Original article: Treatment with alpha-interferon versus alpha-interferon in combination with streptozocin and doxorubicin in patients with malignant carcinoid tumors: A randomized trial

Annals of Oncology 3: 635-638, 1992. © 1992 Kluwer Academic Publishers. Printed in the Netherlands.

Original article Treatment with alpha-interferon versus alpha-interferon in combination with streptozocin and doxorubicin in patients with malignant carcinoid tumors: A randomized trial E. Tiensuu Janson,1 L. Ronnblom,2 H. Ahlstrom,3 D. Grander,4 G. Aim,5 S. Einhorn4 & K. Oberg1 ' Dept. of Internal Medicine, University Hospital, Uppsala; 2Dept. of Internal Medicine, Central Hospital, Boden; xDept. of Diagnostic Radiology, University Hospital, Uppsala; A Division of Experimental Oncology, Radiumhemmet, Karolinska Hospital, Stockholm; ''Interferon Laboratory and Dept. of Veterinary Immunology, Biomedical Center, Uppsala, Sweden

rIFN-a2a at an increased dose of 3 MU/m2 five days/week for a further 6 months. After 12 months 6 patients showed PR, 12 SD and one PD biochemically. Tumor size showed SD in 18 patients and PD in one. One patient died from cardiomyopathy, probably induced by doxorubicin. Antibodies against rIFN-a2a developed in 41% of the patients. In conclusion, we detected no difference in response rates between the two treatment groups. Adverse reactions from the combination were considerable. The frequent development of IFN antibodies might have interfered with the therapeutic results.

Summary. An open randomized trial was performed to compare the effect of recombinant interferon-alpha 2a (rIFN-a2a) (group A, n - 12) versus rlFN-a2a in combination with chemotherapy (group B, n — 11) in patients with malignant carcinoid tumors. Both groups received rIFN-a2a at a dose of 3 MU/m 2 s.c. three times weekly during the first 6 months. IFN was discontinued every third week in group B, followed by an i.v. injection of 2 g streptozocin and 40 mg/m2 doxorubicin. After 6 months group A showed one complete biochemical response (CR), 9 patients with stable disease (SD) and 2 who progressed (PD). Two patients had a partial reduction (PR) of tumor size, 9 showed SD and one PD. AJI patients in group B demonstrated SD. Chemotherapy was withdrawn after 6 months and all patients continued with

Key words: alpha-interferon, carcinoid tumors, chemotherapy, interferon antibody

Introduction

Materials and methods

Malignant mid-gut carcinoid tumors usually present with the carcinoid syndrome when liver metastases have appeared [1]. Medical treatment has previously been focused on chemotherapy with different combinations while alpha-interferon (a-IFN) has been used more recently. Chemotherapy has induced objective responses in 10%-30% of the patients for the most frequently used regimens including streptozocin, 5-fluorouracil and doxorubicin alone or in different combinations [2—4]. These responses have been transient and accompanied by considerable adverse reactions. Alpha-interferons, both natural and recombinant, have been used with promising results, showing biochemical response rates between 39% and 50% in different studies [5-7]. The side effects have been moderate and the symptoms of the carcinoid syndrome have been reduced in about 70% of the patients. This trial was initiated in order to investigate whether the combination of chemotherapy (streptozocin and doxorubicin) and a-IFN could improve the response rates as compared to a-IFN alone in patients with malignant carcinoid tumors.

Twenty-three patients were enrolled in this study. For patient characteristics see Table 1. Only patients with histologically verified malignant carcinoid tumors and increased urinary-5HIAA, WHO performance status of 2 or better and with adequate kidney, liver and bone-marrow function were eligible. Patients were randomized to groups A or B. Group A received treatment with rIFN-a2a at a dose of 3 MU/rcr body surface three times a week s.c. In group B rIFN-a2a was given similarly but for two weeks out of three, its administration was interrupted during the third week and followed by an i.v. injection of streptozocin at a dose of 2 g and doxorubicin at a dose of 40 mg/m2 body surface. At the start of the study patients in group B received an induction treatTable 1. Patient characteristics. A

No. of patients Males/females Median age Median duration of disease before treatment Carcinoid syndrome Median U-5HIAA

(nmols/24 h)'

B

12 5/7

11

60 years (45-68)

60 years (48-70)

12 mo (1-216)

10 mo (2-347)

11

278(126-898)

' Normal range 10-80 nmols/24 h.

8/3

9

338(159-2898)

636 ment of streptozocin at a dose of 1 g/day for 5 days with the addition of doxorubicin at a dose of 40 mg/m2 body surface on day 3. This was followed by initiation of the IFN treatment. After the initial 6 months of treatment, chemotherapy was withdrawn and all patients received rIFN-a2a at a dose of 3 MU/m2 body surface five times/week for an additional 6 months. Patients were monitored by routine hematology, liver function tests, thyroid autoantibodies, anti-nuclear antibodies and anti-IFN antibodies every third month. The tumor marker U-5HIAA (determined according to the method described earlier [8|) was also measured every third month, and calculated as the mean of two 24-h period collections. Tumor size was monitored every six months by computed tomography and ultrasound, and liver biopsies were taken before and at the end of the study. Tumor cells obtained from the liver biopsies were used in an enzyme assay estimating the induction of 2'5'A-oligoadenylate synthetase by IFN. This investigation was performed in 12 patients and has previously been reported [9]. A complete biochemical response was defined as normalization of U-5HIAA, while a partial biochemical response was considered when U-5HIAA was reduced by 50% or more. An increase in U-5H1AA by 25% or more was designated as tumor progression. Reduction in tumor size, calculated as the product of two perpendicular diameters of the two largest metastases by more than 50%, was considered as partial response, while an increase of more than 25% was designated progression. Informed consent was obtained from all patients before they were randomized and the protocol was evaluated and accepted by the local ethical committee.

Results Details concerning the responses are given in Table 2. Twenty-three patients were entered of whom 20 were

assessable for response at 6 months. Of the three nonevaluable patients, two discontinued chemotherapy after three months but continued with IFN throughout the initial treatment period, while one discontinued treatment completely after 3 months due to liver toxicity, WHO grade in. In summary, one patient obtained a complete biochemical response, 9 patients showed stable disease and 2 tumor progression in group A, whereas all 10 patients in group B demonstrated stable disease. Two patients in group A showed a 50% reduction of rumor size. One patient in group A developed neutralizing antiIFN antibodies during the first 6 months. After an initial period of reduced symptoms these increased again and the recombinant IFN was therefore exchanged for natural a-IFN after the evaluation at 6 months. After the initial 6 months, 21 patients continued with rIFN-a2a. Of these 21, 18 continued with an increased dose of 3 MU/m2 five times weekly. Three patients continued with the initial dose since two had responded to the lower dose schedule and one had increased liver enzymes. The patients were followed for an additional 6 months. At the end of the treatment period 19 were evaluable for objective responses. In summary, the 19 evaluable patients demonstrated 2 complete biochemical remissions and 4 partial responses (CR + PR 32%), whereas 12 patients showed stabilization (63%) and one progressive disease. One of

Table 2. Response to treatment in individual patients. Patient no.

Previous treatment

Induction of 2'5'A-synth.

Development of IFN-anti bodies

Response 6 mo U-5HIAA/ tumor size

Response 12 mo U-5HIAA/ tumor size

Response 6 mo flush/diarrhoea

Response 12 mo flush/diarrhoea

No No Yes No No No

SD/SD SD/SD PD/PD SD/PR SD/PR CR/SD SD/SD SD/SD PD/SD SD/SD SD/SD SD/SD

SD/SD SD/SD SD/SD SD/SD SD/SD CR/SD SD/SD SD/SD

PR/SD -/PR PR/PR -/PR CR/CR PR/SD -/PR PR/CR

-

PD/SD -/PR PR/PR -/PR PR/CR PR/SD -/PR PR/CR PD/-

CR/SD

-

-

PD/PR/-

Group A 1 2 3 4 5 6 7 8 9 10 11 12

IFN SMS IFN IFN IFN -

1.2 0.7 1.0 5.3 1.3 1.3 1.3

IFN + SMS

_ -

Yes" No

Yes" Yes

Yes" Yes

PR/SD

-

PR/-

Group B 13 14 15 16 17 18 19 20 21 22 23

IFN SMS

IFN + SMS IFN -

32.3 1.6 4.6 7.0 2.6 0.4

No No No No No No Yes No

YesYes No

SD/SD SD/SD

-

PR/PR PR/PR

-

PR/SD

-

-

-

-

SD/SD noneval. noneval. SD/SD SD/SD SD/SD SD/SD SD/SD

PR/SD SD/SD SD/SD SD/SD SD/SD PD/SD PR/SD SD/PD

SD/CR PR/CR CR/PR CR/PR PR/CR

SD/CR PR/CR CR/PR CR/PR PR/CR

_

—

Indicates development of high titers of neutralizing anti-IFN a antibodies

PD/PD

PR/-

PR/-

-

-

637

the 2 nonevaluable patients developed neutralizing anti-IFN antibodies, with biochemical and symptomatic progression. Therefore the rIFN-a2a was exchanged for natural IFN-alpha. After 11 months of treatment one patient died of cardiomyopathy probably related to doxorubicin toxicity. However, the total dose of doxorubicin administered was 630 mg or 360 mg/nr, which is considerably below the cardiotoxic level. Adverse reactions are summarized in Table 3. Fatigue was seen in 40% of the patients, equally distributed between the two groups. Adverse reactions to chemotherapy, such as nausea, alopecia and anorexia, were common. Table 3. Adverse reactions.

Flu-like symptoms Fatigue Nausea Alopecia Weightloss Anorexia Leukopenia Liver toxicity IFN antibodies Thyroid antibodies Anti-nuclear antibodies Skin lesion at injection site Dryness of skin Myalgia Mental depression Cardiomyopathy

Group A

Group B

4 4 1 1 1 6 3 4

3 5 7 3 2 4 4 2 3 1 3 1 2 0 0 1

3 1 3 2 0

Development of autoantibodies [10] as well as antiIFN antibodies [6] has previously been described as an adverse reaction during IFN treatment. Antibodies against rIFN-a2a developed in 9 patients (41%). The characterization of these antibodies is given elsewhere (Ronnblom L et al., manuscript in preparation). Thyroid autoantibodies developed in 4 patients (18%) and anti-nuclear antibodies (ANA) in 7 patients (32%). Discussion The number of patients included in this study is limited because of the rarity of the disease. Furthermore, the study was closed earlier than intended due to the high number of patients who developed neutralizing antibodies against the recombinant IFN used in this trial. During the initial 6 months of the study there was no difference in response rates between the two groups. The overall response rate was one complete biochemical response and one partial response in tumor size (10%). During the second part of the study with single a-IFN therapy at higher dosage there were 6 biochemical responders (32%) while only one patient progressed (5%). Adverse reactions due to chemotherapy were com-

mon and more serious than those from IFN alone. In fact three patients in group B discontinued chemotherapy after 3 months of treatment due to adverse reactions. Furthermore, one patient died from presumed doxorubicin cardiotoxicity. Throughout this study period as many as 41% of the patients developed antibodies against rIFN-a2a. Our data is in accordance with a previous report in which a high incidence of anti-IFN antibodies was noted in patients with hematological malignancies and solid rumors treated with rIFN-a2a [11]. Altogether 8 patients (36%) developed autoimmune reactions during a-IFN treatment. Of the 4 patients who developed autoantibodies against thyroid, none needed substitution therapy with thyroid hormone. Seven patients developed ANA and of these, three patients complained of myalgia, which might be correlated to this antibody development. Tumor cells from four patients induced the enzyme 2'5'-oligoadenylate synthetase >3 times, indicating that the tumors should be sensitive to IFN treatment [9]. Among these one partial response and one minor response were seen while two patients progressed. The two patients with progressive disease developed neutralizing rIFN-a2a antibodies in high titers. This might indicate that anti-IFN antibodies can interfere with therapeutic results. In conclusion, we could not demonstrate any difference in response rates between the two treatment groups. The development of anti-IFN antibodies in 41% of the patients might at least partially account for the low overall response rate. References 1. Grahame-Smith DG. The carcinoid syndrome. William Heneimann Medical Books Ltd London 1972. 2. Moertel CG, Hanley JA. Combination chemotherapy trials in metastatic carcinoid tumor and the malignant carcinoid syndrome. Cancer Clin Trials 1979; 2: 327-34. 3. Kelsen DP, Cheng E, Kemeny N et al. Streptozocin and adriamycin in the treatment of apud tumors (carcinoid, islet cell and medullary carcinomas of the thyroid). Proc Am Assoc Cancer Res 1982; 23: 433. 4. Oberg K, Norheim I, Lundqvist G et al. Cytotoxic treatment in patients with malignant carcinoid tumors; response to streptozocin - alone or in combination with 5-FU. Acta Oncol 1987; 26:429-32. 5. Oberg K, Norheim I, Lind E et al. Treatment of malignant carcinoid tumors with human leukocyte interferon; Long-term results. Cancer Treatm Rep 1986; 70: 1297-304. 6. Oberg K, Aim G, Magnusson A et al. Treatment of malignant carcinoid tumors with recombinant interferon alpha-2b: Development of neutralizing interferon antibodies and possible loss of antitumor activity. JNCI 1989; 81: 531-5. 7. Moertel CG, Rubin J, Kvols LK. Therapy of metastatic carcinoid tumor and the malignant carcinoid syndrome with recombinant leukocyte A interferon. J Clin Oncol 1989; 7: 865-8. K. Wahlund KG, Edlen B. Simple and rapid determination of 5-hydroxyindole-3-acetic acid in urine by direct injection on a liquid chromatographic column. Clin Chim Acta 1981; 110: 71-6.

638 9. Grander D, Oberg K, Lundqvist ML et al. Interferon-induced enhancement of 2'5'-oligoadenylate synthetase in mid-gut carcinoid tumors. Lancet 1990; 336: 337^10. 10. Ronnblom LE, Aim GV, Oberg KE. Autoimmunity after alpha-interferon therapy for malignant carcinoid tumors. Ann Intern Med 1991; 115: 178-83. 11. Itri LM, Champion M, Dennin RA et al. Incidence and clinical significance of neutralizing antibodies in patients receiving recombinant IFN-alpha 2a by intramuscular injection. Cancer 1987; 56:668-74.

Book review Concomitant continuous infusion chemotherapy and radiation. M. Rotman, C. J. Rosenthal (eds). SpringerVerlag, Berlin/Heidelberg/New York/London/Paris/ Tokyo/Hong Kong/Barcelona/Budapest, 1991. 318 pp, DM 198.00. Whether or not the combination of radiotherapy with chemotherapy increases the potential for locoregional control and survival has been a controversial issue throughout the past decade. Thus, there was a clear need for a monography providing the latest information about this combined approach. The volume edited by M. Rotman and C. J. Rosenthai is based on the premise, set forth by many investigators, that continuous intravenous infusions of cytostatic agents not only induce faster tumor regression but also more consistently maintain the response to treatment. This book focuses on three concepts: radio sensitization, radioprotection, and modulation of radioprotection. It consists of a thorough review of the basic principles of infusion chemotherapy and their clinical application with respect to three cytostatic agents, 5-fluorouracil, cisplatin and adriamycin. The book first examines the experimental rationale for continuous-infusion chemotherapy using anti-metabolites, plant alkaloids, alkylating agents, antineoplastic antibiotics and other antineoplastic agents such as TNF and interferon. Of particular interest is the chapter, in this first section which deals with the timespecified delivery of chemotherapy using programmable devices. The importance of treatment schedules

Received 12 February 1992; accepted 12 May 1992. Correspondence to: Eva Tiensuu Janson, MD Dept. of Internal Medicine University Hospital S-751 85 Uppsala Sweden

Annals of Oncology 3: 638, 1992.

when chemical agents are used as radiosensitizers is nicely documented in this chapter. This section also contains two extensive descriptions of data on combination chemotherapy in solid tumors that provide the reader with an overview both of the main anatomical targets for such combination treatments and of the types of concomitant chemoradiotherapy schedules and doses that have been used so far. The second section of the book deals more specifically with the use of sensitizers of hypoxic and non-hypoxic cells: this is a very clear updating on the agents implicated in sensitization mechanisms, especially with respect to the cytokinetics, despite the fact that most of the data presented in this section are already well known, especially by the radiotherapy community. The most interesting part of the book is the one dedicated to the results of continuous-infusion chemotherapy in combination with radiotherapy. A large body of clinical data is indeed presented for tumors of the upper air and food passages (small-cell lung, head and neck, and carcinomas of the oesophagus) the gastro-intestinal and genitourinary tracts. In conclusion, this book is highly recommended for both medical oncologists and radiotherapists who are looking for practical data on the clinical applicability of continuous infusions of chemotherapy in combination with radiation therapy, both in terms of side effects and therapeutic benefit. J. Bernier Bellinzona