these six patients was 33 months (range 8–74). Median TTP was 8.5 months (range 0–74+ months). Two patients (#4 and #6) are still alive and disease-free after 74 and 57 months, respectively. Median survival (from the beginning of BOLD treatment) was 12.5 months with range from 4 to 74+ months. Table 3 compares response rates of BOLD regimen of two studies found in the literature (5,11) to our results of BOLD associated with G-CSF. The results with BOLD and G-CSF are better than the ones with BOLD without G-CSF, but we have to consider that it is not a controlled clinical study.
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SAFETY
The most frequently reported adverse events are summarized in Table 4. Those most commonly observed were as follows: fatigue (100%), constipation (75%), fever (62.5%), musculoskeletal pain (50%), but headache, vomiting, diarrhea and confusion were reported only episodically. Among eight patients, six (75%) reported one or more grade 3 adverse events, namely, diarrhea in patient #1, musculoskeletal pain in #3, fatigue and fever in #4, musculoskeletal pain in #5 and #7, fatigue and headache in #8.
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Hematologic grade 3/4 adverse events were rare (Table 5). They included anemia in two patients (#4 and #7) and neutropenia only in one who was the first patient considered in our trial and who first started G-CSF treatment to recover from neutropenia. In one patient (#4) we registered also grade 3 toxicity with elevated levels of gamma-GT.
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Disease progression was the most common reason for treatment discontinuation. No patients discontinued study treatment because of adverse events.
We discuss here in detail about three patients with CR.
PATIENT #1
A 65-year-old man was referred to our Department of Dermatology in November 1997 with a diagnosis of metastatic melanoma. In June 1997, he had undergone surgical removal of an axillary mass that was histologically revealed to be a metastasis of melanoma. A primary tumor was never found and the patient did not report any past history of cutaneous lesions or any cutaneous procedures such as cryotherapy of electrocautery. In July 1997, an ultrasound of the liver revealed a secondary lesion in the VIII liver segment. He started a treatment with interferon 2b, but in November 1997 a MRI of the brain revealed multiple (at least six) cortical and subcortical frontal, parietal, occipital, thalamic and left posterior periventricular nodular lesions. The patient was referred to our Department where he underwent a first chemotherapeutic regimen with BOLD. Because he presented severe leukopenia after three weeks from the first course, we started treatment with G-CSF (filgrastim 30 mcg subcutis 3 times/week) and the second course was postponed with intervals of 6 weeks between the following cycles. Leukopenia improved and we continued BOLD treatment adding filgrastim in the 6 week intervals to prevent leukopenia. After the third cycle of therapy, the patient was subjected to a repeated MRI of the brain and a total body CT scan that documented the complete disappearance of the metastases in both brain and liver. The patient completed six courses of BOLD with G-CSF and was subsequently followed with laboratory and radiological examinations including MRI, CT scan, sonography, serum S-100 protein levels, which all resulted within normal ranges. After 73 months of disease-free survival he had acute abdominal pain and a total body CT scan showed widespread disease with multiple metastases. The patient died after few days.
PATIENT #4
A 62-year-old woman was referred to our Department in October 1998 for widespread metastatic melanoma with metastases to brain (two lesions), bone (nine lesions), subcutis (at least 20 nodules) and lymph nodes. In 1986, she underwent surgical removal of a pigmentary lesion from her left temporal region that histologically proved to be a superficial spreading melanoma of 4.5 mm thick, Clark's level IV. After 18 months melanoma recurred locally and was again surgically removed. She was disease-free until July 1998 when an inguinal mass was noted on her left groin. The mass was surgically excised and histological diagnosis was metastasis form melanoma. After few weeks several widespread subcutaneous nodules appeared on her trunk and limbs. Contemporarily, the patient experimented intense musculoskeletal pain. A bone scintigraphy revealed several bone metastases documented also by specific X-ray films. Total body CT scan and MRI of the brain were performed revealing two cerebral metastases. After staging procedures the patient started the first cycle of BOLD with G-CSF administered in the intervals. After two courses the patient experimented the remission of pain, and a total body CT scan and a brain MRI documented the regression of brain metastases (Fig. 1). However, she continued to be treated with BOLD and G-CSF for other eight courses until the complete disappearance of subcutaneous nodules and bone metastases (Fig. 2). The patient is currently disease-free and has been in complete remission for 74 months.
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PATIENT #6
A 63-year-old man was referred to our Department in April 2000 with a diagnosis of metastatic melanoma. A pigmentary lesion of the left emithorax had been removed in 1990 and the histologic diagnosis (performed in another hospital) had been junctional nevus. In 1996, a left axillary mass was surgically removed and histologically proved to be a metastasis of melanoma. A retrospective histologic revision of the lesion removed in 1990 at this time provided a diagnosis of superficially spreading melanoma of 0.8 mm Breslow thickness, Clark's level II. After surgery, the patient received chemotherapy with DTIC (200 mg/m2 for 5 days every 28 days for 6 cycles). A total body CT scan performed in June 1998 revealed a single brain lesion localized to the right frontal region and a large metastatic mass that enveloped the left kidney, the left adrenal gland and the spleen. The patient underwent laparotomic resection of the abdominal mass, which on histology showed the picture of metastasis from melanoma. Subsequently, he underwent brain radiotherapy with SD. In March 1999, the brain lesion increased in volume and was subsequently surgically removed. In March 2000, a new total body CT scan revealed the presence of two new cerebral metastases. The patient was then admitted to our hospital and BOLD regimen was started with G-CSF given in the intervals. After two cycles of chemotherapy a CT scan showed the total disappearance of both brain metastases. The patient refused to continue the chemotherapy and is currently followed up with laboratory and radiological exams. The patient is presently disease-free and has been in complete remission for 57 months.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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The efficacy of chemotherapy against melanoma has been disappointing. According to Crosby et al. (9), the gold standard in metastatic melanoma therapy remains DTIC. In control studies this drug showed clinical responses better than other drugs. However, its response rate of 25% is unsatisfactory and its capability to prolong overall survival remains inconclusive (1). To improve response rate and survival, DTIC has often been used in combination with other chemotherapeutic or immunotherapeutic agents. Several multidrug regimens have been studied: BOLD; CBDT (Cisplatin, BCNU, DTIC and Tamoxifen); CVD (Cisplatin, Vinblastine and DTIC). Response rates have been extremely variable, ranging from 9 to 55% (1,10). The BOLD regimen was originally proposed and used in 1980 by Seigler et al. who reported on 40% overall response (5). Unfortunately, these results were not confirmed by subsequent studies (11).
To improve the response, polychemotherapy has been tried in association with immunotherapy. For instance, BOLD has been associated with interferon- and interleukine-2 but without any significant increase in response rate or survival (12). Interferon 2b is currently FDA approved for the adjuvant treatment of stage IIb and stage III melanoma (American Joint Committee on Cancer 1997) (1). In the adjuvant treatment proposed by Kirkwood et al. (8) interferon 2b is administered initially at the dosage of 20 MU/m2/die intravenous for 1 month and then at the dosage of 10 MU/m2/die subcutaneous three times a week for 48 weeks. Several other cytokines including IL-2, IL-7 and IL-12, have been tested for the treatment of human metastatic melanoma (13,14). More recently, GM-CSF has been proven effective in the induction of an antitumor response in preclinical studies (15–22). Therefore, several clinical studies were performed in patients with metastatic disease (23–27) to test the antimelanoma effects of GM-CSF. GM-CSF effect is known to depend on activation of antigen presenting cells and macrophages as well as on the induction of specific antimelanoma immunity (15–27). While treatment with GM-CSF alone in advanced melanoma is not efficacious in eliminating an extensive tumor burden in both preclinical and human studies, it is being intensively studied as an adjuvant therapy and in combination with other immunomodulating or chemotherapeutic agents (28).
G-CSF has been less extensively studied than GM-CSF in the treatment of melanoma. Nevertheless, there are several reports on its antitumor activity against melanoma in both preclinical and preliminary clinical settings. When administered intratumorally, G-CSF exerted antitumor activity against the MmB16 murine melanoma (29). G-CSF, used to prevent IL-2 induced myelosuppression, was able to increase antitumor activity in IL-2 treated mice (30). The injection of rhG-CSF effectively inhibited the development of lung and liver metastasis by activating neutrophils and increasing cell number in murine tumors (31). An antitumor effect has been reported also in clinical studies (32).
Our experience is based on the accidental observation that in our first patient we administered G-CSF after BOLD to treat leukopenia due to aggressive polychemotherapy, registering a quite impressive CR that lasted for more than 5 years. Overall, in this group of eight patients, although still small, we observed 75% of clinical benefit with three CR. With respect to the three patients with CR, we have to emphasize that the diameter of brain metastases at presentation was 5 mm, whereas the patients who were refractory to the treatment had lesions of up to 38 mm. This is in agreement with the usual efficacy profile of antineoplastic agents that is higher against smaller lesions because of their increased proliferation rate compared to larger tumors. Furthermore, in two of three patients who obtained CR, the primary melanoma was of unknown origin and in the two patients who are still alive, brain metastases occurred more than 10 years after the first diagnosis. These clinical features may suggest that melanomas in these patients were immunologically recognized and somehow controlled and may explain the excellent response to this type of regimen that included an immunological modifier such as G-CSF. However, we must consider that in a recent paper on brain metastases from melanoma treated with temozolomide, 7 of 151 patients presented brain metstases 10 or more years after the initial diagnosis (4). In this group of 151 patients, only one was reported to obtain CR and the authors did not specify the duration of response and in this patient the time from the initial diagnosis of melanoma was more than 10 years (4). Therefore, we thought it is worthwhile to report our experience to invite discussions. Sporadic reports of CRs to chemotherapy as well as complete spontaneous regressions of metastatic melanoma do occur. Nevertheless, the brilliant CR, the long duration of the disease-free intervals and the long survival in at least three of eight patients made us to hypothesize that this treatment is indeed effective. In particular, we chose BOLD regimen for the treatment of patients with brain metastases because it includes lomustine, a nitrosurea alkylating agent that, being a small and lipophilic molecule, has the capability to pass the blood–brain barrier. Regarding G-CSF and brain metastases, we have to mention that recently Fujita et al. used it together with chemotherapy to treat cerebral secondary lesions from non-small cell lung cancer obtaining 50% of PR (33). In 1999, Papadopoulos et al. published a paper reporting on two CR (out of 18 patients) after chemotherapy and G-CSF given for primary and recurrent brain tumor (34). The presence of specific receptor for G-CSF on neurons and microglia cells has been well demonstrated (35). The expression of G-CSF in the brain is inversely correlated to tumor progression of gliomas (36). Furthermore, G-CSF increases blood–brain permeability in mice (37). More recently, it has been demonstrated that G-CSF plays an important role for recovery after ischemic or traumatic brain injury (35,37,38). All these observations lead to the hypothesis that G-CSF may be helpful to treat brain metastases by not only preventing leukopenia but also promoting both the permeability of blood–brain barrier and the recovery of peripheral normal neurons.
Although more studies are needed to reproduce, confirm and explain these observations, we believe that the uniqueness of these responses should encourage further research on the use of BOLD and CSF, namely G-CSF, in the treatment of advanced melanoma.
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References |
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