Outpatient treatment with subcutaneous histamine dihydrochloride in combination with interleukin-2 and interferon-{alpha} in patients with metastatic renal cell carcinoma: results of an open single-armed multicentre phase II study

F. Donskov+,1, H. von der Maase1, R. Henriksson2, U. Stierner3, P. Wersäll4, H. Nellemann5, K. Hellstrand6, K. Engman7 and P. Naredi8

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.


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives

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-{alpha} (IFN-{alpha}), 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-{alpha}, 3 MIU s.c., once daily for 1 week, followed by up to nine 4 week cycles of IFN-{alpha}, 3 MIU s.c., days 1–7, weeks 1–4; interleukin-2, 2.4 MIU/m2 s.c., b.i.d., days 1–5, weeks 1 and 2; and histamine dihydrochloride, 1 mg s.c., b.i.d. days 1–5, weeks 1–4.

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-{alpha} 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-{alpha}. Whether histamine might improve efficacy with higher doses of IL-2 and IFN-{alpha} requires further investigation.

Key words: histamine, interferon-{alpha}, interleukin-2, renal cell carcinoma


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Renal cell carcinoma accounts for 2–3% of cancers in adults and is the most common kidney malignancy. Renal cell carcinoma has very few early warning signs and therefore ~30% of patients present with metastases. Thirty per cent to 40% of the remaining patients will develop metastases following nephrectomy for localised disease [1]. The malignancy is highly refractory to systemic chemotherapy [2], conventional radiotherapy [3] and hormone therapy [4]. Patients with metastatic renal cell carcinoma (mRCC) have a poor prognosis, with a median survival of only 8 months [5].

However, there is substantial evidence that mRCC is responsive to immunological treatment. The interest has mainly focused on two immunoactivating cytokines, interferon-{alpha} (IFN-{alpha}) and interleukin-2 (IL-2). Long-term follow-up data from these treatment regimens are available. Treatment with single-agent IFN-{alpha} 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-{alpha} 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-{alpha} 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-{alpha} [19] and IL-2 [15]. In vivo, combined treatment with histamine and IFN-{alpha} almost completely prevents development of B16/F10 lung metastases in mice, whereas IFN-{alpha} 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-{alpha} 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-{alpha} and IL-2 formed the background for this phase II trial, representing the first study of histamine in combination with IL-2 and IFN-{alpha} in patients with mRCC.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Inclusion criteria were: bidimensionally measurable, histologically documented mRCC; age 18–75 years: Karnofsky performance status >=70; life expectancy >3 months; haemoglobin >10 g/dl; white blood cell count >3 x 109 cells/l; platelet count >100 x 109/l; partial thromboplastin time and creatinine <1.5 times the upper limit of normal; and serum bilirubin <1.25 x the upper limit of normal. Exclusion criteria were: brain metastasis; central nervous system disorders; psychiatric disability; pheochromocytoma; glaucoma; abnormal cardiac function; asthma or systemic allergic reaction treated within the last 5 years; bleeding ulcer disease; infections requiring antibiotics; prior chemotherapy, immunotherapy or extensive radiotherapy in the last 4 weeks; and ongoing active malignancies except in situ carcinoma of the cervix or localised carcinomas of the skin. If female, subjects had to be non-nursing/pregnant and using barrier/oral contraception or be surgically sterile/1 year post-menopausal. Beta-blocker medications, H2 receptor antagonists, clonidine and all steroidal medications were disallowed. H1 receptor antagonists were allowed for <5 days to treat skin itching. The study was conducted according to the Declaration of Helsinki and the applicable guidelines for good clinical practice. Approval from the ethics committees and medical agencies was obtained before the start of the study. Written informed consent was obtained from all patients before inclusion.

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 (50–60) 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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Table 1. Baseline patient characteristics for the 46 eligible patients
 
Treatment
The treatment plan consisted of one priming week and up to nine treatment cycles unless unacceptable toxicity or progressive disease occurred (Figure 1). Dosing was as follows.



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Figure 1. Treatment plan.

 
Interferon-{alpha}. Human leucocyte IFN-{alpha}, Interferon Alfanative®, supplied by BioNative, Sweden: 3 million IU as a fixed dose, s.c. once daily, 7 days per week throughout the study. IFN-{alpha} treatment started 5–7 days prior to the first cycle (priming dose).

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 10–20 min (normally 20 min), twice daily, following all cytokine injections, 5 days per week (days 1–5) throughout treatment cycle.

Due to the outpatient nature of this protocol, patients received instruction, guidance and monitoring during the first week (priming dose IFN-{alpha}) 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-{alpha} 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 Kaplan–Meier. 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.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Forty-six patients were eligible and evaluable for toxicity. Forty-two patients were evaluable for response. The four non-evaluable patients received less than one treatment cycle, two because of toxicity, one because of corticosteroid treatment due to severe bone pain and one because of patient request. Another two patients also received less than one treatment cycle as a result of PD, and these patients were included in the response evaluation. Forty patients received one or more cycle and 14 patients completed nine cycles (mean 4.8 ± 3.3 cycles). A total of 222 cycles were given.

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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Table 2. Response to treatment
 

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Table 3. Characteristics of responding patients
 
One PR patient (no. 403) with a 12 x 18 cm right kidney tumour infiltrating the right psoas muscle, responded with disappearance of >90% of tumour (Figure 2). After nine treatment cycles, no right psoas muscle infiltration was seen and the patient had a nephrectomy performed. Vital tumour tissue could only be demonstrated in a 7 mm2 area within the kidney. The patient is alive without evidence of disease at 21+ months. Another PR patient (no. 424) with metastases to the pleura also responded with disappearance of >90% of tumour (Fig-ure 3) and after subsequent surgery of residual tumour had no evidence of disease. This patient is alive with no evidence of disease at 14+ months. Both patients were censored for duration of response at the time of operation.



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Figure 2. Patient no. 403, before and 6 months after therapy. After nine cycles of immunotherapy, the residual tumour was removed by surgery. Vital tumour tissue could only be demonstrated in a 7 mm2 area within the kidney.

 


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Figure 3. Patient no. 424, with metastases to the pleura, responded with disappearance of >90% of tumour after three cycles of immunotherapy, and after subsequent surgery of residual tumour had no evidence of disease.

 
One SD patient achieved a 33% tumour reduction after nine treatment cycles. After subsequent surgery of residual tumour, the patient had no evidence of disease. The patient is alive without evidence of disease at 21+ months. Thus, a total of three patients (7%) had no evidence of disease and were alive at 14+, 21+ and 21+ months after resection of residual tumours.

Survival
Median survival for all eligible patients was 16.3 months [95% confidence interval (CI) 11.1–21.5 months, range 0.8–23.8+ months]. All patients with PR (n = 4) and 11 of 15 patients with SD were alive at 15–24 months. Three of 23 patients with PD were alive. The median survival for patients with PD was 10.1 months (95% CI 6–14.1 months, range 0.8 –22.2 months). The Kaplan–Meier 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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Figure 4. Kaplan–Meier survival estimates for the 46 eligible patients.

 
Time to progressive disease
Median time to progressive disease was 3.3 months (95% CI 0.6–6 months). At the time of analysis, 35 patients had progressed and 24 of these patients had died, giving a censoring rate of 16.7%.

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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Table 4. Interruptions/dose modifications during study
 
Table 5 lists the toxicity to treatment. In general, toxic effects were minor to moderate. There were no treatment-related deaths. No clinical evidence of capillary leak syndrome was seen. Only one grade 4 toxicity (thrombocytopenia with bleeding) was observed, and in this case, thrombocytes returned to normal levels after high dose steroid treatment for 14 days. Most frequent WHO grade 3 toxicities were fatigue/malaise (26%), dyspnoe (11%), nausea (9%), stomatitis (9%), confusion (7%) and neutropenia (7%). Clinical hypothyroidism (grade 3) that required substitution appeared in one patient. Twenty per cent of patients lost more than 10% of their initial body weight during treatment.


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Table 5. Toxicity to treatment (n = 46)a
 
Based on a total of 8880 histamine injections in 222 cycles, toxicity related to histamine was negligible. Most frequent toxicities to histamine were transient grade 1 facial erythema and transient grade 1 metallic taste.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This study is the first trial in mRCC evaluating the efficacy and safety of histamine dihydrochloride (CepleneTM) in combination with low-dose IL-2 and IFN-{alpha}. We observed a median survival of 16.3 months, which is consistent with results previously obtained with intermediate to high doses of IL-2-based immunotherapy [7, 9] and about double of those reported in historical controls [5, 26].

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-{alpha}. Thus, in a recent study with comparably low doses of IL-2 and IFN-{alpha}, 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-{alpha} [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-{alpha} and histamine were almost similar in type and frequency to toxicities described in previous studies using low-dose IL-2 together with IFN-{alpha} [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-{alpha}. Adverse events related to histamine were only minor and seemed not to potentiate the side effects of IL-2 or IFN-{alpha}.

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-{alpha} 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-{alpha}. Whether histamine may improve efficacy with higher doses of IL-2 and IFN-{alpha} requires further investigation.


    Acknowledgements
 
Thia study was supported by grants from Maxim Pharmaceuticals Inc, San Diego, CA, USA and BioNative AB, Umeå, Sweden.


    Footnotes
 
+ Correspondence to: Dr F. Donskov, Department of Oncology, Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus C, Denmark. Tel: +45-8949-2532; Fax: +45-8949-2530; E-mail: fd@microbiology.au.dk Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1999. CA Cancer J Clin 1999; 49: 8–31.[Abstract/Free Full Text]

2. Amato RJ. Chemotherapy for renal cell carcinoma. Semin Oncol 2000; 27: 177–186.[ISI][Medline]

3. Bukowski RM. Natural history and therapy of metastatic renal cell carcinoma: the role of interleukin-2. Cancer 1997; 80: 1198–1220.[ISI][Medline]

4. Motzer RJ, Russo P. Systemic therapy for renal cell carcinoma. J Urol 2000; 163: 408–417.[ISI][Medline]

5. Haas GP, Hillman GG, Redman BG, Pontes JE. Immunotherapy of renal cell carcinoma. CA Cancer J Clin 1993; 43: 177–187.[Abstract/Free Full Text]

6. Minasian LM, Motzer RJ, Gluck L et al. Interferon alfa-2a in advanced renal cell carcinoma: treatment results and survival in 159 patients with long-term follow-up. J Clin Oncol 1993; 11: 1368–1375.[Abstract]

7. Fisher RI, Rosenberg SA, Fyfe G. Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am 2000; 6 (Suppl 1): S55–S57.[ISI][Medline]

8. Negrier S, Maral J, Drevon M et al. Long-term follow-up of patients with metastatic renal cell carcinoma treated with intravenous recombinant interleukin-2 in Europe. Cancer J Sci Am 2000; 6 (Suppl 1): S93–S98.[ISI][Medline]

9. Negrier S, Escudier B, Lasset C et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d’Immunotherapie. N Engl J Med 1998; 338: 1272–1278.[Abstract/Free Full Text]

10. Finke JH, Zea AH, Stanley J et al. Loss of T-cell receptor zeta chain and p56lck in T-cells infiltrating human renal cell carcinoma. Cancer Res 1993; 53: 5613–5616.[Abstract]

11. Tartour E, Latour S, Mathiot C et al. Variable expression of CD3-zeta chain in tumor-infiltrating lymphocytes (TIL) derived from renal-cell carcinoma: relationship with TIL phenotype and function. Int J Cancer 1995; 63: 205–212.[ISI][Medline]

12. Kono K, Salazar-Onfray F, Petersson M et al. Hydrogen peroxide secreted by tumor-derived macrophages down-modulates signal-transducing zeta molecules and inhibits tumor-specific T cell- and natural killer cell-mediated cytotoxicity. Eur J Immunol 1996; 26: 1308–1313.[ISI][Medline]

13. Hellstrand K, Asea A, Dahlgren C, Hermodsson S. Histaminergic regulation of NK cells. Role of monocyte-derived reactive oxygen metabolites. J Immunol 1994; 153: 4940–4947.[Abstract/Free Full Text]

14. Hellstrand K, Hermodsson S. Cell-to-cell mediated inhibition of natural killer cell proliferation by monocytes and its regulation by histamine H2-receptors. Scand J Immunol 1991; 34: 741–752.[ISI]

15. Hellstrand K, Hermodsson S. Synergistic activation of human natural killer cell cytotoxicity by histamine and interleukin-2. Int Arch Allergy Immunol 1990; 92: 379–389.

16. Hansson M, Asea A, Ersson U et al. Induction of apoptosis in NK cells by monocyte-derived reactive oxygen metabolites. J Immunol 1996, 156; 42–47.[Abstract]

17. Hansson M, Hermodsson S, Brune M et al. Histamine protects T cells and natural killer cells against oxidative stress. J Interferon Cytokine Res 1999; 19: 1135–1144.[ISI][Medline]

18. Hellstrand K, Hermodsson S. Histamine H2-receptor-mediated regulation of human natural killer cell activity. J Immunol 1986; 137: 656–660.[Abstract/Free Full Text]

19. Hellstrand K, Kylefjord H, Asea A, Hermodsson S. Regulation of the natural killer cell response to interferon-alpha by biogenic amines. J Interferon Res 1992; 12: 199–206.[ISI][Medline]

20. Asea A, Hermodsson S, Hellstrand K. Histaminergic regulation of natural killer cell-mediated clearance of tumour cells in mice. Scand J Immunol 1996; 43: 9–15.[ISI][Medline]

21. Hellstrand K, Asea A, Hermodsson S. Role of histamine in natural killer cell-mediated resistance against tumor cells. J Immunol 1990; 145: 4365–4370.[Abstract/Free Full Text]

22. Hellstrand K, Hermodsson S, Naredi P et al. Histamine and cytokine therapy. Acta Oncol 1998; 37: 347–353.[ISI][Medline]

23. Brune M, Hellstrand K. Remission maintenance therapy with histamine and interleukin-2 in acute myelogenous leukaemia. Br J Haematol 1996; 92: 620–626.[ISI][Medline]

24. Mellqvist UH, Wallhult E, Brune M et al. Histamine dihydrochloride, interleukin-2 and interferon-alfa in multiple myeloma. Int J Immunother 1999; 15: 125–130.[ISI]

25. Agarwala SS, Glaspy J, O’Day SJ et al. Results from a randomized phase III study comparing combined treatment with histamine dihydrochloride plus interleukin-2 versus interleukin-2 alone in patients with metastatic melanoma. J Clin Oncol 2002; 20: 125–133.

26. Patel NP, Lavengood RW. Renal cell carcinoma: natural history and results of treatment. J Urol 1978; 119: 722–726.[ISI][Medline]

27. Negrier S, Caty A, Lesimple T et al. Treatment of patients with metastatic renal carcinoma with a combination of subcutaneous interleukin-2 and interferon alfa with or without fluorouracil. Groupe Francais d’Immunotherapie, Federation Nationale des Centres de Lutte Contre le Cancer. J Clin Oncol 2000; 18: 4009–4015.[Abstract/Free Full Text]

28. Motzer RJ, Mazumdar M, Bacik J et al. Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999; 17: 2530–2540.[Abstract/Free Full Text]

29. Fyfe G, Fisher RI, Rosenberg SA et al. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 1995; 13: 688–696.[Abstract]

30. Wagner JR, Walther MM, Linehan WM et al. Interleukin-2 based immunotherapy for metastatic renal cell carcinoma with the kidney in place. J Urol 1999; 162: 43–45.[ISI][Medline]

31. Belldegrun A, Shvarts O, Figlin RA. Expanding the indications for surgery and adjuvant interleukin-2-based immunotherapy in patients with advanced renal cell carcinoma. Cancer J Sci Am 2000; 6 (Suppl 1): S88–S92.[ISI][Medline]

32. Fallick ML, McDermott DF, LaRock D et al. Nephrectomy before interleukin-2 therapy for patients with metastatic renal cell carcinoma. J Urol 1997; 158: 1691–1695.[ISI][Medline]

33. Walther MM, Yang JC, Pass HI et al. Cytoreductive surgery before high dose interleukin-2 based therapy in patients with metastatic renal cell carcinoma. J Urol 1997; 158: 1675–1678.[ISI][Medline]

34. Henriksson R, Nilsson S, Colleen S et al. Survival in renal cell carcinoma-a randomized evaluation of tamoxifen vs interleukin 2, alpha-interferon (leucocyte) and tamoxifen. Br J Cancer 1998; 77: 1311–1317.[ISI][Medline]

35. von der Maase H, Geertsen P, Thatcher N et al. Recombinant interleukin-2 in metastatic renal cell carcinoma—a European multicentre phase II study. Eur J Cancer 1991; 27: 1583–1589.[ISI][Medline]