Annals of Oncology Advance Access originally published online on September 15, 2006
Annals of Oncology 2006 17(12):1835-1841; doi:10.1093/annonc/mdl311
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© 2006 European Society for Medical Oncology
melanoma |
Temozolomide in combination with celecoxib in patients with advanced melanoma. A phase II study of the Hellenic Cooperative Oncology Group
1 First Department of Medicine, University of Athens, Medical School, Athens, Greece
2 First Department of Medical Oncology, St Savas Anticancer Hospital, Athens, Greece
3 Department of Pathology, Sotiria General Hospital, "WHO Melanoma Program", Athens, Greece
4 Department of Plastic Surgery and Microsurgery, G. Gennimatas General Hospital, Athens, Greece
5 Second Department of Pr. Medicine, "Attikon" Hospital, University of Athens, Athens, Greece
6 Cancer Research UK Medical Oncology Unit, Churchill Hospital, University of Oxford, UK
7 Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki, School of Medicine, Thessaloniki, Greece
* Correspondence to: Dr H. Gogas, Assistant Professor in Medical Oncology, First Department of Internal Medicine, Medical School, University of Athens, PO Box 14120, Athens 115 10, Greece. Tel: 0 30 944 68 11 59; Fax: 0 30 10 77 81 517; E-mail: hgogas{at}hol.gr
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Abstract |
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Background: There is now increasing evidence that a constitutive expression of cyclooxygenase (COX)-2 plays a role in the development and progression of malignant epithelial tumors. Expression of COX-2 is seen in 93% of melanomas, as determined by immunohistochemistry. Temozolomide (TMZ) has demonstrated activity against melanoma and has been investigated as single agent or in combination. We designed a phase II study to assess the efficacy and toxicity of the combination of TMZ and celecoxib (a COX-2 inhibitor) in patients with advanced melanoma.
Patients and methods: From January 2003 to July 2004, 52 patients were enrolled in the study. Nineteen patients were M1a, six M1b and 27 M1c. Patients received TMZ 200 mg/m2 per day p.o. for 5 consecutive days every 4 weeks and celecoxib 400 mg b.i.d. p.o. for a maximum of six cycles. Celecoxib was continued until progression.
Results: The median age was 63 years. There were 29 males and 23 females. Among 50 assessable patients, there were 11 (21.5%) objective responses including five complete responses and six partial responses. Twenty patients (38.5%) had stabilization of their disease, and 19 (36.5%) progressed. The median time to progression was 4.6 months and the median survival 9.5 months. Twenty-two patients (41.5%) completed all cycles of treatment. Median relative dose intensity of TMZ was 0.99 (range 0.6–1.2). Most commonly seen toxic effects included anemia (27.5%), neutropenia (17.5%), thrombocytopenia (33%), nausea/vomiting (75%), gastrointestinal (52%) and fatigue (46.5%). One patient discontinued due to severe toxicity. COX-2 was determined by immunohistochemistry and was expressed in all cases.
Conclusion: The combination of TMZ and celecoxib is safe and potentially effective in the treatment of metastatic melanoma. Randomized studies are needed to explore the role of celecoxib in combination with chemotherapy or as maintenance treatment in these patients.
Key words: celecoxib, metastatic melanoma, temozolomide
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Malignant melanoma accounts for 2% of all cancers in the USA and Europe and its incidence is increasing [1]. The median survival for patients with stage IV melanoma is only 6–9 months with an estimated 5-year survival rate of <5% [1, 2]. Unfortunately, these survival figures have not changed in > 22 years of clinical study. Systemic therapy with palliative intent is the mainstay of treatment.
A number of chemotherapy agents have demonstrated activity in metastatic melanoma, including dacarbazine (DTIC), the nitrosoureas, platinum analogs, vinca alkaloids and the taxanes [3].
Temozolomide (TMZ) is an oral alkylating agent that has demonstrated antitumor activity against melanoma [4, 5]. In phase I and II trials, patients with advanced metastatic melanoma achieved overall response rates of 17%–21% with single-agent TMZ. It can cross the blood-brain barrier and consequently can achieve effective concentration in the brain. In a recently published phase II study by our group, the combination of TMZ and docetaxel (Taxotere) was effective and well-tolerated [overall response (ORR) 27%, complete response (CR) 8% and partial response (PR) 19%] and demonstrated encouraging antitumor activity against brain metastases [6]. Additionally, in a large, randomized, phase III trial in 305 patients with advanced metastatic melanoma, TMZ demonstrated efficacy equivalent to that of single-agent DTIC [7].
Cyclooxygenase (COX)-2 is an inducible enzyme involved in the production of prostaglandins in inflammatory processes. There is now increasing evidence that constitutive expression of COX-2 plays a role in development and progression of malignant epithelial tumors. Expression of COX-2 in malignant melanoma has been investigated by immunohistochemistry in 28 cases of primary skin melanoma and four benign nevi [8]. COX-2 was expressed in 26 cases (93%) of melanomas, with a moderate to strong expression in 19 cases (68%). Benign nevi as well as normal epithelium were negative in all cases. These results indicate that COX-2 is expressed in malignant melanoma and may be involved in regulation of melanoma invasion.
Another group failed to demonstrate COX-2 expression in melanoma tissue samples [9], but showed that COX-2 inhibitors were able to induce apoptosis in melanoma cells independently of enzyme expression. Although the expression, and role, of COX-2 in melanoma remains to be defined, the possibility exists for therapeutic benefit from inhibitors of the enzyme.
We designed a study to assess efficacy and safety of combination therapy with celecoxib in patients with advanced metastatic melanoma and assess the impact of this regimen on brain metastases.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Patients who had proven advanced metastatic melanoma were eligible for the study provided they fulfilled the following criteria: no previous chemotherapy for metastatic disease; performance status (PS) two or less on the European Cooperative Oncology Group scale; full recovery from previous radiotherapy, adjuvant biological therapy, or surgery; measurable disease; age 18 years or older; life expectancy at least 3 months; adequate bone marrow reserve (absolute neutrophil count
1500 per µl, platelets 100.000 per µl, hemoglobulin 10 g/dl); urea and serum creatinine <1.5 times the upper limits of laboratory normal (ULN); adequate hepatic function (total bilirubin <1.5x ULN, aspartate aminotransferase <3x ULN, and alkaline phosphatase 
2x ULN, unless disease was arising from bone) and adequate birth control measures. Patients with brain metastases were allowed to take part in the study if no prior central nervous system (CNS) radiation or radiosurgery was administered. Patients were excluded from the study if they were pregnant or nursing (pregnancy tests were carried out within 24 h before starting the study drugs); if they had uncontrolled vomiting that would interfere with the administration of oral medications; or if they had clinically significant comorbidity that would interfere with the study evaluation. Since celecoxib is a sulfonamide, patients with a known or suspected allergy to sulfa drugs were excluded from participating. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin three or more times a week was not allowed. Prior treatment had to have been completed at least 4 weeks before administration of a study drug. Institutional Review Boards in participating institutions and the Hellenic Drug Organization approved the protocol. All patients gave written informed consent, according to institutional guidelines.
treatment
Patients received TMZ and celecoxib (Celebrex®). TMZ was administered orally under fasting conditions once a day for 5 consecutive days at a starting dose of 200 mg/m2 (total dose per cycle 1000 mg/m2). The following antiemetic medications were administered prophylactically on day 1 of each cycle: 8 mg ondansetron p.o. before TMZ. On day 2, all patients received 8 mg of ondansetron p.o. before TMZ. The prophylactic use of ondansetron before treatment with TMZ on days 3–5 was optional. Treatment cycles were repeated every 28 days in the absence of disease progression or toxicity. The dose was reduced by 25% when grade 3 or 4 (400 mg once daily) hematologic toxicity [National Cancer Institute Common Toxicity Criteria (NCI-CTC)] occurred. A 50% dose reduction was required in cases of grade 3 or 4 non-hematologic toxicity (NCI-CTC). Patients requiring more than two dose reductions were removed from the study.
Celecoxib was given orally at 400 mg b.i.d., starting at the first day of chemotherapy until disease progression. Pfizer Inc. supplied celecoxib 200-mg capsules to the study sites free of charge. This dose was chosen because it was previously reported to cause a reduction in the number of colorectal adenomas in a recently completed trial [10]. No dose escalation of celecoxib was allowed. Dose reductions or discontinuations of celecoxib were allowed if, in the judgment of the investigators, a particular toxicity was deemed likely to be due to celecoxib.
evaluations
A prestudy evaluation was completed within 2 weeks of a patient's receiving the study drugs. Computed tomography (CT) of the brain was carried out in every patient before initiation of the treatment. Patients underwent clinical examination, determination of complete blood count and biochemical analysis during every treatment cycle. A formal radiological evaluation of disease with CT or magnetic resonance imaging of the brain included was carried out every second cycle. Patients were assessable for response if they received two or more cycles of treatment. If there was no disease progression after one cycle, at least two cycles were administered with continuation for a maximum of six cycles if a response occurred. Responses were assessed using World Health Organization (WHO) response criteria. Patients were assessable for toxicity if they had received at least one cycle of treatment. The severity of adverse events was assessed before each cycle using NCI-CTC.
statistical methods
The primary objective of the study was to assess the response rate and toxicity of patients in the intent-to-treat (ITT) population. Secondary objectives were to assess the time to progression (TTP) and overall survival (OS). Sample size calculation was on the basis of response rate. According to Simon's two-stage optimal design, with a minimum expected response of 10% and an expected response rate of 25%, a sample of 21 patients was required in the first step. If a minimum of three responses were observed, it was planned to accrue 50 patients. At the second phase, if at least eight responses occurred the probability of accepting an ineffective treatment would be 10%. On the other hand, the risk of rejecting a treatment with a response rate of >25% would be 10%. TTP was calculated from the date of initiation of treatment to the first progression of the disease. However, patients who died due to disease-related factors without having previous documentation of disease progression were considered as an event at the estimation of TTP. Survival time was calculated from the date of initiation of treatment to the date of death or day of last follow-up. The Kaplan–Meier method was used to calculate TTP, median follow-up and OS curves [11]. Exact confidence intervals (CIs) were used to determine the 95% upper and lower CIs of a response rate [12]. In order to identify significant factors for survival and TTP, Cox proportional hazard models were used [13]. Variables included in the models were age (as a continuous variable), PS (0 or 1), number of metastatic sites (1, 2, 3 or more) and stage [M1a: distant skin, subcutaneous or nodal metastasis; M1b: lung metastasis; M1c: all other visceral metastases or any distant metastatic site associated with elevated lactate dehydrogenase (LDH)]. Analysis was carried out on an ITT basis.
immunochemistry
Immunohistochemical examination was carried out retrospectively on tissue samples taken for routine diagnostic purposes from 48 out of the 52 patients who underwent excision of skin tumors at the Department of Pathology, Sotiria General Hospital, ‘WHO Melanoma Program’, Athens, Greece. Thirty cases were melanomas metastatic to the lymph nodes or skin, whereas the other 18 cases were melanomas within the vertical growth phase (Clark level 3, 4 and 5). Tissue samples were fixed in 4% neutral buffered formaldehyde and embedded in paraffin. Routine H and E sections were carried out for histopathological evaluation. Immunohistochemical staining was carried out according to standard procedures. Briefly, slides were boiled in citrate buffer in a pressure cooker for 5 min and incubated with the monoclonal COX-2 antibody (1:2000; Transduction Laboratories) overnight at 4°C, followed by incubation with a biotinylated anti-mouse secondary antibody and the multilink biotin–streptavidin-amplified detection system (Biogenex, San Ramon, CA). Staining was visualized using a Fastred chromogen system (Immunotech, Hamburg, Germany). The intensity of the COX-2 immunostaining in tumor cells as well as surrounding inflammatory cells was evaluated independently by two pathologists and scored semiquantitatively as –, negative; +, weak; ++, moderate and +++, strong positive.
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results |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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patients
From January 2003 to July 2004, 52 patients were enrolled. Patients' demographics are shown in Table 1. The median age was 63 years. There were 29 males and 23 females, 19 patients were M1a disease, six M1b and 27 M1c.
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response to treatment
The response rates are shown in Table 2. Assessment of objective response in the ITT population showed CRs in five patients (10%, 95% CI 3.2–21.0) and a PR in six individuals (11%, 95% CI 4.3–23.4). Disease was stable in 20 patients and 19 progressed. Two patients were not assessable for response, one discontinued due to toxicity and one due to sudden death due to myocardial infraction.
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The majority of objective responses were documented in soft tissue and lymph nodes. All five patients with CRs were M1a and two out of six patients who showed a PR had disease in soft tissue and skin with normal LDH levels. In two patients with liver metastases, a PR was achieved with durations of 3.4 and 6.4 months, respectively. The median duration of response was 7.0 months (range 3.3–19.3, 95% CI 3.0–9.9). Among six patients who presented with brain metastases, five (83%) remained stable and one had disease progression. In three patients with disease at other sites, disease was stable both in brain and extracranial sites. The median time of stable disease in the brain was 5 months (range 1.2–7 months). At the median follow-up of 23.4 months, only six (13%) patients developed brain metastases.
TTP and OS
With a median follow-up of 23.4 months (range 1.5–33.1, 95% CI 21.1–25.8), in the ITT population, the median OS was 9.5 months (range 1.5–33.1+ months; 95% CI 5.3–13.8). Survival of 23 patients (44.2%) was longer than 12 months. At the time we ceased collecting data, 11 patients (21%) remained alive. The median TTP was 4.6 months (range 0.9–23.4+ months; 95% CI 2.7–6.5) (Figure 1).
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In univariate analysis, the number of metastatic sites and the presence of visceral metastases emerged as important determinants of TTP and OS. For OS, PS was also a significant factor. In multivariate COX analysis, the presence of visceral metastases was identified as a significant adverse prognostic factor for disease progression. Also, PS affected the hazard of death (Tables 3 and 4).
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safety
All 52 patients were assessable for toxicity. A median of four cycles was administered. Treatment characteristics are shown in Table 5. Treatment was well-tolerated with most adverse events being mild to moderate in severity. The most frequent adverse events observed were nausea and vomiting (74%), gastrointestinal (dyspepsia/heartburn, constipation) (58%), fatigue (46.5%), thrombocytopenia (33%), anemia (27.5%), neutropenia (17.5%) and leucopenia (22%) (Table 6). There were no non-hematologic grade 3 or 4 adverse events. The percentage of patients who discontinued the study because of adverse events was 6%. There was one death due to myocardial infarction after the second cycle and one discontinuation of treatment after the first cycle due to febrile neutropenia with grade 4, anemia, leucopenia, neutropenia, lymphopenia, thrombocytopenia and grade 2 allergic reaction due to the severe condition of the patient testing for clarifying if the allergic reaction would be attributed to celebrex or to TMZ was not carried out. Celecoxib was not reduced or discontinued due to toxicity in any additional patient. TMZ was dose reduced in six patients due to hematological toxicity.
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immunohistological examination
Expression of COX-2 was noted in melanoma cells in all examined cases. A diffuse granular cytoplasmic staining pattern with moderate to severe intensity was found in primary and metastatic melanomas, as well as in recurrences (Figs 2 and 3). Inflammatory cells, mainly macrophages, were also stained positively, while the stroma was negative for COX-2.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Chemotherapy for advanced melanoma remains palliative, and survival after diagnosis is short. Numerous trials of single agents and combinations of chemotherapy have been carried out, but DTIC still remains the standard regimen.
TMZ is a prodrug that hydrolyzes to 5-(3-Methyltriazen-1-y) imidazole-4-carboximide (MTIC) at physiological pH [14]. Its complete oral bioavailability and its ability to cross the blood-brain barrier [15] make it an attractive alternative to DTIC, which possesses neither of these properties. TMZ has shown activity against CNS metastases in melanoma and other malignancies [16]. This could be an advantage in melanoma as CNS metastases are a frequent cause of death. In phase I and II trials with single-agent TMZ, overall response rates of 17%–21% were achieved [4, 5]. Combining TMZ with other drugs in several phase II/III in melanoma has demonstrated satisfactory activity and tolerability with these regimens [1, 17–19].
The rationale for designing this phase II trial was on the basis of the potential for improved antitumor activity. As demonstrated by immunohistochemistry, COX-2 is widely expressed in malignant melanoma [8]. COX-2 is an inducible enzyme linked to tumor growth and angiogenesis [20]. This is consistent with epidemiological data that show reduced cancer risk in patients chronically taking NSAIDs [21]. Selective COX-2 inhibitors such as celecoxib, potent inhibitors of angiogenesis in vitro and in vivo, can prevent tumor genesis and suppress established tumor growth in animals [20, 22, 23]. In patients with familial adenomatous polyposis, celecoxib was shown to decrease the member and size of colorectal polyps, which are angiogenesis-dependent precancerous lesions [10, 24]. Additionally, there is a growing evidence of COX-2 inhibitors having antitumor effects for themselves especially in combination with cytotoxic chemotherapy [25]. Given the conflicting reports on the role of COX-2 in melanoma, we undertook to evaluate expression in tumor samples from patients in the study. The aims were to determine enzyme expression, and investigate the possibility of a relationship with response to treatment.
We investigated whether celecoxib can be administered with TMZ. We observed a response rate of 21 to the combination of celecoxib and TMZ. Although higher than that seen in a phase III trial of single-agent TMZ [7], the response rate is to those observed in phase II studies of the drug [4, 5] or single-agent celecoxib [26]. The high proportion of M1a patients in our study complicates the evaluation of the OS and TTP observed, but these were in line with those achieved with TMZ alone [7, 27, 28]. Phase II data in melanoma are notoriously difficult to interpret, and patient selection is likely to bear heavily on results. Despite large differences in median survivals reported at this stage, those agents that have gone on to be tested in phase III trials have subsequently yielded very similar outcomes.
Patients with brain metastases were included in our study, and stabilization of CNS disease was seen in five out of six (83%) of our patients, lasting a median of 5.5 months. Additionally, as has already been reported by our group [6, 28] and others [29–31], only 13% of patients in this study went on to develop CNS involvement, indicating that TMZ may prevent the occurrence of metastasis to the brain. Whether celecoxib enhanced the activity of TMZ in the CNS remains to be proved.
This regimen is safe and well-tolerated, with adverse events being mild to moderate in the majority of patients. Myelosuppression, the predominant toxicity associated with TMZ therapy, was reversible and noncumulative. Nausea and vomiting were experienced by three quarters of the patients and gastrointestinal side-effects by half. Fatigue was encountered by 50% of the patients. The latter toxic effects have been reported in trials with single-agent TMZ [6, 7, 28]. However, higher percentages encountered here could be attributed to the addition of celecoxib. One patient discontinued treatment due to toxicity, and one sudden death due to cardiac condition was reported. This patient had increased baseline cardiovascular risk factors. It is not clear that this was treatment related as similar reports are common in trials of patients with metastatic disease. Moreover, the cardiovascular risks described with celecoxib [32] are not an issue in patients with metastatic melanoma who have a dismal prognosis, and are not anticipated to remain on treatment for more than a few weeks. Therefore, TMZ can be safely combined with celecoxib at the doses used in this study.
We also found that all the tumor tissue samples examined expressed COX-2, confirming its potential as a target for melanoma treatment. If the safety issues concerning cardiovascular events are resolved, celecoxib could have a role in adjuvant therapy, where its use might also help in the management of influenza-like symptoms in patients receiving interferon. In conclusion, the combination of TMZ and celecoxib is safe and potentially effective in the treatment of metastatic melanoma.
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This study was supported by unrestricted educational grant by Pfizer.
Received for publication March 27, 2006. Revision received July 13, 2006. Accepted for publication July 13, 2006.
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References |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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