Br. J. Surg. 1990, Vol. 77, July. 725-730
K. E. Bakkevold, A. Pettersen, B. A r n e s j ~ and 6. Espehaug* Department of Surgery, Haukeland University Hospital, and *Section for Medical Informatics and Statistics, University of Bergen, Bergen, Norway Correspondence to: Dr K. E. Bakkevold, Department of
Surgery, Haugesund Hospital, 5500 Haugesund, Norway
Tamoxifen therapy in unresectable adenocarcinoma of the pancreas and the papilla of Vater Between 1984 and 1987, 176 Norwegian patients with histologically verified unresectable pancreatic adenocarcinoma were randomized to double-blind treatment with oral tamoxifen (30 mg daily: 48 men and 44 women) or placebo (47 men and 37 women). Analysis of oestrogen receptor activity in the carcinomas was not performed. There were no statistically significant differences between the two groups according to age, Karnofsky performance index, tumour node metastasis ( TNM) stage, operative treatment or other patient characteristics. The tamoxifen or placebo treatment continued to death or to 10 months after accrual into the trial was stopped. In the tamoxifen group, the mean and median survivals were 205 and 11.5 days, respectively. These values did not differ statistically from the 192 and 122 days, respectively, observed in the placebo group. Additional retrospective analyses of sex and stage revealed no beneficial effect of tamoxifen upon survival. For women in stage 111 (any T N l MO), mean and median survivals were 2.5.5 and 191 days, respectively, compared with values of 84 and 45 days, respectively, in the placebo group (P = 0.01 I ) . After 2-5 years, three (7 per cent) women in the tamoxifen group were still alive compared with no survivors in the placebo group. No male patients survived beyond 2.5 years. This therapeutic result in a small subgroup of women is probably incidental and not an effect of tamoxifen. Keywords: Pancreas,adenocarcinoma,unresectable,tamoxifen,randomized,double-blind,trial
Despite considerable sophistication of diagnostic techniques, 'early' detection of pancreatic carcinoma is still rare. About 80 per cent of Norwegian patients have advanced regional disease or distant spread at the time of primary diagnosis and treatment'. The treatment results are poor, with a 1-year survival rate slightly above 10 per cent'. Even if curative surgical resection is possible, the 5-year survival rate is only 3-1 3 per cent2-'. Treatment with radiation and/or cytotoxic drugs in patients with unresectable carcinoma does not improve long-term survival in most However, Mallinson et al.' showed significantly improved survival in patients with unresectable pancreatic carcinoma treated with combination chemotherapy and Dobelbower'6 and Dobelbower and Milligan" have shown that radiotherapy can provide long-term survival rates in unresectable carcinoma that are as high as those achieved by curative resection alone. Some intriguing data suggest that sex steroid hormones are involved in the development of exocrine pancreatic carcinoma. Firstly, there is a n excess incidence of pancreatic cancer in men aged less than 50 years, whereas the ma1e:female incidence ratio decreases with age and approaches unity above the age of 70 Secondly, a higher incidence of ovarian stromal and endometrial hyperplasia is present post-mortem in women with pancreatic carcinoma, which suggests excessive sex hormone activity in this malignancy2'. Thirdly, prior oophorectomy, spontaneous abortion and uterine myomatous change are significantly commoner in women with cancer of the pancreas than in controls2'. In addition, previously oophorectomized patients develop pancreatic cancer a t a substantially earlier age. Finally, the growth of a transplanted ductular pancreatic carcinoma cell line in hamster cheek pouches is reduced by oestrogen treatment22. Oestrogens could influence the development of pancreatic carcinoma by binding to intracellular receptors or to specific
oestrogen binding proteins. In fact, oestrogen receptor activity and/or specific oestrogen binding proteins have been demonstrated in pancreatic carcinoma as well as in normal pancreatic tissue by five different research g r o ~ p s ~ ~ - ~ ' . In mice, the antioestrogenic drug tamoxifen accumulates to a higher extent in the pancreas than in established oestrogen target organs such as the mammary gland and uterus2'. Tamoxifen has been shown to increase the survival of patients with unresectable pancreatic carcinoma in two small uncontrolled ~ t u d i e s ~ ' . whereas ~' another study demonstrated no such response3'. The present study examines the potential value of tamoxifen in a controlled study of 176 patients with unresectable pancreatic cancer.
This study was written on behalf of the Norwegian Pancrearic Cancer Trial. K. E. Bakkevold is trial co-ordinaror and Fellow ofrhe Norwegian Cancer Society.
Eligibility ,jbr the trial Only patients with histologically or cytologically verified adenocarcinoma of the exocrine pancreas or the papilla of Vater were included
0007-1 323/90/070725-06
0 1990 Butterworth-Heinemann
Ltd
Patients and methods Thirty-eight Norwegian hospitals participated in the present trial. In all, 472 patients with pancreatic cancer were entered into the trial between April 1984 and April 1987. Radical resection was performed in 108 patients during this period. One patient had a second-look operation. Data regarding the case history, diagnosis and resectability assessment, macroscopic and microscopic examinations, surgical procedure and postoperative follow-up were recorded on standardized forms which were regularly submitted to the study headquarters for computation. The Norwegian Pancreatic Cancer Trial comprises two randomized studies: ( 1 ) a study to evaluate the effect on survival of adjuvant chemotherapy (5-fluorouracil,Adriamycin ' (Farmitalia Carlo Erba, Milan, Italy) and mitomycin C ; modified FAM) after radical resection uersus surgery alone. Patient accrual in this study is still in progress and the trial will not be discussed further; and (2) an investigation to elucidate the effect of oral tamoxifen oersus placebo on survival in patients with advanced unresectable pancreatic carcinoma. Twentyseven hospitals entered patients into the study, which forms the basis of the present report.
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Tarnoxifen in pancreatic cancer: K. E. Bakkevold et al.
in the trial. Patients with pancreatic tumour and liver metastasis who had not been operated on were included after histological or cytological verification of the metastasis. Patients with endocrine tumour, cholangiocarcinoma, metastatic pancreatic tumour, cystadenocarcinoma and histologically or cytologically unverified primary pancreatic tumour were excluded. Selection of patients
Eligible patients with non-resectable primary turnours or regional lymph node metastasis not removable en bloc with the primary tumour (as judged by operative assessment) or patients with distant metastasis were included in the study. Oestrogen receptor analysis o n material from the primary tumour or metastasis was not performed and receptor status was not used as a criterion for inclusion or stratification. Exclusion criteria
Exclusion criteria were age above 75 years, Karnofsky index below 60, previous radical resection for pancreatic cancer, previous chemotherapy or radiotherapy for malignant disease, concomitant separate malignant disease or current receipt of hormonal therapy or tamoxifen. Randomization
Randomization was undertaken by using a table of random numbers in blocks of ten patients. Five patients in each block received tamoxifen and five received placebo. Each participating hospital was supplied with a suficient number of blocks corresponding to the expected number of patients. The prepacked tablets (ten tablet packs in each block) were marked with a five-digit number which was used as the personal registration number for each patient and used on all the treatment and follow-up forms. Patients who fulfilled the entry criteria were randomized shortly before hospital discharge and after written informed consent. Randomization was performed by Haukeland University Hospital Pharmacy and a tablet pack containing 3 months' tablet supply was marked with the name and registration number and sent to the patient via the local doctor. Identical tablet packs were supplied via the local doctor every third month. All patient codes were kept secret by the pharmacy and could be broken only in case of emergency. Thus the randomization process and coding was completely blinded for the patients, the local doctors, the study chairman and the headquarters staff. The tamoxifen and placebo tablets were indistinguishable both in appearance and taste.
Therapy Nohadex- (ICI, Macclesfield, UK) 10 mg tablets (dose 30 mg tamoxifen daily) or placebo tablets of identical appearance were taken in the morning. Treatment was given on an outpatient basis until the patient wished to discontinue medication or could no longer tolerate the tablets. If there was proven considerable disease progression, medication could be discontinued and palliative radiation or cytotoxic therapy was instituted without withdrawal from the study. Studv design and statistical methods
The therapeutic goal was to increase median survival from 6 months to 9, 10 or 12 months. Group size estimation was based o n this goal. Using a = 0.05 and fi = 0.10.222, 146 and 86 patients, respectively, were needed to detect such differences. Treatment duration was calculated from the day of randomization to either the death of the patient or the end of follow-up; in patients included in the later stages of the trial treatment continued to 10monthsafteraccrual to thestudy hadended. Non-censored variables were compared by x2 analysis; survival time was described by Kaplan-Meier plots3'. Survival in the two groups was compared by the log rank test33. Using a two-tailed test, a P value i 0. 05 was regarded as statistically significant. All randomized patients, withdrawals included or excluded, were analysed. In addition, the entire material was retrospectively (after randomization) stratified according to sex, stage of disease, and surgery or n o surgery. These subgroups were also analysed including and excluding withdrawn patients. The computations were performed using the B M D P (BMDP Statistical Software, Los Angeles, California, USA) statistical program package implemented on the Univac 1100 (Sperry Univac, Salt Lake City, Utah, USA) computer of the University of Bergen. Staging
The tumour node metastasis (TNM)clinical classification for carcinoma of the pancreas or the papilla of Vater was used34. The classification criteria as well as stage grouping (I-IV) are shown in Table I . Ethical considerations Written informed consent was obtained from all patients. The regional oficial ethics committee of Western Norway approved the trial. Patient characreristics Clinical characteristics of patients included and of patients excluded before randomization are presented in Table 2.
Table 1 TNM clinical classi~cutionof included patients with carcinoma of the pancreas or papilla 01' Vater _____________
Stage
Pancreas
T (Primary tumour) N o evidence of primary tumour TO T1 Tumour limited to pancreas T l a : tumour < 2 cm in its greatest dimension T l b : tumour > 2 cm in its greatest dimension T2 Tumours extending beyond confines of pancreas involving one or more of the duodenum, bile duct, peripancreatic fat and/or nerves T3 Tumours extending beyond confines of pancreas involving one or more of the stomach, spleen, colon or adjacent large vessels TX Minimum requirements to assess primary tumour cannot be met N (Lymph nodes) NO N o evidence of regional lymph node involvement N1 Evidence of involvement of regional lymph nodes related to primary tumour NX Minimum requirements to assess regional lymph nodes cannot be met M (Distant metastasis) No evidence of distant metastasis MO M1 Evidence of distant metastasis Minimum requirements to assess presence of distant metastasis MX cannot be met
726
Papilla of Vater
Tumour limited to the papilla T l a and T l b : as for pancreas Tumour extending beyond confines of papilla involving one or more of the duodenum, bile duct or pancreas Tumour extending beyond confines of papilla involving one or more of the stomach, colon or adjacent large vessels As for pancreas As for pancreas As for pancreas As [or pancreas
Stage grouping Stage 1 Stage I1 Stage I11 Stage IV
T1 T2 T3 Any T Any T
NO NO N1
Any N
MO MO MO M1
Br. J. Surg., Vol. 77, No. 7 , July1990
Tamoxifen in pancreatic cancer: K . E. Bakkevold et al.
Table 2
Characteristics of patients
Tamoxifen group (n=92)
Placebo group (n= 84)
Age (years) Mean(s.e.m.) 95 per cent confidence interval Median(s.e.)
64.3(0.8) 62.7-65.9 66.0(0.9)
65.5(09) 63.7-67.3 66.0(0.9)
Karnofsky index Mean(s.e.m.) 95 per cent confidence interval Median(s.e.)
76.7(1.5) 736-79.7 gOa(2.9)
77.8(1.4) 75%30.6 80.0(2.9)
Diagnostic delay (days)? Mean(s.e.m.) 95 per cent confidence interval Median(s.e.)
133.4(20.7) 924-174.5 SS.O(S.5)
113.8(9.7) 944-133.2 91.5(12.7)
P*
Excluded patients (n= 187)
0.82
71.8(0.8) 70.2-73.3 75.0(1.2)
0.92
63.2(1.6) 60.146.3 60.0(2.9)
0.30
125.7(12.1) 101'8-149.6 71.0(9.0) 121.7(11,7) 98.6-144.8 72.0(26.0)
s-bilirubin before operation (pmolfl) Mean(s.e.m.) 95 per cent confidence interval Median(s.e.)
90.0(11.4) 67.3-1 12.8 61G(26-6)
88.9(12.9) 63.2-1 14.7 3 0 q 2 1.4)
0.2 1
Sex No. of men No. of women
48(52) 44(48)
47(56) 37(44)
0.73
Tumour site Papilla Head Body Tail Total Incomplete data
1(1) 46(68) 19(28) 2(3) 68(100) 24
2(3) 48(74) 12(18) 3(5) 65(100) 19
2(2) 12(13) 17(18) 51(55)
2(2) 13(15) 16(19) 43(51)
7(4) 18(10) 21(11) 99(53)
O(0) O(0)
O(0) 742) 1(1)
1(1) 90) 16(9)
TNM stage I (TlT2NOMO) I1 (T3NOMO) 111 (Any T NlMO) IV (Any T Any N M1) 1-11 (Tl-T3NOMO) 1-111 (TXNXMO) I-IV (TXNXMX) 11-111 (T3NXMO) 11-IV (T3NXMX) Preoperative biliary drainage Endoscopic Percutaneous transhepatic None Incomplete data
1(1) 8(9) 1(1)
703) OW)
8(10) 4(5) 72(86) 8
6(8) 6(8) 66(85) 6
2(3)
Surgical procedure Whipple's operation Exploratory laparotomy Biliodigestive anastomosis Biliodigestive anastomosis + gastroenterostomy Incomplete data
29(44) 20(30) 3
2(3) 14(23) 29(47) 17(27) 5
Surgical details No. operated on No. not operated on No. with complications after surgery (not fatal) No. without complications Incomplete data or not operated on
66(74) 23(26) 9(14) 56(86) 27
62(78) 17(22) 12(19) 51(81) 21
15 (23)
055
89(48) 98(52) 5(4) 98(74) 28(21) 2(1) 133( 100) 54
W7) 0.84
0.70
2(1) 16(10) 25(15) 126(75) 20
0.98
1(1) 30(24) 49(39) 46(37) 10
0.43
126(71) 51(29) 36(30) 85(70) 66
Values in parentheses are percentages unless otherwise stated; * ,y2 analysis between tamoxifen and placebo groups; t time in days between onset of symptoms and diagnosis Withdrawals (Table 3) The survival analyses were performed both including and excluding withdrawn patients.
Eualuarion of outcome and follow-up After hospital discharge all patients were followed at the local outpatient clinic every third month for 2 years and then every sixth month for up to 5 years or until disease progression prohibited further outpatient visits. Evaluation included clinical examination and estimation of the Karnofsky index and registration of postoperative complications,
Br. J. Surg., Vol. 77, No. 7 , July 1990
compliance, adverse effects of therapy and survival. The follow-up results were registered on standardized record forms and submitted to the study headquarters. Further information concerning survival was obtained via the Cancer Registry of Norway in Oslo. Norway. Three months after hospital discharge 60 patients (56 per cent of all randomized patients still being alive) were adequately followed up. This figure diminished to 40 per cent after 12 months and to 14 per cent after 2 Years. compliance At each follow-up visit patient compliance was estimated by counting the number of unused tablets.
727
Tamoxifen in paacreatic cancer: K. E. Bakkevold et al.
Table 3
Withdrawal of patients after randomization
No. of patients Tamoxifen Unwillingness to comply with treatment for at least 6 weeks Violation of entry criteria A malignancy other than pancreatic carcinoma Age over 75 years Karnofsky index below 60 Radically resected with free margin Radically resected without free margin Total
Placebo
1
-
1
3 2
performed before hospital discharge. The time interval between operation and randomization is shown in T a b l e 5 . Three patients randomized before surgery had to be excluded. The survival time was calculated fom the day of randomization to death or for censored patients to 16 March 1988, when the survival analyses were performed. Survival data were partly based on information via the Cancer Registry of Norway, including all cancer deaths until 31 December 1987. Survival
6 1 1
1 1
10
8
Table 4 Reasons for exclusion of patients before randomizution No. of patients (n=187)
Patients older than 75 years and/or Karnofsky index below 60 Postoperative death Unwillingness Other concomitant type of malignant disease Patients receiving therapy with tamoxifen Autopsy diagnosis Patients receiving cytotoxic chemotherapy Unknown
140 16 7 1 2 3 15 3
Table 5 Time betneen operution and randomization for surgically treared patients and between diagnosis and randomization ,for non-surgically treated patients
Mean no. of days
95% confidence
Median
Patient group
interval
no. of days
Operated on Tamoxifen Placebo
l3.9( 1.3) l6.0( 1.8)
11.3-16.5 12.3- 19.6
13.0(1.2) 13.31.2)
Not operated on Tamoxifen Placebo
20.1 (3.5) 20.8(3.8)
12.9-27.2 12’8-28.7
19.5(4.0) 15.0(4.0)
Values in parentheses are standard errors
For the patients randomized to tamoxifen treatment, mean and median survivals were 205 and 1 15 days, respectively, compared with values of 192 and 122 days in the placebo group. The difference was not statistically significant (P=0.731, power=0.816). A similar analysis of the two groups after exclusion of the withdrawn patients revealed no difference ( P = 0.81, power = 0.782). Figures 1-3 demonstrate the life table analyses and the overall survival for all randomized patients and for the two sexes. With one exception there was no survival difference when comparing sex, stage or surgery/no surgery with matched placebo groups. The exception comprised female patients in stage 111. They had mean and median survivals of 255 and 191 days, respectively, in the tamoxifen group and 84 and 45 days in the placebo group (P=O.O11). An analysis of all randomized women, however, revealed no survival difference (P=O.8549, power=0.261). The survival of those patients who were alive after 60, 90, 100, 150, 365, 550 and 730 days in both groups was also calculated to look for a delayed treatment effect. No treatment effect could be discerned when analysing the whole group or when examining either sex independently. Long-term survival
Eight patients in the tamoxifen group and seven in the placebo group survived for more than 1 year. In the tamoxifen group, seven of the women (16 per cent) survived for more than 1 year and two (5 per cent) are still alive after 3 years. There were no survivors beyond 2 5 years in the placebo group (Table 6). Adverse reactions
Three patients in the tamoxifen group had mild adverse reactions: none was fatal. One woman develoDed hirsutism. one a vaginal discharge and one, who had livlr metastases: displayed a hepatotoxic reaction which subsided after stopping the drug. There were no adverse reactions in men or in the placebo group.
Results In the present Norwegian trial patients with unresectable, histologically proven pancreatic carcinoma were accrued between April 1984 and April 1987. In all, 177 fulfilled the inclusion criteria and were randomized to receive tamoxifen or placebo. One patient had incorrectly been randomized twice and was excluded. A total of 187 patients was excluded before randomization. Characteristics of included and excluded patients are presented in Table 2 . Statistically, these characteristics were equally distributed between the tamoxifen and placebo groups. In the same period, 107 patients were radically resected and were eligible only for the FAM study. One patient had a second-look operation. The reasons for patient exclusion before randomization are given in Table 4 . Eighteen of the excluded patients were eligible. Among these 15 received chemotherapy but there is no information about survival in this group. Eighteen patients were withdrawn from the study after randomization (Table 3), one in accord with criteria stated in the trial protocol and 17 because they were not eligible. Survival analyses were performed for all randomized patients irrespective of the eligibility criteria. According to the protocol, randomization should have been
728
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5
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0
I
I
I
100
200
I 300
I 400
I 500
I 600
700
800
I 900
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Figure 1 L f e table analysis of totalsurvival for all randomizedpatients; log rank test P = 0.7312, power = 0.816; (----), tamoxifen group: (-). placebo group
Br. J. Surg., Vol. 77, No. 7 , July1990
Tamoxifen in pancreatic cancer: K. E. Bakkevold et al. Quality of life After 3 months’ follow-up, 60 per cent of the patients were at home; 32 per cent had a feeling of improvement, 49 per cent felt worse and 18 per cent were unchanged. Fifty-seven per cent had severe pain or pain of moderate severity requiring analgesics; 28 per cent complained of nausea or vomiting and 25 per cent had diarrhoea/steatorrhoea. Their functional condition as judged by the Karnofsky index was 60 or lower in 50 per cent of the patients. As measured by the above parameters, the quality of life after 3, 6 and 9 months in both groups was compared using xz analysis. There were no differences between the groups.
before the analyses were started. In spite of this, the tamoxifen and placebo groups seemed to be well balanced and without any statistically significant differences (Table 2). There was no effect of tamoxifen upon survival. The median survival time of 115 days observed in the tamoxifen-treated patients was shorter than the 8 5 and 7 months found in the and Trannesen small non-randomized studies by Theve et et They used historical control groups in which median survival was 2.5 and 3 months, respectively. The difference between the results of their studies and the present one clearly demonstrates the value of properly balanced, doubly blinded, randomized trials involving a sufficient number of patients. Seven of the patients in the placebo group were still alive 1 year after randomization and four of them even after 2 years. treated 14 patients with tamoxifen. They Crowson et started with a loading dose of 160 mg followed by a maintenance dose of 40 mg daily. They found no response at all. Only one patient survived for more than 6 months. The comparatively poor prognosis observed in their study may be explained by differences in the patient population. Wong et aI.j5,in an uncontrolled study, treated 24 patients with 40mg tamoxifen daily and found an overall median survival of 7 months. Corresponding figures for the female and male subgroups were 10 and 4 months, respectively. Six women in their study survived for more than 1 year and three for more than 2 years. They suggest that a subgroup of patients with unresectable ductal adenocarcinoma of the pancreas may have a survival benefit from tamoxifen treatment and that this benefit is confined to postmenopausal women. We found a statistically significant tamoxifen effect in women in stage 111. In our trial, however, the patients were not stratified into sex and stage subgroups before randomization. Although there were
Discussion Selection of patients for the present trial was performed at each participating hospital in accord with a trial protocol without any stratification. This was done because firm conclusions with regard to influential prognostic factors can hardly be drawn beforehand. TNM staging34 was performed retrospectively during the last 6 months of the patient accrual period, but
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600
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400
500
600
I 700
800
900
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Figure 2 Liye table analysis of total survival.for all randomized male patients; og rank test P=0,4138, power=0.334; (----). tamoxqen group; (-), placebo group
Figure 3 L$e table analysis of total survivalfor all randomized female pafients; log rank test P=O.8549, power =0,261; (----), tatnoxifen group; (-), placebo group
Table 6 Long-term survival in patienis randomized to tamoxifen or placebo Tamoxifen group Time (years)
No. of men (n= 48)
No. of women (n=44)
Placebo group
Total ( n =92)
No. of men (n = 47)
No. of women (n= 37)
Total ( n = 84)
1 1.5
2 2.5 3 Values in parentheses are percentages
Br. J. Surg., Vol. 77, No. 7. July 1990
729
Tamoxifen in pancreatic cancer: K. E. Bakkevold at al.
statistically significant differences, the results, therefore, neither support not exclude the suggestion by Wong et al.35regarding an effect of tamoxifen in postmenopausal women. Probably the improved survival in this small subgroup of women is incidental and not a beneficial effect of tamoxifen. Proof of the suggestion by Wong et al. can be obtained only by conducting a controlled trial in postmenopausal women. In conclusion, oral tamoxifen seems to be ineffective in the treatment of patients with unresectable pancreatic carcinoma.
Acknowledgements The study was carried out on behalf of the Norwegian Pancreatic Cancer Trial generously supported by the Norwegian Cancer Society and ICI-Pharma. Grethe Bildsy, Kristin Christie Nitter, Liv Wiese Hansen and Tone Nesfossen were responsible for the management of the trial secretariat. Erik Bdegird, Haukeland University Hospital Pharmacy, assisted in patient registration, randomization and drug supply. We are indebted to Tore Ekeli (ICI-Pharma) for his enthusiasm and continuing support during the trial.
8. 9. 10. 11. 12. 13. 14. 15.
16. 17.
Other participants in the study 0 . Modalsli, 0. Rygvold, P. S. Efskind, T. Hasselgird, S. T. Andersen, B. Nilsen, K. Solheim, A. Rosseland, F. Vaagenes, 0. P. N. Griiner, A. Bergan, T. Harbitz, T. Llatveit, E. Ofstad, L. E. Staxrud, A. Noess, K. Strand, G. Tjsnnljord, P. Farup, B. Lie, A. Nilsen, 0. Holter, M. Tsnder, H. Erichsen, P. Klafstad, J. Sauar, G . Hopen, G. Lande, A. Baardsen, 0. Hoie, Y. Benestad, S. Aune, A. Olsen, K. Svendby, E. Refsdal, J. Kolnes, A. Viste, J. A. Ssreide, 0. Dahl, A. Horn, S. Haram, E. Lien, I. H. Nygaard, 0. J. Lange, L. Hope, R. Mirvik, K. Skreden, K. Johannessen, T. Bjerkeset, E. Ellekjcer, R. Capoferro, S. Danielsen, G. Thorsen.
Participating Norwegian hospitals Bstfold Central Hospital, Fredrikstad; Baerum Hospital, Baerum; Akershus Central Hospital, Lsrenskog; Rikshospitalet, Oslo; Ullevil Hospital, Oslo; Aker Hospital, Oslo; Lovisenberg Hospital, Oslo; Hedmark Central Hospital, Elverum; Lillehammer Hospital, Lillehammer; Gjsvik Hospital, G j ~ v i k ; Buskerud Central Hospital, Drammen; Vestfold Central Hospital, Tsnsberg; Telemark Central Hospital, Skien; Aust-Agder Central Hospital, Arendal; Vest-Agder Central Hospital; Kristiansand; Rogaland Central Hospital, Stavanger; Haugesund Hospital, Haugesund; Haukeland University Hospital, Bergen; Sogn og Fjordane Central Hospital, Fsrde; Alesund Hospital, Alesund; Molde Hospital, Molde; Kristiansund Hospital, Kristiansund; Trondheim University Hospital, Trondheim; Orkdal Hospital, Orkdal; Innherred Hospital, Levanger; Nordland Central Hospital, Bods; Harstad Hospital, Harstad.
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Moossa HR. Pancreatic cancer. Approach to diagnosis, selection for surgery and choice of operation. Cancer 1982; 50: 2689-98. Cooperman AM, Herter FP, Marboe CA, Helmreich ZV, Perzin KH. Pancreatoduodenal resection and total pancreatectomy - an institutional review. Surgery 1981; 90:707-12. Grace PA, Pitt HA, Tompkins RK, DenBesten L, Longmire WP. Decreasing morbidity and mortality after pancreatoduodenectomy. Am J Surg 1986; 15: 141-9. Gilsdorf RB, Spanos P. Factors influencing morbidity and mortality in pancreatoduodenectomy. Ann Surg 1973; 177: 332-7. Sato T, Saitoh Y, Noto N, Matsuno S. Factors influencing the late results of operation for carcinoma of the pancreas. Am J Surg 1978; 136: 582-6. Andren-Sandberg A, Ihse I. Factors influencing survival after total pancreatectomy in patients with pancreatic cancer. Ann Surg 1983; 198: 605-10.
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26. 27. 28.
29. 30. 31. 32. 33. 34. 35.
Kairaluoma MI, Partio E, Stihlberg M, Laitinen S . Pancreatic and periampullary carcinoma. Ann Chir Gynaecol 1984; 73: 199-205. Zimmerman SE, Smith FP, Schein PS. Chemotherapy of pancreatic carcinoma. Cancer 1981; 47: 1724-8. Cullinan SA, Moertel CG, Fleming TR et al. Comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma. JAMA 1985; 253: 2061-7. Andrkn-Sandberg A, Holmberg JT, Ihse I. Treatment of unresectable pancreatic carcinoma with 5-fluorouracil, vincristine, and CCNU. Scand J Gastroenterol 1983; 18: 609-12. Smith FP, Hoth DF, Levin B et al. S-Fluorouraci\, Adriamycin, and mitomycin-C (FAM) chemotherapy for advanced adenocarcinoma of the pancreas. Cancer 1980; 46: 2014-18. Harvey JH, Schein PS. Chemotherapy of pancreatic carcinoma. World J Surg 1984; 8: 935-9. O’Connell MJ. Current status of chemotherapy for advanced pancreatic and gastric cancer. J Clin Oncol 1985; 3: 1032-9. Mallinson CN, Rake MO, Cocking JB et al. Chemotherapy in pancreatic cancer: results of a controlled, prospective, randomised. multicentre trial. Br M e d J 1980; 281: 1589-91. Dobelbower RR. Current radiotherapeutic approaches to pancreatic cancer. Cuncer 1981; 47: 1729-33. Dobelbower RR, Milligan AJ. Treatment of pancreatic cancer by radiation therapy. World J Surg 1984; 8: 919-28. Andren-Sandberg A, Johansson J. Hormonal influence on pancreatic cancer. I n / J Pancreatol 1990 (in press). Bourhis J, Lacaine F, Augusti M, Huguier M. Protective effect of oestrogen in pancreatic cancer. Lancet 1987; ii:977. Soloway HB, Sommers SC. Endocrinopathy associated with pancreatic carcinomas. Ann Sury 1966; 164: 300-4. Lin RS, Kessler 11. A multifactorial model for pancreatic cancer in man. JAMA 1981; 245: 147-52. Lacaine F, Houry S, Clough K, Lointier P, Huguier M. Is pancreatic tumor growth inhibited by sex steroid hormones. Dig Dis Sci 1986; 3.1(Suppl 10): 685. Greenway B, Iqbal MJ, Johnson PJ, Williams R. Oestrogen receptor proteins in malignant and fetal pancreas. Br Med J 1981; 283: 751-3. Molteni A, Bahu RM, Battifora HA et al. Estradiol receptor assays in normal and neoplastic tissues. Ann CIin Lab Sci 1979; 9: 103-8. Satake K, Yoshimoto T, Mukai R, Umiyama K. Estrogen receptors in 7,12 dimethylbenz(a)anthracene (DMBA) induced pancreatic carcinomas in rats and in human pancreatic carcinoma. Clin Onrol 1982; 8: 49-53. Benz C, Hollander C, Miller B. Endocrine-responsive pancreatic carcinoma: steroid binding and cytotoxicity studies in human tumor cell lines. Cancer Res 1986; 46: 2276-81. Andren-Sandberg A, Borg S, Dawiskiba I, Ihse I, Ferno M. Estrogen-receptors and estrogen-binding protein in pancreatic cancer. Digestion 1982; 25: 12. Wilking N, Appelgren LE, Carlstrsm K, Pousette AA, Theve NO. The distribution and metabolism of C14-labelled tamoxifen in spayed female mice. Acta Pharm T o s 1982; 50: 161-8. Theve NO, Pousette AA, Carlstrsm K. Adenocarcinoma of the pancreas - a hormone sensitive tumour? Clin Oncol 1983; 9: 193-8. Tsnnesen K, Kamp-Jensen M. Antiestrogen therapy in pancreatic carcinoma: a preliminary report. Eur J Surg Oncol 1981; 12: 69-70. Crowson MC, Dorrell A, Rolfe EB, Fielding JWL. A phase I1 study to evaluate tamoxifen in pancreatic adenocarcinoma. Eur J Surg Oncol 1986; 12: 335-6. Kaplan EL, Meyer P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457-81. Pet0 R, Pike MC, Armitage P et al. Design and analysis of randomised clinical trials requiring prolonged observation of each patient. Br J Cancer 1977; 35: 1-39. Gazet J-C. Surgeons as philatelist: collectors classifiers. Part I: The problem in pancreatic cancer: staging. Eur J Sury Oncol 1986; 12: 325-33. Wong A, Chan A. Arthur K. Therapy in unresectable adenocarcinoma of the pancreas. Cuncer Treat Rep 1987; 71 : 749-50.
Paper accepted 4 January 1990
Br. J. Surg.. Vol. 77, No. 7 . July 1990
K. E. Bakkevold, A. Pettersen, B. A r n e s j ~ and 6. Espehaug* Department of Surgery, Haukeland University Hospital, and *Section for Medical Informatics and Statistics, University of Bergen, Bergen, Norway Correspondence to: Dr K. E. Bakkevold, Department of
Surgery, Haugesund Hospital, 5500 Haugesund, Norway
Tamoxifen therapy in unresectable adenocarcinoma of the pancreas and the papilla of Vater Between 1984 and 1987, 176 Norwegian patients with histologically verified unresectable pancreatic adenocarcinoma were randomized to double-blind treatment with oral tamoxifen (30 mg daily: 48 men and 44 women) or placebo (47 men and 37 women). Analysis of oestrogen receptor activity in the carcinomas was not performed. There were no statistically significant differences between the two groups according to age, Karnofsky performance index, tumour node metastasis ( TNM) stage, operative treatment or other patient characteristics. The tamoxifen or placebo treatment continued to death or to 10 months after accrual into the trial was stopped. In the tamoxifen group, the mean and median survivals were 205 and 11.5 days, respectively. These values did not differ statistically from the 192 and 122 days, respectively, observed in the placebo group. Additional retrospective analyses of sex and stage revealed no beneficial effect of tamoxifen upon survival. For women in stage 111 (any T N l MO), mean and median survivals were 2.5.5 and 191 days, respectively, compared with values of 84 and 45 days, respectively, in the placebo group (P = 0.01 I ) . After 2-5 years, three (7 per cent) women in the tamoxifen group were still alive compared with no survivors in the placebo group. No male patients survived beyond 2.5 years. This therapeutic result in a small subgroup of women is probably incidental and not an effect of tamoxifen. Keywords: Pancreas,adenocarcinoma,unresectable,tamoxifen,randomized,double-blind,trial
Despite considerable sophistication of diagnostic techniques, 'early' detection of pancreatic carcinoma is still rare. About 80 per cent of Norwegian patients have advanced regional disease or distant spread at the time of primary diagnosis and treatment'. The treatment results are poor, with a 1-year survival rate slightly above 10 per cent'. Even if curative surgical resection is possible, the 5-year survival rate is only 3-1 3 per cent2-'. Treatment with radiation and/or cytotoxic drugs in patients with unresectable carcinoma does not improve long-term survival in most However, Mallinson et al.' showed significantly improved survival in patients with unresectable pancreatic carcinoma treated with combination chemotherapy and Dobelbower'6 and Dobelbower and Milligan" have shown that radiotherapy can provide long-term survival rates in unresectable carcinoma that are as high as those achieved by curative resection alone. Some intriguing data suggest that sex steroid hormones are involved in the development of exocrine pancreatic carcinoma. Firstly, there is a n excess incidence of pancreatic cancer in men aged less than 50 years, whereas the ma1e:female incidence ratio decreases with age and approaches unity above the age of 70 Secondly, a higher incidence of ovarian stromal and endometrial hyperplasia is present post-mortem in women with pancreatic carcinoma, which suggests excessive sex hormone activity in this malignancy2'. Thirdly, prior oophorectomy, spontaneous abortion and uterine myomatous change are significantly commoner in women with cancer of the pancreas than in controls2'. In addition, previously oophorectomized patients develop pancreatic cancer a t a substantially earlier age. Finally, the growth of a transplanted ductular pancreatic carcinoma cell line in hamster cheek pouches is reduced by oestrogen treatment22. Oestrogens could influence the development of pancreatic carcinoma by binding to intracellular receptors or to specific
oestrogen binding proteins. In fact, oestrogen receptor activity and/or specific oestrogen binding proteins have been demonstrated in pancreatic carcinoma as well as in normal pancreatic tissue by five different research g r o ~ p s ~ ~ - ~ ' . In mice, the antioestrogenic drug tamoxifen accumulates to a higher extent in the pancreas than in established oestrogen target organs such as the mammary gland and uterus2'. Tamoxifen has been shown to increase the survival of patients with unresectable pancreatic carcinoma in two small uncontrolled ~ t u d i e s ~ ' . whereas ~' another study demonstrated no such response3'. The present study examines the potential value of tamoxifen in a controlled study of 176 patients with unresectable pancreatic cancer.
This study was written on behalf of the Norwegian Pancrearic Cancer Trial. K. E. Bakkevold is trial co-ordinaror and Fellow ofrhe Norwegian Cancer Society.
Eligibility ,jbr the trial Only patients with histologically or cytologically verified adenocarcinoma of the exocrine pancreas or the papilla of Vater were included
0007-1 323/90/070725-06
0 1990 Butterworth-Heinemann
Ltd
Patients and methods Thirty-eight Norwegian hospitals participated in the present trial. In all, 472 patients with pancreatic cancer were entered into the trial between April 1984 and April 1987. Radical resection was performed in 108 patients during this period. One patient had a second-look operation. Data regarding the case history, diagnosis and resectability assessment, macroscopic and microscopic examinations, surgical procedure and postoperative follow-up were recorded on standardized forms which were regularly submitted to the study headquarters for computation. The Norwegian Pancreatic Cancer Trial comprises two randomized studies: ( 1 ) a study to evaluate the effect on survival of adjuvant chemotherapy (5-fluorouracil,Adriamycin ' (Farmitalia Carlo Erba, Milan, Italy) and mitomycin C ; modified FAM) after radical resection uersus surgery alone. Patient accrual in this study is still in progress and the trial will not be discussed further; and (2) an investigation to elucidate the effect of oral tamoxifen oersus placebo on survival in patients with advanced unresectable pancreatic carcinoma. Twentyseven hospitals entered patients into the study, which forms the basis of the present report.
725
Tarnoxifen in pancreatic cancer: K. E. Bakkevold et al.
in the trial. Patients with pancreatic tumour and liver metastasis who had not been operated on were included after histological or cytological verification of the metastasis. Patients with endocrine tumour, cholangiocarcinoma, metastatic pancreatic tumour, cystadenocarcinoma and histologically or cytologically unverified primary pancreatic tumour were excluded. Selection of patients
Eligible patients with non-resectable primary turnours or regional lymph node metastasis not removable en bloc with the primary tumour (as judged by operative assessment) or patients with distant metastasis were included in the study. Oestrogen receptor analysis o n material from the primary tumour or metastasis was not performed and receptor status was not used as a criterion for inclusion or stratification. Exclusion criteria
Exclusion criteria were age above 75 years, Karnofsky index below 60, previous radical resection for pancreatic cancer, previous chemotherapy or radiotherapy for malignant disease, concomitant separate malignant disease or current receipt of hormonal therapy or tamoxifen. Randomization
Randomization was undertaken by using a table of random numbers in blocks of ten patients. Five patients in each block received tamoxifen and five received placebo. Each participating hospital was supplied with a suficient number of blocks corresponding to the expected number of patients. The prepacked tablets (ten tablet packs in each block) were marked with a five-digit number which was used as the personal registration number for each patient and used on all the treatment and follow-up forms. Patients who fulfilled the entry criteria were randomized shortly before hospital discharge and after written informed consent. Randomization was performed by Haukeland University Hospital Pharmacy and a tablet pack containing 3 months' tablet supply was marked with the name and registration number and sent to the patient via the local doctor. Identical tablet packs were supplied via the local doctor every third month. All patient codes were kept secret by the pharmacy and could be broken only in case of emergency. Thus the randomization process and coding was completely blinded for the patients, the local doctors, the study chairman and the headquarters staff. The tamoxifen and placebo tablets were indistinguishable both in appearance and taste.
Therapy Nohadex- (ICI, Macclesfield, UK) 10 mg tablets (dose 30 mg tamoxifen daily) or placebo tablets of identical appearance were taken in the morning. Treatment was given on an outpatient basis until the patient wished to discontinue medication or could no longer tolerate the tablets. If there was proven considerable disease progression, medication could be discontinued and palliative radiation or cytotoxic therapy was instituted without withdrawal from the study. Studv design and statistical methods
The therapeutic goal was to increase median survival from 6 months to 9, 10 or 12 months. Group size estimation was based o n this goal. Using a = 0.05 and fi = 0.10.222, 146 and 86 patients, respectively, were needed to detect such differences. Treatment duration was calculated from the day of randomization to either the death of the patient or the end of follow-up; in patients included in the later stages of the trial treatment continued to 10monthsafteraccrual to thestudy hadended. Non-censored variables were compared by x2 analysis; survival time was described by Kaplan-Meier plots3'. Survival in the two groups was compared by the log rank test33. Using a two-tailed test, a P value i 0. 05 was regarded as statistically significant. All randomized patients, withdrawals included or excluded, were analysed. In addition, the entire material was retrospectively (after randomization) stratified according to sex, stage of disease, and surgery or n o surgery. These subgroups were also analysed including and excluding withdrawn patients. The computations were performed using the B M D P (BMDP Statistical Software, Los Angeles, California, USA) statistical program package implemented on the Univac 1100 (Sperry Univac, Salt Lake City, Utah, USA) computer of the University of Bergen. Staging
The tumour node metastasis (TNM)clinical classification for carcinoma of the pancreas or the papilla of Vater was used34. The classification criteria as well as stage grouping (I-IV) are shown in Table I . Ethical considerations Written informed consent was obtained from all patients. The regional oficial ethics committee of Western Norway approved the trial. Patient characreristics Clinical characteristics of patients included and of patients excluded before randomization are presented in Table 2.
Table 1 TNM clinical classi~cutionof included patients with carcinoma of the pancreas or papilla 01' Vater _____________
Stage
Pancreas
T (Primary tumour) N o evidence of primary tumour TO T1 Tumour limited to pancreas T l a : tumour < 2 cm in its greatest dimension T l b : tumour > 2 cm in its greatest dimension T2 Tumours extending beyond confines of pancreas involving one or more of the duodenum, bile duct, peripancreatic fat and/or nerves T3 Tumours extending beyond confines of pancreas involving one or more of the stomach, spleen, colon or adjacent large vessels TX Minimum requirements to assess primary tumour cannot be met N (Lymph nodes) NO N o evidence of regional lymph node involvement N1 Evidence of involvement of regional lymph nodes related to primary tumour NX Minimum requirements to assess regional lymph nodes cannot be met M (Distant metastasis) No evidence of distant metastasis MO M1 Evidence of distant metastasis Minimum requirements to assess presence of distant metastasis MX cannot be met
726
Papilla of Vater
Tumour limited to the papilla T l a and T l b : as for pancreas Tumour extending beyond confines of papilla involving one or more of the duodenum, bile duct or pancreas Tumour extending beyond confines of papilla involving one or more of the stomach, colon or adjacent large vessels As for pancreas As for pancreas As for pancreas As [or pancreas
Stage grouping Stage 1 Stage I1 Stage I11 Stage IV
T1 T2 T3 Any T Any T
NO NO N1
Any N
MO MO MO M1
Br. J. Surg., Vol. 77, No. 7 , July1990
Tamoxifen in pancreatic cancer: K . E. Bakkevold et al.
Table 2
Characteristics of patients
Tamoxifen group (n=92)
Placebo group (n= 84)
Age (years) Mean(s.e.m.) 95 per cent confidence interval Median(s.e.)
64.3(0.8) 62.7-65.9 66.0(0.9)
65.5(09) 63.7-67.3 66.0(0.9)
Karnofsky index Mean(s.e.m.) 95 per cent confidence interval Median(s.e.)
76.7(1.5) 736-79.7 gOa(2.9)
77.8(1.4) 75%30.6 80.0(2.9)
Diagnostic delay (days)? Mean(s.e.m.) 95 per cent confidence interval Median(s.e.)
133.4(20.7) 924-174.5 SS.O(S.5)
113.8(9.7) 944-133.2 91.5(12.7)
P*
Excluded patients (n= 187)
0.82
71.8(0.8) 70.2-73.3 75.0(1.2)
0.92
63.2(1.6) 60.146.3 60.0(2.9)
0.30
125.7(12.1) 101'8-149.6 71.0(9.0) 121.7(11,7) 98.6-144.8 72.0(26.0)
s-bilirubin before operation (pmolfl) Mean(s.e.m.) 95 per cent confidence interval Median(s.e.)
90.0(11.4) 67.3-1 12.8 61G(26-6)
88.9(12.9) 63.2-1 14.7 3 0 q 2 1.4)
0.2 1
Sex No. of men No. of women
48(52) 44(48)
47(56) 37(44)
0.73
Tumour site Papilla Head Body Tail Total Incomplete data
1(1) 46(68) 19(28) 2(3) 68(100) 24
2(3) 48(74) 12(18) 3(5) 65(100) 19
2(2) 12(13) 17(18) 51(55)
2(2) 13(15) 16(19) 43(51)
7(4) 18(10) 21(11) 99(53)
O(0) O(0)
O(0) 742) 1(1)
1(1) 90) 16(9)
TNM stage I (TlT2NOMO) I1 (T3NOMO) 111 (Any T NlMO) IV (Any T Any N M1) 1-11 (Tl-T3NOMO) 1-111 (TXNXMO) I-IV (TXNXMX) 11-111 (T3NXMO) 11-IV (T3NXMX) Preoperative biliary drainage Endoscopic Percutaneous transhepatic None Incomplete data
1(1) 8(9) 1(1)
703) OW)
8(10) 4(5) 72(86) 8
6(8) 6(8) 66(85) 6
2(3)
Surgical procedure Whipple's operation Exploratory laparotomy Biliodigestive anastomosis Biliodigestive anastomosis + gastroenterostomy Incomplete data
29(44) 20(30) 3
2(3) 14(23) 29(47) 17(27) 5
Surgical details No. operated on No. not operated on No. with complications after surgery (not fatal) No. without complications Incomplete data or not operated on
66(74) 23(26) 9(14) 56(86) 27
62(78) 17(22) 12(19) 51(81) 21
15 (23)
055
89(48) 98(52) 5(4) 98(74) 28(21) 2(1) 133( 100) 54
W7) 0.84
0.70
2(1) 16(10) 25(15) 126(75) 20
0.98
1(1) 30(24) 49(39) 46(37) 10
0.43
126(71) 51(29) 36(30) 85(70) 66
Values in parentheses are percentages unless otherwise stated; * ,y2 analysis between tamoxifen and placebo groups; t time in days between onset of symptoms and diagnosis Withdrawals (Table 3) The survival analyses were performed both including and excluding withdrawn patients.
Eualuarion of outcome and follow-up After hospital discharge all patients were followed at the local outpatient clinic every third month for 2 years and then every sixth month for up to 5 years or until disease progression prohibited further outpatient visits. Evaluation included clinical examination and estimation of the Karnofsky index and registration of postoperative complications,
Br. J. Surg., Vol. 77, No. 7 , July 1990
compliance, adverse effects of therapy and survival. The follow-up results were registered on standardized record forms and submitted to the study headquarters. Further information concerning survival was obtained via the Cancer Registry of Norway in Oslo. Norway. Three months after hospital discharge 60 patients (56 per cent of all randomized patients still being alive) were adequately followed up. This figure diminished to 40 per cent after 12 months and to 14 per cent after 2 Years. compliance At each follow-up visit patient compliance was estimated by counting the number of unused tablets.
727
Tamoxifen in paacreatic cancer: K. E. Bakkevold et al.
Table 3
Withdrawal of patients after randomization
No. of patients Tamoxifen Unwillingness to comply with treatment for at least 6 weeks Violation of entry criteria A malignancy other than pancreatic carcinoma Age over 75 years Karnofsky index below 60 Radically resected with free margin Radically resected without free margin Total
Placebo
1
-
1
3 2
performed before hospital discharge. The time interval between operation and randomization is shown in T a b l e 5 . Three patients randomized before surgery had to be excluded. The survival time was calculated fom the day of randomization to death or for censored patients to 16 March 1988, when the survival analyses were performed. Survival data were partly based on information via the Cancer Registry of Norway, including all cancer deaths until 31 December 1987. Survival
6 1 1
1 1
10
8
Table 4 Reasons for exclusion of patients before randomizution No. of patients (n=187)
Patients older than 75 years and/or Karnofsky index below 60 Postoperative death Unwillingness Other concomitant type of malignant disease Patients receiving therapy with tamoxifen Autopsy diagnosis Patients receiving cytotoxic chemotherapy Unknown
140 16 7 1 2 3 15 3
Table 5 Time betneen operution and randomization for surgically treared patients and between diagnosis and randomization ,for non-surgically treated patients
Mean no. of days
95% confidence
Median
Patient group
interval
no. of days
Operated on Tamoxifen Placebo
l3.9( 1.3) l6.0( 1.8)
11.3-16.5 12.3- 19.6
13.0(1.2) 13.31.2)
Not operated on Tamoxifen Placebo
20.1 (3.5) 20.8(3.8)
12.9-27.2 12’8-28.7
19.5(4.0) 15.0(4.0)
Values in parentheses are standard errors
For the patients randomized to tamoxifen treatment, mean and median survivals were 205 and 1 15 days, respectively, compared with values of 192 and 122 days in the placebo group. The difference was not statistically significant (P=0.731, power=0.816). A similar analysis of the two groups after exclusion of the withdrawn patients revealed no difference ( P = 0.81, power = 0.782). Figures 1-3 demonstrate the life table analyses and the overall survival for all randomized patients and for the two sexes. With one exception there was no survival difference when comparing sex, stage or surgery/no surgery with matched placebo groups. The exception comprised female patients in stage 111. They had mean and median survivals of 255 and 191 days, respectively, in the tamoxifen group and 84 and 45 days in the placebo group (P=O.O11). An analysis of all randomized women, however, revealed no survival difference (P=O.8549, power=0.261). The survival of those patients who were alive after 60, 90, 100, 150, 365, 550 and 730 days in both groups was also calculated to look for a delayed treatment effect. No treatment effect could be discerned when analysing the whole group or when examining either sex independently. Long-term survival
Eight patients in the tamoxifen group and seven in the placebo group survived for more than 1 year. In the tamoxifen group, seven of the women (16 per cent) survived for more than 1 year and two (5 per cent) are still alive after 3 years. There were no survivors beyond 2 5 years in the placebo group (Table 6). Adverse reactions
Three patients in the tamoxifen group had mild adverse reactions: none was fatal. One woman develoDed hirsutism. one a vaginal discharge and one, who had livlr metastases: displayed a hepatotoxic reaction which subsided after stopping the drug. There were no adverse reactions in men or in the placebo group.
Results In the present Norwegian trial patients with unresectable, histologically proven pancreatic carcinoma were accrued between April 1984 and April 1987. In all, 177 fulfilled the inclusion criteria and were randomized to receive tamoxifen or placebo. One patient had incorrectly been randomized twice and was excluded. A total of 187 patients was excluded before randomization. Characteristics of included and excluded patients are presented in Table 2 . Statistically, these characteristics were equally distributed between the tamoxifen and placebo groups. In the same period, 107 patients were radically resected and were eligible only for the FAM study. One patient had a second-look operation. The reasons for patient exclusion before randomization are given in Table 4 . Eighteen of the excluded patients were eligible. Among these 15 received chemotherapy but there is no information about survival in this group. Eighteen patients were withdrawn from the study after randomization (Table 3), one in accord with criteria stated in the trial protocol and 17 because they were not eligible. Survival analyses were performed for all randomized patients irrespective of the eligibility criteria. According to the protocol, randomization should have been
728
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0
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I
I
100
200
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I 400
I 500
I 600
700
800
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Figure 1 L f e table analysis of totalsurvival for all randomizedpatients; log rank test P = 0.7312, power = 0.816; (----), tamoxifen group: (-). placebo group
Br. J. Surg., Vol. 77, No. 7 , July1990
Tamoxifen in pancreatic cancer: K. E. Bakkevold et al. Quality of life After 3 months’ follow-up, 60 per cent of the patients were at home; 32 per cent had a feeling of improvement, 49 per cent felt worse and 18 per cent were unchanged. Fifty-seven per cent had severe pain or pain of moderate severity requiring analgesics; 28 per cent complained of nausea or vomiting and 25 per cent had diarrhoea/steatorrhoea. Their functional condition as judged by the Karnofsky index was 60 or lower in 50 per cent of the patients. As measured by the above parameters, the quality of life after 3, 6 and 9 months in both groups was compared using xz analysis. There were no differences between the groups.
before the analyses were started. In spite of this, the tamoxifen and placebo groups seemed to be well balanced and without any statistically significant differences (Table 2). There was no effect of tamoxifen upon survival. The median survival time of 115 days observed in the tamoxifen-treated patients was shorter than the 8 5 and 7 months found in the and Trannesen small non-randomized studies by Theve et et They used historical control groups in which median survival was 2.5 and 3 months, respectively. The difference between the results of their studies and the present one clearly demonstrates the value of properly balanced, doubly blinded, randomized trials involving a sufficient number of patients. Seven of the patients in the placebo group were still alive 1 year after randomization and four of them even after 2 years. treated 14 patients with tamoxifen. They Crowson et started with a loading dose of 160 mg followed by a maintenance dose of 40 mg daily. They found no response at all. Only one patient survived for more than 6 months. The comparatively poor prognosis observed in their study may be explained by differences in the patient population. Wong et aI.j5,in an uncontrolled study, treated 24 patients with 40mg tamoxifen daily and found an overall median survival of 7 months. Corresponding figures for the female and male subgroups were 10 and 4 months, respectively. Six women in their study survived for more than 1 year and three for more than 2 years. They suggest that a subgroup of patients with unresectable ductal adenocarcinoma of the pancreas may have a survival benefit from tamoxifen treatment and that this benefit is confined to postmenopausal women. We found a statistically significant tamoxifen effect in women in stage 111. In our trial, however, the patients were not stratified into sex and stage subgroups before randomization. Although there were
Discussion Selection of patients for the present trial was performed at each participating hospital in accord with a trial protocol without any stratification. This was done because firm conclusions with regard to influential prognostic factors can hardly be drawn beforehand. TNM staging34 was performed retrospectively during the last 6 months of the patient accrual period, but
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600
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400
500
600
I 700
800
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Figure 2 Liye table analysis of total survival.for all randomized male patients; og rank test P=0,4138, power=0.334; (----). tamoxqen group; (-), placebo group
Figure 3 L$e table analysis of total survivalfor all randomized female pafients; log rank test P=O.8549, power =0,261; (----), tatnoxifen group; (-), placebo group
Table 6 Long-term survival in patienis randomized to tamoxifen or placebo Tamoxifen group Time (years)
No. of men (n= 48)
No. of women (n=44)
Placebo group
Total ( n =92)
No. of men (n = 47)
No. of women (n= 37)
Total ( n = 84)
1 1.5
2 2.5 3 Values in parentheses are percentages
Br. J. Surg., Vol. 77, No. 7. July 1990
729
Tamoxifen in pancreatic cancer: K. E. Bakkevold at al.
statistically significant differences, the results, therefore, neither support not exclude the suggestion by Wong et al.35regarding an effect of tamoxifen in postmenopausal women. Probably the improved survival in this small subgroup of women is incidental and not a beneficial effect of tamoxifen. Proof of the suggestion by Wong et al. can be obtained only by conducting a controlled trial in postmenopausal women. In conclusion, oral tamoxifen seems to be ineffective in the treatment of patients with unresectable pancreatic carcinoma.
Acknowledgements The study was carried out on behalf of the Norwegian Pancreatic Cancer Trial generously supported by the Norwegian Cancer Society and ICI-Pharma. Grethe Bildsy, Kristin Christie Nitter, Liv Wiese Hansen and Tone Nesfossen were responsible for the management of the trial secretariat. Erik Bdegird, Haukeland University Hospital Pharmacy, assisted in patient registration, randomization and drug supply. We are indebted to Tore Ekeli (ICI-Pharma) for his enthusiasm and continuing support during the trial.
8. 9. 10. 11. 12. 13. 14. 15.
16. 17.
Other participants in the study 0 . Modalsli, 0. Rygvold, P. S. Efskind, T. Hasselgird, S. T. Andersen, B. Nilsen, K. Solheim, A. Rosseland, F. Vaagenes, 0. P. N. Griiner, A. Bergan, T. Harbitz, T. Llatveit, E. Ofstad, L. E. Staxrud, A. Noess, K. Strand, G. Tjsnnljord, P. Farup, B. Lie, A. Nilsen, 0. Holter, M. Tsnder, H. Erichsen, P. Klafstad, J. Sauar, G . Hopen, G. Lande, A. Baardsen, 0. Hoie, Y. Benestad, S. Aune, A. Olsen, K. Svendby, E. Refsdal, J. Kolnes, A. Viste, J. A. Ssreide, 0. Dahl, A. Horn, S. Haram, E. Lien, I. H. Nygaard, 0. J. Lange, L. Hope, R. Mirvik, K. Skreden, K. Johannessen, T. Bjerkeset, E. Ellekjcer, R. Capoferro, S. Danielsen, G. Thorsen.
Participating Norwegian hospitals Bstfold Central Hospital, Fredrikstad; Baerum Hospital, Baerum; Akershus Central Hospital, Lsrenskog; Rikshospitalet, Oslo; Ullevil Hospital, Oslo; Aker Hospital, Oslo; Lovisenberg Hospital, Oslo; Hedmark Central Hospital, Elverum; Lillehammer Hospital, Lillehammer; Gjsvik Hospital, G j ~ v i k ; Buskerud Central Hospital, Drammen; Vestfold Central Hospital, Tsnsberg; Telemark Central Hospital, Skien; Aust-Agder Central Hospital, Arendal; Vest-Agder Central Hospital; Kristiansand; Rogaland Central Hospital, Stavanger; Haugesund Hospital, Haugesund; Haukeland University Hospital, Bergen; Sogn og Fjordane Central Hospital, Fsrde; Alesund Hospital, Alesund; Molde Hospital, Molde; Kristiansund Hospital, Kristiansund; Trondheim University Hospital, Trondheim; Orkdal Hospital, Orkdal; Innherred Hospital, Levanger; Nordland Central Hospital, Bods; Harstad Hospital, Harstad.
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Paper accepted 4 January 1990
Br. J. Surg.. Vol. 77, No. 7 . July 1990
