Departments of 1Oncology and 5Radiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Oncology, Umeå University Hospital, Umeå, Departments of 3Oncology and 6Virology, Sahlgrenska University Hospital, Göteborg; 4Department of Oncology, Radiumhemmet, Karolinska Hospital, Stockholm; 7Umbilicus Nordica, Umeå; 8Department of Surgery, Umeå University Hospital, Umeå, Sweden
Received 27 June 2001; revised 3 September 2001; accepted 20 September 2001.
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Abstract |
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Histamine inhibits formation and release of monocyte/macrophage-derived reactive oxygen metabolites and thereby protects natural killer (NK) and T cells against oxidative inhibition. Efficacy and safety of histamine, when given in combination with interleukin-2 (IL-2) and interferon- (IFN-
), were evaluated in patients with metastatic renal cell carcinoma (mRCC).
Patients and methods
Forty-eight mRCC patients were included. The self-administered, outpatient regimen included IFN-, 3 MIU s.c., once daily for 1 week, followed by up to nine 4 week cycles of IFN-
, 3 MIU s.c., days 17, weeks 14; interleukin-2, 2.4 MIU/m2 s.c., b.i.d., days 15, weeks 1 and 2; and histamine dihydrochloride, 1 mg s.c., b.i.d. days 15, weeks 14.
Results
Forty-six patients were eligible. Forty-two patients were evaluable for response with four partial responses (9% of eligible patients, 10% of evaluable patients). Fifteen patients (36%) had stable disease. After subsequent surgery of residual tumours, three patients (7%) had no evidence of disease at 14+, 21+ and 21+ months. Median survival time for all patients was 16.3 months. One grade 4 toxicity (thrombocytopenia) was observed. Most frequent grade 3 toxicities were fatigue/malaise (26%), dyspnoe (11%), nausea (9%) and stomatitis (9%). Four patients discontinued due to treatment-related toxicity. There were no treatment-related deaths.
Conclusions
The present combination of histamine with IL-2 and IFN- as self-administered outpatient therapy is a safe and well-tolerated regimen. However, histamine does not appear to add efficacy with respect to response in this low-dose schedule of IL-2 and IFN-
. Whether histamine might improve efficacy with higher doses of IL-2 and IFN-
requires further investigation.
Key words: histamine, interferon-, interleukin-2, renal cell carcinoma
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Introduction |
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However, there is substantial evidence that mRCC is responsive to immunological treatment. The interest has mainly focused on two immunoactivating cytokines, interferon- (IFN-
) and interleukin-2 (IL-2). Long-term follow-up data from these treatment regimens are available. Treatment with single-agent IFN-
demonstrates an overall response rate (RR) of 10% and a median survival of 11.4 months, with 3% of patients alive at 5 years or more [6]. The US experience with high-dose bolus i.v. IL-2 demonstrates an overall RR of 15% and a median survival of 16.3 months, with 10% of patients alive 10 years after treatment [7]. European experience with high-dose continuous i.v. IL-2 demonstrates an overall RR of 15% and a median survival of 10 months, with 8% of patients alive 5 years after treatment [8]. Combined IL-2 and IFN-
therapy results in a significantly increased 1-year event-free survival, but does not significantly affect overall survival [9]. These data demonstrate that manipulating the immune system to induce durable tumour regression is possible.
Our present study deals with a new concept of how to increase the efficacy of IL-2 and IFN- by the addition of histamine dihydrochloride (CepleneTM). The concept is based on the following laboratory observations. In mRCC [10, 11] and human metastatic malignant melanoma [12], tumour infiltrating T cells and natural killer (NK) cells show signs of oxidative damage. Monocytes/macrophages produce reactive oxygen metabolites, especially hydrogen peroxide [13], which effectively inhibit proliferation [10, 14] and cytotoxicity [15] of human NK cells in vitro. T cells and, particularly, NK cells are susceptible to oxidative stress and eventually undergo apoptosis [16, 17]. Histamine, acting via H2 receptors on monocytes, inhibit formation and release of hydrogen peroxide in monocytes [13, 14, 18]. Histamine synergically augments human NK cell cytotoxicity in vitro when concomitantly treated with IFN-
[19] and IL-2 [15]. In vivo, combined treatment with histamine and IFN-
almost completely prevents development of B16/F10 lung metastases in mice, whereas IFN-
as monotherapy only modestly affects development of lung metastases [20]. Combined treatment with histamine and IL-2 synergically eliminates YAC-1 [20] and B16 [20, 21] lung metastases in mice, whereas IL-2 as monotherapy is significantly less effective. This effect is mimicked by the H2 receptor agonist dimaprit, and blocked by the H2 receptor antagonists cimetidine and ranitidine [21]. Depletion of NK cells strongly aggravates B16 metastases and abrogates the antitumour effect of histamine [21].
Clinical experience with histamine in combination with IL-2 and/or IFN- is limited but increasing. Clinical trials have been performed in metastatic melanoma [22], acute myelogenous leukaemia [23] and multiple myeloma [24]. Furthermore, results from a phase III trial in metastatic malignant melanoma have demonstrated a survival benefit in patients with liver metastases treated with IL-2 and histamine [25].
The observation that histamine in vitro and in vivo syner-gically increases efficacy of both IFN- and IL-2 formed the background for this phase II trial, representing the first study of histamine in combination with IL-2 and IFN-
in patients with mRCC.
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Patients and methods |
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Between November 1998 and February 2000, 48 patients from one Danish (26 patients) and three Swedish centres (11, six and five patients, respectively) entered the study. However, two patients were ineligible because of age (76 years) and insufficient haemoglobin level in one case, and low Karnofsky performance status (5060) in the other case. These two patients were excluded from all further analysis. Table 1 lists baseline patient characteristics for the 46 eligible patients.
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Interleukin-2. Aldesleukin, rIL-2, Proleukin®, Chiron, The Netherlands: 2.4 million IU/m2, s.c., twice daily (6 h minimum between treatments), 5 days per week, weeks 1 and 2.
Histamine dihydrochloride. CepleneTM, supplied by Maxim Pharmaceuticals Inc, San Diego, CA, USA: 1 mg in 1 mL by slow s.c. injection not to exceed 0.1 mg/min, which equals an injection period of 1020 min (normally 20 min), twice daily, following all cytokine injections, 5 days per week (days 15) throughout treatment cycle.
Due to the outpatient nature of this protocol, patients received instruction, guidance and monitoring during the first week (priming dose IFN-) and during the first days of IL-2 and histamine injections before self-administration in the patients home began.
Evaluation of patients
Toxicity evaluation, physical examination and laboratory tests were performed every 4 weeks. Patients were evaluated for response every third month until progressive disease was observed. Responses were reconfirmed after at least 4 weeks. A single central radiologist and the investigators from the centres not treating the patient reviewed objective responses.
Dose modifications
Toxicity was graded according to CALGB expanded common toxicity criteria. In general, no dose reduction of either study drug was done in case of grade 1 or 2 toxicity. In case of grade 3 or 4 toxicity, treatment was interrupted until toxicity returned to grade 2 or less. IL-2 and IFN- was then restarted at the 50% dose level. Histamine was restarted at 100% dose level.
Management of toxicity
All patients received the following as needed to minimise toxicity: paracetamol, metroclopramid, ondansetron, loperamid, omeprazole, furosemide or mucopolysaccharidepolysulphate.
Response criteria
Standard criteria (World Health Organisation) were used for classifying response. Complete response (CR) was disappearance of all known disease. Partial response (PR) was total tumour size decrease by at least 50%. Stable disease (SD) was <50% decrease or <25% increase in the sum of the sizes of all measurable lesions. Progressive disease (PD), measured with reference to baseline value/tumour size nadir, was >25% increase in the sum of the sizes of all measurable lesions, a 50% or greater increase in the size of any single lesion or the appearance of a new lesion.
Follow-up
Responses were evaluated every 3 months until PD. Patients were followed for survival every 3 months until death. No patients were lost to follow-up.
Statistics
Response duration was measured from the date on which the objective response criterion was first met and until disease progression. If surgical resection of a residual tumour was performed, the response duration was censored at the date of surgery. Time to PD was measured from first day of treatment until disease progression. Overall survival was measured from first day of treatment until death or last follow-up evaluation.
The cumulated survival rate was analysed according to criteria by KaplanMeier. The log-rank test was used to analyse survival differences among subgroups of patients. All calculations were performed using SPSS 10.0 statistical software.
The data of duration of response and survival were updated 9 February 2001.
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Results |
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Tumour response
Four patients (9% of eligible patients, 10% of evaluable patients) achieved a PR (Table 2). Three of the four responding patients achieved a PR at the 3 month evaluation, and the other patient at the 6 month evaluation. Fifteen patients (36%) achieved SD. Three of four responders had a prior nephrectomy. Responding sites included kidney, lung, pleura, soft tissue, liver, bone and local recurrence in the kidney bed. Table 3 lists the characteristics of responding patients.
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Survival
Median survival for all eligible patients was 16.3 months [95% confidence interval (CI) 11.121.5 months, range 0.823.8+ months]. All patients with PR (n = 4) and 11 of 15 patients with SD were alive at 1524 months. Three of 23 patients with PD were alive. The median survival for patients with PD was 10.1 months (95% CI 614.1 months, range 0.8 22.2 months). The KaplanMeier plot of overall survival is shown in Figure 4. At the time of analysis, 27 patients had died, giving a censoring rate of 41.3%. The median follow-up time was 20.1 months and the minimum length of follow-up 12 months.
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Of the 15 patients achieving SD, four patients had not progressed at 15+, 16+, 18+ and 21+ months.
Nine patients (20%) with suspected PD at evaluation continued on treatment and were re-evaluated for response after at least 4 weeks. All nine patients had PD at re-evaluation. In the analysis of time to PD, the initial date of first observed PD was used.
Toxicity
The 46 patients received a total of 222 cycles. Treatment was given as full dose, without delays, in 17 patients (37%). Table 4 lists the reasons for dose modifications and/or interruptions. The cause was most often treatment-related toxicity (17 patients, 37%), frequently because of malaise grade 3 (five patients), nausea grade 2 or 3 (three patients), disorientation/somnolence (three patients) or thrombocytopenia (three patients). Four patients discontinued permanently because of toxicity. As seen in Table 4, treatment was also interrupted for reasons unrelated to the study drug in four patients (9%) and because of evidence of progressive disease in seven patients (15%).
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Discussion |
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The overall response rate of only 9% with no CRs was disappointing. On the other hand, three patients (7%) had no evidence of disease and were alive at 14+, 21+ and 21+ months after subsequent surgery of residual tumours. Moreover, of the 15 patients achieving SD, four had not progressed at 15+, 16+, 18+ and 21+ months. The fraction of long-term survivors following immunotherapy is probably a better measure of treatment success than the response rate, because many responses are only short and of limited value to the patient. Thus, it may be a limitation to only look at the conventional response criteria, i.e. CRs and PRs, when the therapeutic effects of biomodulators are evaluated. The possibility that SD may also represent a positive treatment result for the patient should be taken into consideration.
The reason for the low response rate may be explained by the low doses given of IL-2 and IFN-. Thus, in a recent study with comparably low doses of IL-2 and IFN-
, an even lower response rate (1.4%) was observed [27]. Another reason for the low response rate may be unfavourable patient selection. The patients in the present study had several poor prognostic parameters according to Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic criteria [28]. Only 15% of patients had favourable prognosis, 59% had an intermediate prognosis and 26% had a poor prognosis based on these criteria (Table 1).
Only 59% of patients had prior nephrectomy performed as compared with 85% in the US high-dose bolus IL-2 trial [29] and 93% in the randomised trial by Negrier et al. [9]. At the National Institute of Health between 1986 and 1996, no responses to high-dose IL-2 were noted in primary renal tumours of patients with the majority of disease at extrarenal sites [30]. One proposed mechanism of action is that nephrectomy may eliminate immunosuppressive substances produced by bulky tumours [31]. In the present study, only one patient responded in the primary renal tumour, whereas three of four responding patients had nephrectomy prior to immunotherapy. However, the impact of nephrectomy prior to IL-2-based immunotherapy remains controversial [3133].
The expected median survival time in the present study for all patients was 10 months based on the MSKCC prognostic criteria [28]. Although one should be cautious when comparing survival obtained in different studies, the observed median survival time for all patients of 16.3 months should be noted. Despite a low response rate, the survival seems to be similar to that reported in other studies using higher doses of IL-2 and IFN- [7, 9]. A randomised phase III study in metastatic melanoma [25] demonstrated a survival benefit without a response benefit in patients with liver metastases receiving IL-2 and histamine, compared with patients receiving IL-2 alone. This may indicate that a survival benefit following cytokine therapy can be obtained without improving the response rate.
In general, toxicity was manageable in an outpatient setting. Adverse events noted in patients treated with this combination of IL-2, IFN- and histamine were almost similar in type and frequency to toxicities described in previous studies using low-dose IL-2 together with IFN-
[27, 34].
There were no treatment-related deaths and no use of the intensive care unit, as is often seen in studies using high-dose bolus i.v. IL-2 [29] or continuous intravenous infusion of IL-2 [9, 35].
This study documented the safety of histamine as a self-administered home-based treatment together with IL-2 and IFN-. Adverse events related to histamine were only minor and seemed not to potentiate the side effects of IL-2 or IFN-
.
In conclusion, this multicentre phase II study represents the first experience with histamine in mRCC. The present combination of histamine with IL-2 and IFN- as self-administered outpatient therapy is a safe and well-tolerated regimen. However, histamine does not appear to add efficacy with respect to response in this low dose schedule of IL-2 and IFN-
. Whether histamine may improve efficacy with higher doses of IL-2 and IFN-
requires further investigation.
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Acknowledgements |
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Footnotes |
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